0A4F4F9BD490A749D5437F821CF06DF1
21 CFR 312
https://www.govinfo.gov/content/pkg/CFR-2012-title21-vol5/pdf/CFR-2012-title21-vol5-part312.pdf
http://leaux.net/URLS/ConvertAPI Text Files/97A42489EABD2354DFC802B92AD81066.en.txt
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| Indicators in focus are typically shown highlighted in yellow; |
Peer Indicators (that share the same Vulnerability association) are shown highlighted in pink; |
"Outside" Indicators (those that do NOT share the same Vulnerability association) are shown highlighted in green; |
Trigger Words/Phrases are shown highlighted in gray. |
Link to Orphaned Trigger Words (Appendix (Indicator List, Indicator Peers, Trigger Words, Type/Vulnerability/Indicator Overlay)
Applicable Type / Vulnerability / Indicator Overlay for this Input
Political / Illegal Activity
Searching for indicator illegal:
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p.000076: copies of them) to FDA. The sponsor shall dis- continue shipments of the drug to any investigator who has
p.000076: failed to maintain or make available records or reports of the investigation as required by this part.
p.000076: (b) Controlled substances. If an inves- tigational new drug is a substance list- ed in any schedule of the
p.000076: Controlled Substances Act (21 U.S.C. 801; 21 CFR part 1308), records concerning ship- ment, delivery,
p.000076: receipt, and disposition of the drug, which are required to be kept under this part or other applica- ble
p.000076: parts of this chapter shall, upon the request of a properly authorized em- ployee of the Drug Enforcement
p.000076: Ad- ministration of the U.S. Department of Justice, be made available by the in- vestigator or sponsor to
p.000076: whom the re- quest is made, for inspection and copy- ing. In addition, the sponsor shall as- sure that
p.000076: adequate precautions are taken, including storage of the inves- tigational drug in a securely locked,
p.000076: substantially constructed cabinet, or other securely locked, substantially constructed enclosure, access
p.000076: to which is limited, to prevent theft or diversion of the substance into illegal channels of distribution.
p.000076:
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p.000076: Food and Drug Administration, HHS § 312.64
p.000076:
p.000076:
p.000076: § 312.59 Disposition of unused supply of investigational drug.
p.000076: The sponsor shall assure the return of all unused supplies of the investiga- tional drug from each
p.000076: individual inves- tigator whose participation in the in- vestigation is discontinued or termi- nated. The
p.000076: sponsor may authorize al- ternative disposition of unused supplies of the investigational drug provided
p.000076: this alternative disposition does not expose humans to risks from the drug. The sponsor shall
p.000076: maintain written records of any disposition of the drug in accordance with § 312.57.
p.000076: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000076: FR 23031, June 17, 1987; 67 FR 9586, Mar. 4,
p.000076: 2002]
p.000076:
p.000076: § 312.60 General responsibilities of in- vestigators.
p.000076: An investigator is responsible for en- suring that an investigation is con- ducted according to the
p.000076: signed investi- gator statement, the investigational plan, and applicable regulations; for protecting
p.000076: the rights, safety, and wel- fare of subjects under the investiga- tor’s care; and for the control
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p.000077: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000077: FR 23031, June 17, 1987; 67 FR 9586, Mar. 4,
p.000077: 2002]
p.000077:
p.000077: § 312.68 Inspection of investigator’s records and reports.
p.000077: An investigator shall upon request from any properly authorized officer or
p.000077:
p.000078: 78
p.000078: 21 CFR Ch. I (4–1–12 Edition)
p.000078: employee of FDA, at reasonable times, permit such officer or employee to have access to, and copy and
p.000078: verify any records or reports made by the investi- gator pursuant to § 312.62. The investi- gator is not required
p.000078: to divulge subject names unless the records of particular individuals require a more detailed study of
p.000078: the cases, or unless there is reason to believe that the records do not represent actual case studies, or do
p.000078: not represent actual results obtained.
p.000078: § 312.69 Handling of controlled sub- stances.
p.000078: If the investigational drug is subject to the Controlled Substances Act, the investigator shall take
p.000078: adequate pre- cautions, including storage of the in- vestigational drug in a securely locked, substantially
p.000078: constructed cabinet, or other securely locked, substantially constructed enclosure, access to which is
p.000078: limited, to prevent theft or diversion of the substance into illegal channels of distribution.
p.000078: § 312.70 Disqualification of a clinical investigator.
p.000078: (a) If FDA has information indicating that an investigator (including a spon- sor-investigator) has repeatedly
p.000078: or de- liberately failed to comply with the re- quirements of this part, part 50, or part 56 of this chapter, or
p.000078: has submitted to FDA or to the sponsor false informa- tion in any required report, the Center for Drug
p.000078: Evaluation and Research or the Center for Biologics Evaluation and Research will furnish the investi-
p.000078: gator written notice of the matter complained of and offer the investi- gator an opportunity
p.000078: to explain the matter in writing, or, at the option of the investigator, in an informal con- ference.
p.000078: If an explanation is offered but not accepted by the Center for Drug Evaluation and Research or the Center for
p.000078: Biologics Evaluation and Research, the investigator will be given an oppor- tunity for a regulatory hearing
p.000078: under part 16 on the question of whether the investigator is entitled to receive in- vestigational new
p.000078: drugs.
p.000078: (b) After evaluating all available in- formation, including any explanation presented by the
p.000078: investigator, if the
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p.000078:
p.000078:
p.000078: Food and Drug Administration, HHS § 312.80
p.000078:
p.000078:
p.000078: Commissioner determines that the in- vestigator has repeatedly or delib- erately failed to comply
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Political / Indigenous
Searching for indicator native:
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p.000052:
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p.000052: Food and Drug Administration, HHS § 312.8
p.000052:
p.000052:
p.000052: Subject means a human who partici- pates in an investigation, either as a recipient of the
p.000052: investigational new drug or as a control. A subject may be a healthy human or a patient with a
p.000052: disease.
p.000052: [52 FR 8831, Mar. 19, 1987, as amended at 64
p.000052: FR 401, Jan. 5, 1999; 64 FR 56449, Oct. 20, 1999;
p.000052: 73 FR 22815, Apr. 28, 2008]
p.000052:
p.000052: § 312.6 Labeling of an investigational new drug.
p.000052: (a) The immediate package of an in- vestigational new drug intended for human use shall bear a label
p.000052: with the statement ‘‘Caution: New Drug—Lim- ited by Federal (or United States) law to investigational use.’’
p.000052: (b) The label or labeling of an inves- tigational new drug shall not bear any statement that is false or
p.000052: misleading in any particular and shall not represent that the investigational new drug is safe or
p.000052: effective for the purposes for which it is being investigated.
p.000052: (c) The appropriate FDA Center Di- rector, according to the procedures set forth in §§ 201.26 or 610.68
p.000052: of this chap- ter, may grant an exception or alter- native to the provision in paragraph (a) of this section,
p.000052: to the extent that this provision is not explicitly required by statute, for specified lots, batches, or
p.000052: other units of a human drug product that is or will be included in the Stra- tegic National Stockpile.
p.000052: [52 FR 8831, Mar. 19, 1987, as amended at 72
p.000052: FR 73599, Dec. 28, 2007]
p.000052:
p.000052: § 312.7 Promotion of investigational drugs.
p.000052: (a) Promotion of an investigational ne drug. A sponsor or investigator, or any person acting on behalf of a
p.000052: sponsor or investigator, shall not represent in a promotional context that an investiga- tional new drug is
p.000052: safe or effective for the purposes for which it is under in- vestigation or otherwise promote the drug.
p.000052: This provision is not intended to restrict the full exchange of scientific information concerning the
p.000052: drug, in- cluding dissemination of scientific findings in scientific or lay media. Rather, its
p.000052: intent is to restrict pro- motional claims of safety or effective- ness of the drug for a use for
p.000052: which it is under investigation and to preclude commercialization of the drug before it
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p.000053: is approved for commercial distribu- tion.
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p.000054: Food and Drug Administration, HHS § 312.21
p.000054:
p.000054:
p.000054: certified public accountant has re- viewed and approved the calculations.
p.000054: [74 FR 40899, Aug. 13, 2009]
p.000054: § 312.10 Waivers.
p.000054: (a) A sponsor may request FDA to waive applicable requirement under this part. A waiver request may be
p.000054: sub- mitted either in an IND or in an infor- mation amendment to an IND. In an emergency, a request
p.000054: may be made by telephone or other rapid communica- tion means. A waiver request is re- quired to
p.000054: contain at least one of the following:
p.000054: (1) An explanation why the sponsor’s
p.000054: compliance with the requirement is un- necessary or cannot be achieved;
p.000054: (2) A description of an alternative submission or course of action that satisfies the purpose
p.000054: of the require- ment; or
p.000054: (3) Other information justifying a waiver.
p.000054: (b) FDA may grant a waiver if it finds that the sponsor’s noncompliance would not pose a significant and
p.000054: unrea- sonable risk to human subjects of the investigation and that one of the fol- lowing is met:
p.000054: (1) The sponsor’s compliance with the requirement is unnecessary for the agency to evaluate the
p.000054: application, or compliance cannot be achieved;
p.000054: (2) The sponsor’s proposed alter- native satisfies the requirement; or
p.000054: (3) The applicant’s submission other- wise justifies a waiver.
p.000054: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000054: FR 23031, June 17, 1987; 67 FR 9585, Mar. 4,
p.000054: 2002]
p.000054:
p.000054: Subpart B—Investigational New Drug Application (IND)
p.000054: § 312.20 Requirement for an IND.
p.000054: (a) A sponsor shall submit an IND to FDA if the sponsor intends to conduct a clinical investigation
p.000054: with an inves- tigational new drug that is subject to
p.000054: § 312.2(a).
p.000054: (b) A sponsor shall not begin a clin- ical investigation subject to § 312.2(a) until the investigation is
p.000054: subject to an IND which is in effect in accordance with § 312.40.
p.000054: (c) A sponsor shall submit a separate IND for any clinical investigation in-
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p.000055:
p.000055: volving an exception from informed consent under § 50.24 of this chapter. Such a clinical
p.000055: investigation is not permitted to proceed without the prior written authorization from FDA. FDA shall provide
p.000055: a written determination 30 days after FDA receives the IND or earlier.
p.000055: [52 FR 8831, Mar. 19, 1987, as amended at 61
p.000055: FR 51529, Oct. 2, 1996; 62 FR 32479, June 16,
p.000055: 1997]
p.000055: § 312.21 Phases of an investigation.
p.000055: An IND may be submitted for one or more phases of an investigation. The clinical investigation of a
p.000055: previously untested drug is generally divided into three phases. Although in general the phases are
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p.000078: continued ap- proval of the drug product for which the data were submitted cannot be jus- tified, the
p.000078: Commissioner will proceed to withdraw approval of the drug prod- uct in accordance with the applicable
p.000078: provisions of the act.
p.000078: (f) An investigator who has been de- termined to be ineligible to receive in- vestigational drugs may be
p.000078: reinstated as eligible when the Commissioner de- termines that the investigator has pre-
p.000079: 79
p.000079:
p.000079: sented adequate assurances that the in- vestigator will employ investigational drugs solely in compliance
p.000079: with the provisions of this part and of parts 50 and 56.
p.000079: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000079: FR 23031, June 17, 1987; 55 FR 11580, Mar. 29,
p.000079: 1990; 62 FR 46876, Sept. 5, 1997; 67 FR 9586,
p.000079: Mar. 4, 2002]
p.000079:
p.000079: Subpart E—Drugs Intended to Treat Life-threatening and Se- verely-debilitating Illnesses
p.000079:
p.000079: AUTHORITY: 21 U.S.C. 351, 352, 353, 355, 371;
p.000079: 42 U.S.C. 262.
p.000079: SOURCE: 53 FR 41523, Oct. 21, 1988, unless
p.000079: otherwise noted.
p.000079:
p.000079: § 312.80 Purpose.
p.000079: The purpose of this section is to es- tablish procedures designed to expedite the development, evaluation,
p.000079: and mar- keting of new therapies intended to treat persons with life-threatening and
p.000079: severely-debilitating illnesses, espe- cially where no satisfactory alter- native therapy
p.000079: exists. As stated
p.000079: § 314.105(c) of this chapter, while the statutory standards of safety and effec- tiveness apply to all
p.000079: drugs, the many kinds of drugs that are subject to them, and the wide range of uses for those
p.000079: drugs, demand flexibility in ap- plying the standards. The Food and Drug Administration (FDA) has
p.000079: deter- mined that it is appropriate to exercise the broadest flexibility in applying the statutory standards, while
p.000079: preserving appropriate guarantees for safety and effectiveness. These procedures reflect the recognition that
p.000079: physicians and pa- tients are generally willing to accept greater risks or side effects from prod- ucts that
p.000079: treat life-threatening and se- verely-debilitating illnesses, than they would accept from products that treat
p.000079: less serious illnesses. These procedures also reflect the recognition that the benefits of the drug
p.000079: need to be evalu- ated in light of the severity of the dis- ease being treated. The procedure out-
p.000079: lined in this section should be inter- preted consistent with that purpose.
p.000079:
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p.000079: § 312.81
p.000079: § 312.81 Scope.
p.000079: This section applies to new drug and biological products that are being stud- ied for their safety and
p.000079: effectiveness in treating life-threatening or severely- debilitating diseases.
p.000079: (a) For purposes of this section, the term ‘‘life-threatening’’ means:
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Political / stateless persons
Searching for indicator nation:
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p.000069: (viii) The sponsor fails to submit an accurate annual report of the inves- tigations in accordance with
p.000069: § 312.33.
p.000069: (ix) The sponsor fails to comply with any other applicable requirement of this part, part 50, or part 56.
p.000069: (x) The IND has remained on inactive status for 5 years or more.
p.000069: (xi) The sponsor fails to delay a pro- posed investigation under the IND or to suspend an ongoing
p.000069: investigation that has been placed on clinical hold under § 312.42(b)(4).
p.000069: (2) Phase 2 or 3. FDA may propose to terminate an IND during Phase 2 or Phase 3 if FDA finds that:
p.000069: (i) Any of the conditions in para- graphs (b)(1)(i) through (b)(1)(xi) of this section apply; or
p.000069: (ii) The investigational plan or pro- tocol(s) is not reasonable as a bona fide scientific plan to determine
p.000069: whether or not the drug is safe and effective for use; or
p.000069: (iii) There is convincing evidence that the drug is not effective for the purpose for which it
p.000069: is being inves- tigated.
p.000069: (3) FDA may propose to terminate a treatment IND if it finds that:
p.000069: (i) Any of the conditions in para- graphs (b)(1)(i) through (x) of this sec- tion apply; or
p.000069: (ii) Any of the conditions in
p.000069: § 312.42(b)(3) apply.
p.000069: (c) Opportunity for sponsor response.
p.000069: (1) If FDA proposes to terminate an IND, FDA will notify the sponsor in
p.000069:
p.000070: 70
p.000070: 21 CFR Ch. I (4–1–12 Edition)
p.000070: writing, and invite correction or expla- nation within a period of 30 days.
p.000070: (2) On such notification, the sponsor may provide a written explanation or correction or may request a
p.000070: conference with FDA to provide the requested ex- planation or correction. If the sponsor does not
p.000070: respond to the notification within the allocated time, the IND shall be terminated.
p.000070: (3) If the sponsor responds but FDA
p.000070: does not accept the explanation or cor- rection submitted, FDA shall inform the sponsor in writing of the
p.000070: reason for the nonacceptance and provide the sponsor with an opportunity for a regu- latory hearing
p.000070: before FDA under part 16 on the question of whether the IND should be terminated. The sponsor’s re- quest
p.000070: for a regulatory hearing must be made within 10 days of the sponsor’s receipt of FDA’s notification of
p.000070: non- acceptance.
p.000070: (d) Immediate termination of IND. Not-
p.000070: withstanding paragraphs (a) through
p.000070: (c) of this section, if at any time FDA concludes that continuation of the in- vestigation presents an
p.000070: immediate and substantial danger to the health of in- dividuals, the agency shall imme- diately, by
p.000070: written notice to the spon- sor from the Director of the Center for Drug Evaluation and Research or the
p.000070: Director of the Center for Biologics Evaluation and Research, terminate the IND. An IND so
p.000070: terminated is sub- ject to reinstatement by the Director on the basis of additional submissions that
p.000070: eliminate such danger. If an IND is terminated under this paragraph, the agency will afford the sponsor an
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Health / Drug Dependence
Searching for indicator dependence:
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p.000059: is less directly relevant may be supplied by a bibliography.
p.000059: (ii) If the drug is a combination of
p.000059: drugs previously investigated or mar- keted, the information required under paragraph (a)(9)(i) of
p.000059: this section should be provided for each active drug component. However, if any component in such combination is
p.000059: subject to an
p.000060: 60
p.000060: 21 CFR Ch. I (4–1–12 Edition)
p.000060: approved marketing application or is otherwise lawfully marketed in the United States, the sponsor is
p.000060: not re- quired to submit published material concerning that active drug component unless such material relates
p.000060: directly to the proposed investigational use (in- cluding publications relevant to com- ponent-component
p.000060: interaction).
p.000060: (iii) If the drug has been marketed outside the United States, a list of the countries in which the
p.000060: drug has been marketed and a list of the countries in which the drug has been withdrawn from marketing for
p.000060: reasons potentially related to safety or effectiveness.
p.000060: (10) Additional information. In certain applications, as described below, infor- mation on special topics
p.000060: may be need- ed. Such information shall be sub- mitted in this section as follows:
p.000060: (i) Drug dependence and abuse poten- tial. If the drug is a psychotropic sub- stance or otherwise has
p.000060: abuse poten- tial, a section describing relevant clin- ical studies and experience and studies in test animals.
p.000060: (ii) Radioactive drugs. If the drug is a radioactive drug, sufficient data from animal or human
p.000060: studies to allow a reasonable calculation of radiation-ab- sorbed dose to the whole body and crit- ical
p.000060: organs upon administration to a human subject. Phase 1 studies of ra- dioactive drugs must include
p.000060: studies which will obtain sufficient data for dosimetry calculations.
p.000060: (iii) Pediatric studies. Plans for assess- ing pediatric safety and effectiveness.
p.000060: (iv) Other information. A brief state- ment of any other information that would aid evaluation of
p.000060: the proposed clinical investigations with respect to their safety or their design and poten- tial as
p.000060: controlled clinical trials to sup- port marketing of the drug.
p.000060: (11) Relevant information. If requested by FDA, any other relevant informa- tion needed for review of the
p.000060: applica- tion.
p.000060: (b) Information previously submitted. The sponsor ordinarily is not required to resubmit information
p.000060: previously submitted, but may incorporate the in- formation by reference. A reference to information submitted
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Searching for indicator dependency:
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p.000062: does not include an adverse event or suspected adverse reaction that, had it occurred in a more
p.000062: severe form, might have caused death.
p.000062: Serious adverse event or serious sus- pected adverse reaction. An adverse event or suspected
p.000062: adverse reaction is considered ‘‘serious’’ if, in the view of either the investigator or sponsor, it
p.000062: results in any of the following out- comes: Death, a life-threatening ad- verse event,
p.000062: inpatient hospitalization or prolongation of existing hospitaliza- tion, a persistent or significant inca-
p.000062: pacity or substantial disruption of the ability to conduct normal life func- tions, or a
p.000062: congenital anomaly/birth defect. Important medical events that may not result in death, be life-threat- ening,
p.000062: or require hospitalization may be considered serious when, based upon appropriate medical judgment, they
p.000062: may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of
p.000062: the out- comes listed in this definition. Exam- ples of such medical events include al- lergic
p.000062: bronchospasm requiring inten- sive treatment in an emergency room or at home, blood dyscrasias or convul-
p.000062: sions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.
p.000062: Suspected adverse reaction means any adverse event for which there is a rea- sonable possibility
p.000062: that the drug caused the adverse event. For the pur- poses of IND safety reporting, ‘‘reason- able
p.000062: possibility’’ means there is evi- dence to suggest a causal relationship between the drug and
p.000062: the adverse event. Suspected adverse reaction im- plies a lesser degree of certainty about causality than
p.000062: adverse reaction, which
p.000063: 63
p.000063:
p.000063: means any adverse event caused by a drug.
p.000063: Unexpected adverse event or unexpected suspected adverse reaction. An adverse event or suspected adverse
p.000063: reaction is considered ‘‘unexpected’’ if it is not listed in the investigator brochure or is not listed at
p.000063: the specificity or severity that has been observed; or, if an inves- tigator brochure is not required
p.000063: or available, is not consistent with the risk information described in the gen- eral investigational
p.000063: plan or elsewhere in the current application, as amended. For example, under this definition, he- patic
p.000063: necrosis would be unexpected (by virtue of greater severity) if the inves- tigator brochure referred only
p.000063: to ele- vated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis
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Health / Drug Usage
Searching for indicator drug:
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p.000050:
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p.000050: Pt. 312
p.000050: (c) Clinical investigations designed to obtain evidence that any drug prod- uct containing colloidal silver
p.000050: or silver salts labeled, represented, or promoted for any OTC drug use is safe and effec- tive for the
p.000050: purpose intended must comply with the requirements and pro- cedures governing the use of investiga- tional new
p.000050: drugs as set forth in part 312 of this chapter.
p.000050: (d) After September 16, 1999, any such OTC drug product containing colloidal silver or silver salts
p.000050: initially intro- duced or initially delivered for intro- duction into interstate commerce that is not in
p.000050: compliance with this section is subject to regulatory action.
p.000050: [64 FR 44658, Aug. 17, 1999]
p.000050:
p.000050: PART 312—INVESTIGATIONAL NEW DRUG APPLICATION
p.000050: Subpart A—General Provisions
p.000050: Sec.
p.000050: 312.1 Scope.
p.000050: 312.2 Applicability.
p.000050: 312.3 Definitions and interpretations.
p.000050: 312.6 Labeling of an investigational new drug.
p.000050: 312.7 Promotion of investigational drugs.
p.000050: 312.8 Charging for investigational drugs under an IND.
p.000050: 312.10 Waivers.
p.000050:
p.000050: Subpart B—Investigational New Drug Application (IND)
p.000050: 312.20 Requirement for an IND.
p.000050: 312.21 Phases of an investigation.
p.000050: 312.22 General principles of the IND submis- sion.
p.000050: 312.23 IND content and format.
p.000050: 312.30 Protocol amendments.
p.000050: 312.31 Information amendments.
p.000050: 312.32 IND safety reporting.
p.000050: 312.33 Annual reports.
p.000050: 312.38 Withdrawal of an IND.
p.000050: Subpart C—Administrative Actions
p.000050: 312.40 General requirements for use of an in- vestigational new drug in a clinical in- vestigation.
p.000050: 312.41 Comment and advice on an IND.
p.000050: 312.42 Clinical holds and requests for modi- fication.
p.000050: 312.44 Termination.
p.000050: 312.45 Inactive status.
p.000050: 312.47 Meetings.
p.000050: 312.48 Dispute resolution.
p.000050:
p.000050: 50
p.000050:
p.000050: 21 CFR Ch. I (4–1–12 Edition)
p.000050: Subpart D—Responsibilities of Sponsors and Investigators
p.000050: 312.50 General responsibilities of sponsors.
p.000050: 312.52 Transfer of obligations to a contract research organization.
p.000050: 312.53 Selecting investigators and monitors.
p.000050: 312.54 Emergency research under § 50.24 of this chapter.
p.000050: 312.55 Informing investigators.
p.000050: 312.56 Review of ongoing investigations.
p.000050: 312.57 Recordkeeping and record retention.
p.000050: 312.58 Inspection of sponsor’s records and reports.
p.000050: 312.59 Disposition of unused supply of inves- tigational drug.
p.000050: 312.60 General responsibilities of investiga- tors.
p.000050: 312.61 Control of the investigational drug.
p.000050: 312.62 Investigator recordkeeping and record retention.
p.000050: 312.64 Investigator reports.
p.000050: 312.66 Assurance of IRB review.
p.000050: 312.68 Inspection of investigator’s records and reports.
p.000050: 312.69 Handling of controlled substances.
p.000050: 312.70 Disqualification of a clinical investi- gator.
p.000050:
p.000050: Subpart E—Drugs Intended to Treat Life- threatening and Severely-debilitating Illnesses
p.000050: 312.80 Purpose.
p.000050: 312.81 Scope.
p.000050: 312.82 Early consultation.
p.000050: 312.83 Treatment protocols.
p.000050: 312.84 Risk-benefit analysis in review of marketing applications for drugs to treat life-threatening and
p.000050: severely-debilitating illnesses.
p.000050: 312.85 Phase 4 studies.
p.000050: 312.86 Focused FDA regulatory research.
p.000050: 312.87 Active monitoring of conduct and evaluation of clinical trials.
p.000050: 312.88 Safeguards for patient safety.
p.000050: Subpart F—Miscellaneous
p.000050: 312.110 Import and export requirements.
p.000050: 312.120 Foreign clinical studies not con- ducted under an IND.
p.000050: 312.130 Availability for public disclosure of data and information in an IND.
p.000050: 312.140 Address for correspondence.
p.000050: 312.145 Guidance documents.
p.000050:
p.000050: Subpart G—Drugs for Investigational Use in Laboratory Research Animals or in Vitro Tests
p.000050: 312.160 Drugs for investigational use in lab- oratory research animals or in vitro tests.
p.000050: Subpart H [Reserved]
p.000050:
p.000050:
p.000050:
p.000050:
p.000050:
p.000050:
p.000050:
p.000050: Food and Drug Administration, HHS § 312.2
p.000050:
p.000050: Subpart I—Expanded Access to Investigational Drugs for Treatment Use
p.000050: 312.300 General.
p.000050: 312.305 Requirements for all expanded ac- cess uses.
p.000050: 312.310 Individual patients, including for emergency use.
p.000050: 312.315 Intermediate-size patient popu- lations.
p.000050: 312.320 Treatment IND or treatment pro- tocol.
p.000050: AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353,
p.000050: 355, 360bbb, 371; 42 U.S.C. 262.
p.000050: SOURCE: 52 FR 8831, Mar. 19, 1987, unless
p.000050: otherwise noted.
p.000050: EDITORIAL NOTE: Nomenclature changes to part 312 can be found at 69 FR 13717, Mar. 24,
p.000050: 2004.
p.000050:
p.000050: Subpart A—General Provisions
p.000050: § 312.1 Scope.
p.000050: (a) This part contains procedures and requirements governing the use of in- vestigational new drugs, including
p.000050: pro- cedures and requirements for the sub- mission to, and review by, the Food and Drug Administration of
p.000050: investiga- tional new drug applications (IND’s). An investigational new drug for which an IND is in
p.000050: effect in accordance with this part is exempt from the premar- keting approval requirements that are
p.000050: otherwise applicable and may be shipped lawfully for the purpose of con- ducting clinical
p.000050: investigations of that drug.
p.000050: (b) References in this part to regula-
p.000050: tions in the Code of Federal Regula- tions are to chapter I of title 21, unless otherwise noted.
p.000050: § 312.2 Applicability.
p.000050: (a) Applicability. Except as provided in this section, this part applies to all clinical investigations of
p.000050: products that are subject to section 505 of the Federal Food, Drug, and Cosmetic Act or to the licensing provisions
p.000050: of the Public Health Service Act (58 Stat. 632, as amended (42 U.S.C. 201 et seq.)).
p.000050: (b) Exemptions. (1) The clinical inves- tigation of a drug product that is law- fully marketed in the
p.000050: United States is exempt from the requirements of this part if all the following apply:
p.000050: (i) The investigation is not intended to be reported to FDA as a well-con- trolled study in support of
p.000050: a new indi-
p.000051: 51
p.000051:
p.000051: cation for use nor intended to be used to support any other significant change in the labeling for the drug;
p.000051: (ii) If the drug that is undergoing in- vestigation is lawfully marketed as a prescription drug product, the
p.000051: inves- tigation is not intended to support a significant change in the advertising for the product;
p.000051: (iii) The investigation does not in- volve a route of administration or dos- age level or use in a patient
p.000051: population or other factor that significantly in- creases the risks (or decreases the ac- ceptability of
p.000051: the risks) associated with the use of the drug product;
p.000051: (iv) The investigation is conducted in compliance with the requirements for institutional review set forth in part
p.000051: 56 and with the requirements for informed consent set forth in part 50; and
p.000051: (v) The investigation is conducted in compliance with the requirements of
p.000051: § 312.7.
p.000051: (2)(i) A clinical investigation involv- ing an in vitro diagnostic biological product listed in
p.000051: paragraph (b)(2)(ii) of this section is exempt from the re- quirements of this part if (a) it is
p.000051: in- tended to be used in a diagnostic proce- dure that confirms the diagnosis made by another, medically
p.000051: established, di- agnostic product or procedure and (b) it is shipped in compliance with § 312.160.
p.000051: (ii) In accordance with paragraph (b)(2)(i) of this section, the following products are exempt from
p.000051: the require- ments of this part: (a) blood grouping serum; (b) reagent red blood cells; and
p.000051: (c) anti-human globulin.
p.000051: (3) A drug intended solely for tests in vitro or in laboratory research animals is exempt from the requirements
p.000051: of this part if shipped in accordance with
p.000051: § 312.160.
p.000051: (4) FDA will not accept an applica- tion for an investigation that is ex- empt under the provisions
p.000051: of paragraph (b)(1) of this section.
p.000051: (5) A clinical investigation involving use of a placebo is exempt from the re- quirements of this part if the
p.000051: inves- tigation does not otherwise require submission of an IND.
p.000051: (6) A clinical investigation involving an exception from informed consent under § 50.24 of this chapter
p.000051: is not ex- empt from the requirements of this part.
p.000051:
p.000051:
p.000051:
p.000051:
p.000051:
p.000051:
p.000051:
p.000051:
p.000051: § 312.3
p.000051: (c) Bioavailability studies. The applica- bility of this part to in vivo bio- availability studies in
p.000051: humans is sub- ject to the provisions of § 320.31.
p.000051: (d) Unlabeled indication. This part does not apply to the use in the prac- tice of medicine for
p.000051: an unlabeled indi- cation of a new drug product approved under part 314 or of a licensed biologi- cal
p.000051: product.
p.000051: (e) Guidance. FDA may, on its own initiative, issue guidance on the appli- cability of this part to
p.000051: particular in- vestigational uses of drugs. On request, FDA will advise on the applicability of this part to a
p.000051: planned clinical inves- tigation.
p.000051: [52 FR 8831, Mar. 19, 1987, as amended at 61
p.000051: FR 51529, Oct. 2, 1996; 64 FR 401, Jan. 5, 1999]
p.000051: § 312.3 Definitions and interpretations.
p.000051: (a) The definitions and interpreta- tions of terms contained in section 201 of the Act apply to
p.000051: those terms when used in this part:
p.000051: (b) The following definitions of terms also apply to this part:
p.000051: Act means the Federal Food, Drug, and Cosmetic Act (secs. 201–902, 52 Stat. 1040 et seq., as amended
p.000051: (21 U.S.C. 301–392)).
p.000051: Clinical investigation means any ex- periment in which a drug is adminis- tered or dispensed to, or
p.000051: used involv- ing, one or more human subjects. For the purposes of this part, an experi- ment is any use of
p.000051: a drug except for the use of a marketed drug in the course of medical practice.
p.000051: Contract research organization means a person that assumes, as an independent contractor with the sponsor, one
p.000051: or more of the obligations of a sponsor,
p.000051: e.g., design of a protocol, selection or monitoring of investigations, evalua- tion of reports, and
p.000051: preparation of ma- terials to be submitted to the Food and Drug Administration.
p.000051: FDA means the Food and Drug Ad- ministration.
p.000051: IND means an investigational new drug application. For purposes of this part, ‘‘IND’’ is synonymous
p.000051: with ‘‘No- tice of Claimed Investigational Exemp- tion for a New Drug.’’
p.000051: Independent ethics committee (IEC) means a review panel that is respon- sible for ensuring the
p.000051: protection of the rights, safety, and well-being of human
p.000052: 52
p.000052: 21 CFR Ch. I (4–1–12 Edition)
p.000052: subjects involved in a clinical inves- tigation and is adequately constituted to provide assurance of
p.000052: that protec- tion. An institutional review board (IRB), as defined in § 56.102(g) of this chapter and
p.000052: subject to the require- ments of part 56 of this chapter, is one type of IEC.
p.000052: Investigational ne drug means a new drug or biological drug that is used in a clinical investigation.
p.000052: The term also includes a biological product that is used in vitro for diagnostic purposes. The terms
p.000052: ‘‘investigational drug’’ and ‘‘investigational new drug’’ are deemed to be synonymous for purposes of this
p.000052: part.
p.000052: Investigator means an individual who actually conducts a clinical investiga- tion (i.e., under whose immediate
p.000052: direc- tion the drug is administered or dis- pensed to a subject). In the event an in- vestigation is conducted
p.000052: by a team of individuals, the investigator is the re- sponsible leader of the team. ‘‘Sub-
p.000052: investigator’’ includes any other indi- vidual member of that team.
p.000052: Marketing application means an appli- cation for a new drug submitted under section 505(b) of the act or
p.000052: a biologics license application for a biological product submitted under the Public Health Service
p.000052: Act.
p.000052: Sponsor means a person who takes re- sponsibility for and initiates a clinical investigation. The sponsor may
p.000052: be an individual or pharmaceutical company, governmental agency, academic insti- tution, private organization,
p.000052: or other organization. The sponsor does not ac- tually conduct the investigation unless the sponsor is a
p.000052: sponsor-investigator. A person other than an individual that uses one or more of its own employees to
p.000052: conduct an investigation that it has initiated is a sponsor, not a sponsor-in- vestigator, and the employees are
p.000052: in- vestigators.
p.000052: Sponsor-Investigator means an indi-
p.000052: vidual who both initiates and conducts an investigation, and under whose im- mediate direction the
p.000052: investigational drug is administered or dispensed. The term does not include any person other than an
p.000052: individual. The requirements applicable to a sponsor-investigator under this part include both those
p.000052: ap- plicable to an investigator and a spon- sor.
p.000052:
p.000052:
p.000052:
p.000052:
p.000052:
p.000052:
p.000052:
p.000052: Food and Drug Administration, HHS § 312.8
p.000052:
p.000052:
p.000052: Subject means a human who partici- pates in an investigation, either as a recipient of the
p.000052: investigational new drug or as a control. A subject may be a healthy human or a patient with a
p.000052: disease.
p.000052: [52 FR 8831, Mar. 19, 1987, as amended at 64
p.000052: FR 401, Jan. 5, 1999; 64 FR 56449, Oct. 20, 1999;
p.000052: 73 FR 22815, Apr. 28, 2008]
p.000052:
p.000052: § 312.6 Labeling of an investigational new drug.
p.000052: (a) The immediate package of an in- vestigational new drug intended for human use shall bear a label
p.000052: with the statement ‘‘Caution: New Drug—Lim- ited by Federal (or United States) law to investigational use.’’
p.000052: (b) The label or labeling of an inves- tigational new drug shall not bear any statement that is false or
p.000052: misleading in any particular and shall not represent that the investigational new drug is safe or
p.000052: effective for the purposes for which it is being investigated.
p.000052: (c) The appropriate FDA Center Di- rector, according to the procedures set forth in §§ 201.26 or 610.68
p.000052: of this chap- ter, may grant an exception or alter- native to the provision in paragraph (a) of this section,
p.000052: to the extent that this provision is not explicitly required by statute, for specified lots, batches, or
p.000052: other units of a human drug product that is or will be included in the Stra- tegic National Stockpile.
p.000052: [52 FR 8831, Mar. 19, 1987, as amended at 72
p.000052: FR 73599, Dec. 28, 2007]
p.000052:
p.000052: § 312.7 Promotion of investigational drugs.
p.000052: (a) Promotion of an investigational ne drug. A sponsor or investigator, or any person acting on behalf of a
p.000052: sponsor or investigator, shall not represent in a promotional context that an investiga- tional new drug is
p.000052: safe or effective for the purposes for which it is under in- vestigation or otherwise promote the drug.
p.000052: This provision is not intended to restrict the full exchange of scientific information concerning the
p.000052: drug, in- cluding dissemination of scientific findings in scientific or lay media. Rather, its
p.000052: intent is to restrict pro- motional claims of safety or effective- ness of the drug for a use for
p.000052: which it is under investigation and to preclude commercialization of the drug before it
p.000052:
p.000053: 53
p.000053:
p.000053: is approved for commercial distribu- tion.
p.000053: (b) Commercial distribution of an inves- tigational ne drug. A sponsor or inves- tigator shall not
p.000053: commercially dis- tribute or test market an investiga- tional new drug.
p.000053: (c) Prolonging an investigation. A sponsor shall not unduly prolong an in- vestigation after finding
p.000053: that the re- sults of the investigation appear to es- tablish sufficient data to support a marketing
p.000053: application.
p.000053: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000053: FR 19476, May 22, 1987; 67 FR 9585, Mar. 4,
p.000053: 2002; 74 FR 40899, Aug. 13, 2009]
p.000053:
p.000053: § 312.8 Charging for investigational drugs under an IND.
p.000053: (a) General criteria for charging. (1) A sponsor must meet the applicable re- quirements in paragraph (b) of
p.000053: this sec- tion for charging in a clinical trial or paragraph (c) of this section for charg- ing for
p.000053: expanded access to an investiga- tional drug for treatment use under subpart I of this part, except that
p.000053: spon- sors need not fulfill the requirements in this section to charge for an ap- proved drug
p.000053: obtained from another en- tity not affiliated with the sponsor for use as part of the clinical trial
p.000053: evalua- tion (e.g., in a clinical trial of a new use of the approved drug, for use of the approved drug as an
p.000053: active control).
p.000053: (2) A sponsor must justify the
p.000053: amount to be charged in accordance with paragraph (d) of this section.
p.000053: (3) A sponsor must obtain prior writ- ten authorization from FDA to charge for an investigational drug.
p.000053: (4) FDA will withdraw authorization to charge if it determines that charg- ing is interfering with the
p.000053: development of a drug for marketing approval or that the criteria for the authorization are no longer
p.000053: being met.
p.000053: (b) Charging in a clinical trial—(1) Charging for a sponsor’s drug. A sponsor who wishes to charge
p.000053: for its investiga- tional drug, including investigational use of its approved drug, must:
p.000053: (i) Provide evidence that the drug has a potential clinical benefit that, if demonstrated in the clinical
p.000053: investiga- tions, would provide a significant ad- vantage over available products in the diagnosis,
p.000053: treatment, mitigation, or prevention of a disease or condition;
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053: § 312.8
p.000053: (ii) Demonstrate that the data to be obtained from the clinical trial would be essential to
p.000053: establishing that the drug is effective or safe for the purpose of obtaining initial approval of a drug, or
p.000053: would support a significant change in the labeling of an approved drug (e.g., new indication,
p.000053: inclusion of com- parative safety information); and
p.000053: (iii) Demonstrate that the clinical trial could not be conducted without charging because the cost of the
p.000053: drug is extraordinary to the sponsor. The cost may be extraordinary due to manufac- turing complexity,
p.000053: scarcity of a nat- ural resource, the large quantity of drug needed (e.g., due to the size or du- ration
p.000053: of the trial), or some combina- tion of these or other extraordinary circumstances (e.g., resources
p.000053: available to a sponsor).
p.000053: (2) Duration of charging in a clinical trial. Unless FDA specifies a shorter pe- riod, charging may
p.000053: continue for the length of the clinical trial.
p.000053: (c) Charging for expanded access to in- vestigational drug for treatment use. (1) A sponsor who wishes to
p.000053: charge for ex- panded access to an investigational drug for treatment use under subpart I of this part
p.000053: must provide reasonable assurance that charging will not inter- fere with developing the drug for mar- keting
p.000053: approval.
p.000053: (2) For expanded access under § 312.320 (treatment IND or treatment protocol), such assurance must include:
p.000053: (i) Evidence of sufficient enrollment in any ongoing clinical trial(s) needed for marketing approval to
p.000053: reasonably assure FDA that the trial(s) will be successfully completed as planned;
p.000053: (ii) Evidence of adequate progress in the development of the drug for mar- keting approval; and
p.000053: (iii) Information submitted under the general investigational plan (§ 312.23(a)(3)(iv))
p.000053: specifying the drug development milestones the sponsor plans to meet in the next year.
p.000053: (3) The authorization to charge is limited to the number of patients au- thorized to receive the
p.000053: drug under the treatment use, if there is a limitation.
p.000053: (4) Unless FDA specifies a shorter pe- riod, charging for expanded access to an investigational drug for
p.000053: treatment use under subpart I of this part may continue for 1 year from the time of
p.000054: 54
p.000054: 21 CFR Ch. I (4–1–12 Edition)
p.000054: FDA authorization. A sponsor may re- quest that FDA reauthorize charging for additional periods.
p.000054: (d) Costs recoverable hen charging for an investigational drug. (1) A sponsor may recover only the
p.000054: direct costs of making its investigational drug avail- able.
p.000054: (i) Direct costs are costs incurred by a sponsor that can be specifically and exclusively attributed to
p.000054: providing the drug for the investigational use for which FDA has authorized cost recov- ery. Direct
p.000054: costs include costs per unit to manufacture the drug (e.g., raw ma- terials, labor, and nonreusable supplies and
p.000054: equipment used to manufacture the quantity of drug needed for the use for which charging is authorized)
p.000054: or costs to acquire the drug from another manufacturing source, and direct costs to ship and handle
p.000054: (e.g., store) the drug.
p.000054: (ii) Indirect costs include costs in- curred primarily to produce the drug for commercial sale (e.g.,
p.000054: costs for fa- cilities and equipment used to manu- facture the supply of investigational drug, but
p.000054: that are primarily intended to produce large quantities of drug for eventual commercial sale) and research and
p.000054: development, administrative, labor, or other costs that would be in- curred even if the
p.000054: clinical trial or treatment use for which charging is au- thorized did not occur.
p.000054: (2) For expanded access to an inves- tigational drug for treatment use under §§ 312.315
p.000054: (intermediate-size pa- tient populations) and 312.320 (treat- ment IND or treatment protocol), in
p.000054: addition to the direct costs described in paragraph (d)(1)(i) of this section, a sponsor may recover the
p.000054: costs of moni- toring the expanded access IND or pro- tocol, complying with IND reporting requirements, and
p.000054: other administrative costs directly associated with the ex- panded access IND.
p.000054: (3) To support its calculation for cost recovery, a sponsor must provide sup- porting documentation to show
p.000054: that the calculation is consistent with the requirements of paragraphs (d)(1) and, if applicable, (d)(2)
p.000054: of this section. The documentation must be accompanied by a statement that an independent
p.000054:
p.000054:
p.000054:
p.000054:
p.000054:
p.000054:
p.000054:
p.000054: Food and Drug Administration, HHS § 312.21
p.000054:
p.000054:
p.000054: certified public accountant has re- viewed and approved the calculations.
p.000054: [74 FR 40899, Aug. 13, 2009]
p.000054: § 312.10 Waivers.
p.000054: (a) A sponsor may request FDA to waive applicable requirement under this part. A waiver request may be
p.000054: sub- mitted either in an IND or in an infor- mation amendment to an IND. In an emergency, a request
p.000054: may be made by telephone or other rapid communica- tion means. A waiver request is re- quired to
p.000054: contain at least one of the following:
p.000054: (1) An explanation why the sponsor’s
p.000054: compliance with the requirement is un- necessary or cannot be achieved;
p.000054: (2) A description of an alternative submission or course of action that satisfies the purpose
p.000054: of the require- ment; or
p.000054: (3) Other information justifying a waiver.
p.000054: (b) FDA may grant a waiver if it finds that the sponsor’s noncompliance would not pose a significant and
p.000054: unrea- sonable risk to human subjects of the investigation and that one of the fol- lowing is met:
p.000054: (1) The sponsor’s compliance with the requirement is unnecessary for the agency to evaluate the
p.000054: application, or compliance cannot be achieved;
p.000054: (2) The sponsor’s proposed alter- native satisfies the requirement; or
p.000054: (3) The applicant’s submission other- wise justifies a waiver.
p.000054: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000054: FR 23031, June 17, 1987; 67 FR 9585, Mar. 4,
p.000054: 2002]
p.000054:
p.000054: Subpart B—Investigational New Drug Application (IND)
p.000054: § 312.20 Requirement for an IND.
p.000054: (a) A sponsor shall submit an IND to FDA if the sponsor intends to conduct a clinical investigation
p.000054: with an inves- tigational new drug that is subject to
p.000054: § 312.2(a).
p.000054: (b) A sponsor shall not begin a clin- ical investigation subject to § 312.2(a) until the investigation is
p.000054: subject to an IND which is in effect in accordance with § 312.40.
p.000054: (c) A sponsor shall submit a separate IND for any clinical investigation in-
p.000054:
p.000055: 55
p.000055:
p.000055: volving an exception from informed consent under § 50.24 of this chapter. Such a clinical
p.000055: investigation is not permitted to proceed without the prior written authorization from FDA. FDA shall provide
p.000055: a written determination 30 days after FDA receives the IND or earlier.
p.000055: [52 FR 8831, Mar. 19, 1987, as amended at 61
p.000055: FR 51529, Oct. 2, 1996; 62 FR 32479, June 16,
p.000055: 1997]
p.000055: § 312.21 Phases of an investigation.
p.000055: An IND may be submitted for one or more phases of an investigation. The clinical investigation of a
p.000055: previously untested drug is generally divided into three phases. Although in general the phases are
p.000055: conducted sequentially, they may overlap. These three phases of an investigation are a follows:
p.000055: (a) Phase 1. (1) Phase 1 includes the initial introduction of an investiga- tional new drug into
p.000055: humans. Phase 1 studies are typically closely monitored and may be conducted in patients or normal volunteer
p.000055: subjects. These stud- ies are designed to determine the me- tabolism and pharmacologic actions of the drug
p.000055: in humans, the side effects as- sociated with increasing doses, and, if possible, to gain early evidence on
p.000055: ef- fectiveness. During Phase 1, sufficient information about the drug’s phar- macokinetics and
p.000055: pharmacological ef- fects should be obtained to permit the design of well-controlled, scientifically valid,
p.000055: Phase 2 studies. The total num- ber of subjects and patients included in Phase 1 studies varies with the
p.000055: drug, but is generally in the range of 20 to 80.
p.000055: (2) Phase 1 studies also include stud- ies of drug metabolism, structure-ac- tivity relationships, and
p.000055: mechanism of action in humans, as well as studies in which investigational drugs are used as research tools to
p.000055: explore biological phenomena or disease processes.
p.000055: (b) Phase 2. Phase 2 includes the con- trolled clinical studies conducted to evaluate the effectiveness of
p.000055: the drug for a particular indication or indica- tions in patients with the disease or condition under
p.000055: study and to deter- mine the common short-term side ef- fects and risks associated with the drug.
p.000055: Phase 2 studies are typically well controlled, closely monitored, and con- ducted in a relatively small number of
p.000055:
p.000055:
p.000055:
p.000055:
p.000055:
p.000055:
p.000055:
p.000055:
p.000055: § 312.22
p.000055: patients, usually involving no more than several hundred subjects.
p.000055: (c) Phase 3. Phase 3 studies are ex- panded controlled and uncontrolled trials. They are performed
p.000055: after pre- liminary evidence suggesting effective- ness of the drug has been obtained, and are intended to gather
p.000055: the additional information about effectiveness and safety that is needed to evaluate the overall
p.000055: benefit-risk relationship of the drug and to provide an adequate basis for physician labeling. Phase 3
p.000055: studies usually include from several hundred to several thousand subjects.
p.000055: § 312.22 General principles of the IND submission.
p.000055: (a) FDA’s primary objectives in re- viewing an IND are, in all phases of the investigation, to assure the
p.000055: safety and rights of subjects, and, in Phase 2 and 3, to help assure that the quality of the scientific
p.000055: evaluation of drugs is ade- quate to permit an evaluation of the drug’s effectiveness and safety. There-
p.000055: fore, although FDA’s review of Phase 1 submissions will focus on assessing the safety of Phase 1 investigations, FDA’s
p.000055: review of Phases 2 and 3 submissions will also include an assessment of the scientific quality of the
p.000055: clinical inves- tigations and the likelihood that the investigations will yield data capable of meeting
p.000055: statutory standards for marketing approval.
p.000055: (b) The amount of information on a
p.000055: particular drug that must be submitted in an IND to assure the accomplish- ment of the objectives
p.000055: described in paragraph (a) of this section depends upon such factors as the novelty of the drug, the extent
p.000055: to which it has been studied previously, the known or sus- pected risks, and the developmental phase
p.000055: of the drug.
p.000055: (c) The central focus of the initial IND submission should be on the gen- eral investigational plan and the
p.000055: proto- cols for specific human studies. Subse- quent amendments to the IND that contain new or revised
p.000055: protocols should build logically on previous submissions and should be supported by additional information,
p.000055: including the results of animal toxicology studies or other human studies as appropriate. Annual
p.000055: reports to the IND should serve as the focus for reporting the status of studies
p.000056: 56
p.000056: 21 CFR Ch. I (4–1–12 Edition)
p.000056: being conducted under the IND and should update the general investiga- tional plan for the coming
p.000056: year.
p.000056: (d) The IND format set forth in
p.000056: § 312.23 should be followed routinely by sponsors in the interest of fostering an efficient review of
p.000056: applications. Spon- sors are expected to exercise consider- able discretion, however, regarding the content of
p.000056: information submitted in each section, depending upon the kind of drug being studied and the nature of the
p.000056: available information. Section
p.000056: 312.23 outlines the information needed for a commercially sponsored IND for a new molecular entity. A
p.000056: sponsor-inves- tigator who uses, as a research tool, an investigational new drug that is al- ready subject
p.000056: to a manufacturer’s IND or marketing application should follow the same general format, but ordi- narily
p.000056: may, if authorized by the manu- facturer, refer to the manufacturer’s IND or marketing application in pro-
p.000056: viding the technical information sup- porting the proposed clinical investiga- tion. A sponsor-investigator who
p.000056: uses an investigational drug not subject to a manufacturer’s IND or marketing ap- plication is ordinarily
p.000056: required to sub- mit all technical information sup- porting the IND, unless such informa- tion may
p.000056: be referenced from the sci- entific literature.
p.000056: § 312.23 IND content and format.
p.000056: (a) A sponsor who intends to conduct a clinical investigation subject to this part shall submit an
p.000056: ‘‘Investigational New Drug Application’’ (IND) includ- ing, in the following order:
p.000056: (1) Cover sheet (Form FDA–1571). A cover sheet for the application con- taining the following:
p.000056: (i) The name, address, and telephone number of the sponsor, the date of the application, and the name of
p.000056: the inves- tigational new drug.
p.000056: (ii) Identification of the phase or phases of the clinical investigation to be conducted.
p.000056: (iii) A commitment not to begin clin- ical investigations until an IND cov- ering the investigations is in effect.
p.000056: (iv) A commitment that an Institu- tional Review Board (IRB) that com- plies with the requirements set forth
p.000056: in
p.000056:
p.000056:
p.000056:
p.000056:
p.000056:
p.000056:
p.000056:
p.000056: Food and Drug Administration, HHS § 312.23
p.000056:
p.000056:
p.000056: part 56 will be responsible for the ini- tial and continuing review and ap- proval of each of the
p.000056: studies in the pro- posed clinical investigation and that the investigator will report to the IRB
p.000056: proposed changes in the research activ- ity in accordance with the require- ments of part 56.
p.000056: (v) A commitment to conduct the in- vestigation in accordance with all other applicable regulatory
p.000056: require- ments.
p.000056: (vi) The name and title of the person responsible for monitoring the conduct and progress of the clinical
p.000056: investiga- tions.
p.000056: (vii) The name(s) and title(s) of the person(s) responsible under § 312.32 for review and evaluation of
p.000056: information relevant to the safety of the drug.
p.000056: (viii) If a sponsor has transferred any obligations for the conduct of any clin- ical study to a contract research
p.000056: orga- nization, a statement containing the name and address of the contract re- search organization,
p.000056: identification of the clinical study, and a listing of the obligations transferred. If all obliga-
p.000056: tions governing the conduct of the study have been transferred, a general statement of this
p.000056: transfer—in lieu of a listing of the specific obligations trans- ferred—may be submitted.
p.000056: (ix) The signature of the sponsor or
p.000056: the sponsor’s authorized representa- tive. If the person signing the applica- tion does not reside or
p.000056: have a place of business within the United States, the IND is required to contain the name and address
p.000056: of, and be countersigned by, an attorney, agent, or other au- thorized official who resides or
p.000056: main- tains a place of business within the United States.
p.000056: (2) A table of contents.
p.000056: (3) Introductory statement and general investigational plan. (i) A brief introduc- tory statement giving the
p.000056: name of the drug and all active ingredients, the drug’s pharmacological class, the structural
p.000056: formula of the drug (if known), the formulation of the dosage form(s) to be used, the route of
p.000056: admin- istration, and the broad objectives and planned duration of the proposed clin- ical investigation(s).
p.000056: (ii) A brief summary of previous human experience with the drug, with reference to other IND’s if
p.000056: pertinent,
p.000057: 57
p.000057:
p.000057: and to investigational or marketing ex- perience in other countries that may be relevant to the safety of
p.000057: the pro- posed clinical investigation(s).
p.000057: (iii) If the drug has been withdrawn from investigation or marketing in any country for any reason related
p.000057: to safe- ty or effectiveness, identification of the country(ies) where the drug was withdrawn and
p.000057: the reasons for the withdrawal.
p.000057: (iv) A brief description of the overall plan for investigating the drug product for the following year. The plan
p.000057: should include the following: (a) The rationale for the drug or the research study; (b) the indication(s) to
p.000057: be studied; (c) the general approach to be followed in evaluating the drug; (d) the kinds of
p.000057: clinical trials to be conducted in the first year following the submission (if plans are not developed
p.000057: for the entire year, the sponsor should so indicate);
p.000057: (e) the estimated number of patients to be given the drug in those studies; and
p.000057: (f) any risks of particular severity or seriousness anticipated on the basis of the toxicological data
p.000057: in animals or prior studies in humans with the drug or related drugs.
p.000057: (4) [Reserved]
p.000057: (5) Investigator’s brochure. If required under § 312.55, a copy of the investiga- tor’s brochure,
p.000057: containing the fol- lowing information:
p.000057: (i) A brief description of the drug substance and the formulation, includ- ing the structural formula,
p.000057: if known.
p.000057: (ii) A summary of the pharma- cological and toxicological effects of the drug in animals
p.000057: and, to the extent known, in humans.
p.000057: (iii) A summary of the pharmaco- kinetics and biological disposition of the drug in animals and, if
p.000057: known, in humans.
p.000057: (iv) A summary of information relat- ing to safety and effectiveness in hu- mans obtained from prior clinical
p.000057: stud- ies. (Reprints of published articles on such studies may be appended when useful.)
p.000057: (v) A description of possible risks and side effects to be anticipated on the basis of prior experience with
p.000057: the drug under investigation or with related drugs, and of precautions or special monitoring to be
p.000057: done as part of the in- vestigational use of the drug.
p.000057:
p.000057:
p.000057:
p.000057:
p.000057:
p.000057:
p.000057:
p.000057:
p.000057: § 312.23
p.000057: (6) Protocols. (i) A protocol for each planned study. (Protocols for studies not submitted initially
p.000057: in the IND should be submitted in accordance with
p.000057: § 312.30(a).) In general, protocols for Phase 1 studies may be less detailed and more flexible than
p.000057: protocols for Phase 2 and 3 studies. Phase 1 protocols should be directed primarily at pro- viding an
p.000057: outline of the investigation— an estimate of the number of patients to be involved, a description of safety
p.000057: exclusions, and a description of the dosing plan including duration, dose, or method to be used in
p.000057: determining dose—and should specify in detail only those elements of the study that are critical to
p.000057: safety, such as necessary monitoring of vital signs and blood chemistries. Modifications of the
p.000057: ex- perimental design of Phase 1 studies that do not affect critical safety as- sessments are required to
p.000057: be reported to FDA only in the annual report.
p.000057: (ii) In Phases 2 and 3, detailed proto-
p.000057: cols describing all aspects of the study should be submitted. A protocol for a Phase 2 or 3 investigation
p.000057: should be de- signed in such a way that, if the spon- sor anticipates that some deviation from the
p.000057: study design may become nec- essary as the investigation progresses, alternatives or contingencies to pro-
p.000057: vide for such deviation are built into the protocols at the outset. For exam- ple, a protocol for a
p.000057: controlled short- term study might include a plan for an early crossover of nonresponders to an alternative
p.000057: therapy.
p.000057: (iii) A protocol is required to contain
p.000057: the following, with the specific ele- ments and detail of the protocol re- flecting the above
p.000057: distinctions depend- ing on the phase of study:
p.000057: (a) A statement of the objectives and purpose of the study.
p.000057: (b) The name and address and a state- ment of the qualifications (curriculum vitae or other statement of
p.000057: qualifica- tions) of each investigator, and the name of each subinvestigator (e.g., re- search fellow,
p.000057: resident) working under the supervision of the investigator; the name and address of the research fa- cilities
p.000057: to be used; and the name and address of each reviewing Institutional Review Board.
p.000057: (c) The criteria for patient selection and for exclusion of patients and an es-
p.000057:
p.000058: 58
p.000058: 21 CFR Ch. I (4–1–12 Edition)
p.000058: timate of the number of patients to be studied.
p.000058: (d) A description of the design of the study, including the kind of control group to be used, if any,
p.000058: and a descrip- tion of methods to be used to minimize bias on the part of subjects, investiga- tors, and
p.000058: analysts.
p.000058: (e) The method for determining the dose(s) to be administered, the planned maximum dosage, and the duration
p.000058: of individual patient exposure to the drug.
p.000058: (f) A description of the observations and measurements to be made to fulfill the objectives of the study.
p.000058: (g) A description of clinical proce- dures, laboratory tests, or other meas- ures to be taken to monitor
p.000058: the effects of the drug in human subjects and to minimize risk.
p.000058: (7) Chemistry, manufacturing, and con- trol information. (i) As appropriate for the particular
p.000058: investigations covered by the IND, a section describing the composition, manufacture, and control of the
p.000058: drug substance and the drug product. Although in each phase of the investigation sufficient information is
p.000058: required to be submitted to assure the proper identification, quality, purity, and strength of the
p.000058: investigational drug, the amount of information need- ed to make that assurance will vary with the phase of
p.000058: the investigation, the proposed duration of the investigation, the dosage form, and the amount of in- formation
p.000058: otherwise available. FDA recognizes that modifications to the method of preparation of the new drug
p.000058: substance and dosage form and changes in the dosage form itself are likely as the investigation
p.000058: progresses. There- fore, the emphasis in an initial Phase 1 submission should generally be placed on the
p.000058: identification and control of the raw materials and the new drug sub- stance. Final specifications for
p.000058: the drug substance and drug product are not expected until the end of the inves- tigational process.
p.000058: (ii) It should be emphasized that the
p.000058: amount of information to be submitted depends upon the scope of the proposed clinical investigation. For example, al-
p.000058: though stability data are required in all phases of the IND to demonstrate that the new drug substance
p.000058: and drug product are within acceptable chemical
p.000058:
p.000058:
p.000058:
p.000058:
p.000058:
p.000058:
p.000058:
p.000058: Food and Drug Administration, HHS § 312.23
p.000058:
p.000058:
p.000058: and physical limits for the planned du- ration of the proposed clinical inves- tigation, if very short-term
p.000058: tests are proposed, the supporting stability data can be correspondingly limited.
p.000058: (iii) As drug development proceeds and as the scale or production is changed from the
p.000058: pilot-scale produc- tion appropriate for the limited initial clinical investigations to the larger-
p.000058: scale production needed for expanded clinical trials, the sponsor should sub- mit information amendments to
p.000058: sup- plement the initial information sub- mitted on the chemistry, manufac- turing, and control
p.000058: processes with in- formation appropriate to the expanded scope of the investigation.
p.000058: (iv) Reflecting the distinctions de-
p.000058: scribed in this paragraph (a)(7), and based on the phase(s) to be studied, the submission is required to
p.000058: contain the following:
p.000058: (a) Drug substance. A description of the drug substance, including its phys- ical, chemical, or
p.000058: biological character- istics; the name and address of its man- ufacturer; the general method of prepa- ration of the
p.000058: drug substance; the ac- ceptable limits and analytical methods used to assure the identity, strength, quality,
p.000058: and purity of the drug sub- stance; and information sufficient to support stability of the drug
p.000058: substance during the toxicological studies and the planned clinical studies. Reference to the current
p.000058: edition of the United States Pharmacopeia—National For- mulary may satisfy relevant require- ments in this
p.000058: paragraph.
p.000058: (b) Drug product. A list of all compo-
p.000058: nents, which may include reasonable alternatives for inactive compounds, used in the manufacture of
p.000058: the inves- tigational drug product, including both those components intended to appear in the drug product and
p.000058: those which may not appear but which are used in the manufacturing process, and, where applicable, the
p.000058: quantitative composi- tion of the investigational drug prod- uct, including any reasonable vari- ations
p.000058: that may be expected during the investigational stage; the name and ad- dress of the drug product manufac-
p.000058: turer; a brief general description of the manufacturing and packaging proce- dure as appropriate for the product;
p.000058: the acceptable limits and analytical meth-
p.000059: 59
p.000059:
p.000059: ods used to assure the identity, strength, quality, and purity of the drug product; and
p.000059: information suffi- cient to assure the product’s stability during the planned clinical studies.
p.000059: Reference to the current edition of the United States Pharmacopeia—National Formulary may satisfy certain require-
p.000059: ments in this paragraph.
p.000059: (c) A brief general description of the composition, manufacture, and control of any placebo used in
p.000059: a controlled clinical trial.
p.000059: (d) Labeling. A copy of all labels and labeling to be provided to each investi- gator.
p.000059: (e) Environmental analysis require- ments. A claim for categorical exclu- sion under § 25.30 or 25.31
p.000059: or an environ- mental assessment under § 25.40.
p.000059: (8) Pharmacology and toxicology infor- mation. Adequate information about pharmacological and
p.000059: toxicological studies of the drug involving labora- tory animals or in vitro, on the basis of which the sponsor
p.000059: has concluded that it is reasonably safe to conduct the proposed clinical investigations. The kind,
p.000059: duration, and scope of animal and other tests required varies with the du- ration and nature of the proposed
p.000059: clin- ical investigations. Guidance docu- ments are available from FDA that de- scribe ways in which
p.000059: these require- ments may be met. Such information is required to include the identification and qualifications
p.000059: of the individuals who evaluated the results of such stud- ies and concluded that it is reasonably safe to
p.000059: begin the proposed investiga- tions and a statement of where the in- vestigations were conducted and
p.000059: where the records are available for inspec- tion. As drug development proceeds, the sponsor is
p.000059: required to submit infor- mational amendments, as appropriate, with additional information pertinent to safety.
p.000059: (i) Pharmacology and drug disposition.
p.000059: A section describing the pharma- cological effects and mechanism(s) of action of the drug in
p.000059: animals, and in- formation on the absorption, distribu- tion, metabolism, and excretion of the drug, if
p.000059: known.
p.000059: (ii) Toxicology. (a) An integrated sum- mary of the toxicological effects of the drug in animals and in vitro.
p.000059: Depend- ing on the nature of the drug and the
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059: § 312.23
p.000059: phase of the investigation, the descrip- tion is to include the results of acute, subacute, and chronic
p.000059: toxicity tests; tests of the drug’s effects on reproduc- tion and the developing fetus; any spe- cial
p.000059: toxicity test related to the drug’s particular mode of administration or conditions of use (e.g.,
p.000059: inhalation, der- mal, or ocular toxicology); and any in vitro studies intended to evaluate drug toxicity.
p.000059: (b) For each toxicology study that is intended primarily to support the safe- ty of the proposed clinical
p.000059: investiga- tion, a full tabulation of data suitable for detailed review.
p.000059: (iii) For each nonclinical laboratory study subject to the good laboratory practice regulations under part
p.000059: 58, a statement that the study was con- ducted in compliance with the good laboratory practice
p.000059: regulations in part 58, or, if the study was not conducted in compliance with those regulations, a brief
p.000059: statement of the reason for the noncompliance.
p.000059: (9) Previous human experience ith the investigational drug. A summary of pre- vious human experience
p.000059: known to the applicant, if any, with the investiga- tional drug. The information is re- quired to
p.000059: include the following:
p.000059: (i) If the investigational drug has been investigated or marketed pre- viously, either in the
p.000059: United States or other countries, detailed information about such experience that is relevant to the
p.000059: safety of the proposed investiga- tion or to the investigation’s rationale. If the drug has been the subject of con-
p.000059: trolled trials, detailed information on such trials that is relevant to an as- sessment of the drug’s
p.000059: effectiveness for the proposed investigational use(s) should also be provided. Any published material
p.000059: that is relevant to the safety of the proposed investigation or to an assessment of the drug’s
p.000059: effectiveness for its proposed investigational use should be provided in full. Published material that
p.000059: is less directly relevant may be supplied by a bibliography.
p.000059: (ii) If the drug is a combination of
p.000059: drugs previously investigated or mar- keted, the information required under paragraph (a)(9)(i) of
p.000059: this section should be provided for each active drug component. However, if any component in such combination is
p.000059: subject to an
p.000060: 60
p.000060: 21 CFR Ch. I (4–1–12 Edition)
p.000060: approved marketing application or is otherwise lawfully marketed in the United States, the sponsor is
p.000060: not re- quired to submit published material concerning that active drug component unless such material relates
p.000060: directly to the proposed investigational use (in- cluding publications relevant to com- ponent-component
p.000060: interaction).
p.000060: (iii) If the drug has been marketed outside the United States, a list of the countries in which the
p.000060: drug has been marketed and a list of the countries in which the drug has been withdrawn from marketing for
p.000060: reasons potentially related to safety or effectiveness.
p.000060: (10) Additional information. In certain applications, as described below, infor- mation on special topics
p.000060: may be need- ed. Such information shall be sub- mitted in this section as follows:
p.000060: (i) Drug dependence and abuse poten- tial. If the drug is a psychotropic sub- stance or otherwise has
p.000060: abuse poten- tial, a section describing relevant clin- ical studies and experience and studies in test animals.
p.000060: (ii) Radioactive drugs. If the drug is a radioactive drug, sufficient data from animal or human
p.000060: studies to allow a reasonable calculation of radiation-ab- sorbed dose to the whole body and crit- ical
p.000060: organs upon administration to a human subject. Phase 1 studies of ra- dioactive drugs must include
p.000060: studies which will obtain sufficient data for dosimetry calculations.
p.000060: (iii) Pediatric studies. Plans for assess- ing pediatric safety and effectiveness.
p.000060: (iv) Other information. A brief state- ment of any other information that would aid evaluation of
p.000060: the proposed clinical investigations with respect to their safety or their design and poten- tial as
p.000060: controlled clinical trials to sup- port marketing of the drug.
p.000060: (11) Relevant information. If requested by FDA, any other relevant informa- tion needed for review of the
p.000060: applica- tion.
p.000060: (b) Information previously submitted. The sponsor ordinarily is not required to resubmit information
p.000060: previously submitted, but may incorporate the in- formation by reference. A reference to information submitted
p.000060: previously must identify the file by name, reference number, volume, and page number where the
p.000060: information can be found. A
p.000060:
p.000060:
p.000060:
p.000060:
p.000060:
p.000060:
p.000060:
p.000060: Food and Drug Administration, HHS § 312.30
p.000060:
p.000060:
p.000060: reference to information submitted to the agency by a person other than the sponsor is required to
p.000060: contain a writ- ten statement that authorizes the ref- erence and that is signed by the person who submitted the
p.000060: information.
p.000060: (c) Material in a foreign language. The sponsor shall submit an accurate and complete English translation
p.000060: of each part of the IND that is not in English. The sponsor shall also submit a copy of each original
p.000060: literature publication for which an English translation is sub- mitted.
p.000060: (d) Number of copies. The sponsor shall submit an original and two copies of all submissions to the
p.000060: IND file, in- cluding the original submission and all amendments and reports.
p.000060: (e) Numbering of IND submissions. Each submission relating to an IND is required to be numbered
p.000060: serially using a single, three-digit serial number. The initial IND is required to be numbered 000; each
p.000060: subsequent submission (e.g., amendment, report, or correspondence) is required to be numbered chrono-
p.000060: logically in sequence.
p.000060: (f) Identification of exception from in- formed consent. If the investigation in- volves an exception from
p.000060: informed con- sent under § 50.24 of this chapter, the sponsor shall prominently identify on the cover sheet
p.000060: that the investigation is subject to the requirements in § 50.24 of this chapter.
p.000060: [52 FR 8831, Mar. 19, 1987, as amended at 52
...
p.000060: provisions under which new protocols may be submitted and changes in previously submitted proto-
p.000060: cols may be made. Whenever a sponsor intends to conduct a clinical investiga- tion with an exception from
p.000060: informed consent for emergency research as set forth in § 50.24 of this chapter, the spon- sor shall submit
p.000060: a separate IND for such investigation.
p.000061: 61
p.000061:
p.000061: (a) Ne protocol. Whenever a sponsor intends to conduct a study that is not covered by a protocol
p.000061: already con- tained in the IND, the sponsor shall submit to FDA a protocol amendment containing the
p.000061: protocol for the study. Such study may begin provided two conditions are met: (1) The sponsor has
p.000061: submitted the protocol to FDA for its review; and (2) the protocol has been approved by the
p.000061: Institutional Review Board (IRB) with responsibility for re- view and approval of the study in ac-
p.000061: cordance with the requirements of part
p.000061: 56. The sponsor may comply with these
p.000061: two conditions in either order.
p.000061: (b) Changes in a protocol. (1) A sponsor shall submit a protocol amendment de- scribing any change in a Phase 1
p.000061: pro- tocol that significantly affects the safety of subjects or any change in a Phase 2 or 3
p.000061: protocol that significantly affects the safety of subjects, the scope of the investigation, or the scientific
p.000061: quality of the study. Examples of changes requiring an amendment under this paragraph include:
p.000061: (i) Any increase in drug dosage or du- ration of exposure of individual sub- jects to the drug beyond
p.000061: that in the current protocol, or any significant in- crease in the number of subjects under study.
p.000061: (ii) Any significant change in the de- sign of a protocol (such as the addition or dropping of a control group).
p.000061: (iii) The addition of a new test or procedure that is intended to improve monitoring for, or reduce the
p.000061: risk of, a side effect or adverse event; or the dropping of a test intended to monitor safety.
p.000061: (2)(i) A protocol change under para- graph (b)(1) of this section may be made provided two
p.000061: conditions are met:
p.000061: (a) The sponsor has submitted the change to FDA for its review; and
p.000061: (b) The change has been approved by the IRB with responsibility for review and approval of the study. The
p.000061: sponsor may comply with these two conditions in either order.
p.000061: (ii) Notwithstanding paragraph (b)(2)(i) of this section, a protocol change intended to
p.000061: eliminate an appar- ent immediate hazard to subjects may be implemented immediately provided FDA is
p.000061: subsequently notified by pro- tocol amendment and the reviewing
p.000061:
p.000061:
p.000061:
p.000061:
p.000061:
p.000061:
p.000061:
p.000061:
p.000061: § 312.31
p.000061: IRB is notified in accordance with
p.000061: § 56.104(c).
p.000061: (c) Ne investigator. A sponsor shall submit a protocol amendment when a new investigator is added to
p.000061: carry out a previously submitted protocol, except that a protocol amendment is not re- quired when a licensed
p.000061: practitioner is added in the case of a treatment pro- tocol under § 312.315 or § 312.320. Once the
p.000061: investigator is added to the study, the investigational drug may be shipped to the investigator
p.000061: and the in- vestigator may begin participating in the study. The sponsor shall notify FDA of the
p.000061: new investigator within 30 days of the investigator being added.
p.000061: (d) Content and format. A protocol amendment is required to be promi- nently identified as such
p.000061: (i.e., ‘‘Pro- tocol Amendment: New Protocol’’, ‘‘Protocol Amendment: Change in Pro- tocol’’, or
p.000061: ‘‘Protocol Amendment: New Investigator’’), and to contain the fol- lowing:
p.000061: (1)(i) In the case of a new protocol, a copy of the new protocol and a brief de- scription of the most
p.000061: clinically signifi- cant differences between it and pre- vious protocols.
p.000061: (ii) In the case of a change in pro- tocol, a brief description of the change and reference (date and
p.000061: number) to the submission that contained the pro- tocol.
p.000061: (iii) In the case of a new investigator, the investigator’s name, the qualifica- tions to conduct the
p.000061: investigation, ref- erence to the previously submitted pro- tocol, and all additional information about the
p.000061: investigator’s study as is re- quired under § 312.23(a)(6)(iii)(b).
p.000061: (2) Reference, if necessary, to specific technical information in the IND or in a concurrently submitted
p.000061: information amendment to the IND that the spon- sor relies on to support any clinically significant
p.000061: change in the new or amended protocol. If the reference is made to supporting information al-
p.000061: ready in the IND, the sponsor shall identify by name, reference number, volume, and page number
p.000061: the location of the information.
...
p.000062: 4, 2002; 74 FR 40942, Aug. 13, 2009]
p.000062:
p.000062: § 312.31 Information amendments.
p.000062: (a) Requirement for information amend- ment. A sponsor shall report in an in- formation amendment essential
p.000062: infor- mation on the IND that is not within the scope of a protocol amendment, IND safety reports,
p.000062: or annual report. Examples of information requiring an information amendment include:
p.000062: (1) New toxicology, chemistry, or other technical information; or
p.000062: (2) A report regarding the discontinu- ance of a clinical investigation.
p.000062: (b) Content and format of an informa- tion amendment. An information amend- ment is required to bear
p.000062: prominent identification of its contents (e.g., ‘‘In- formation Amendment: Chemistry, Manufacturing, and
p.000062: Control’’, ‘‘Infor- mation Amendment: Pharmacology- Toxicology’’, ‘‘Information Amend- ment:
p.000062: Clinical’’), and to contain the following:
p.000062: (1) A statement of the nature and purpose of the amendment.
p.000062: (2) An organized submission of the data in a format appropriate for sci- entific review.
p.000062: (3) If the sponsor desires FDA to com- ment on an information amendment, a request for such comment.
p.000062: (c) When submitted. Information amendments to the IND should be sub- mitted as necessary but,
p.000062: to the extent feasible, not more than every 30 days.
p.000062: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000062: FR 23031, June 17, 1987; 53 FR 1918, Jan. 25,
p.000062: 1988; 67 FR 9585, Mar. 4, 2002]
p.000062:
p.000062:
p.000062:
p.000062:
p.000062:
p.000062:
p.000062:
p.000062: Food and Drug Administration, HHS § 312.32
p.000062:
p.000062:
p.000062: § 312.32 IND safety reporting.
p.000062: (a) Definitions. The following defini- tions of terms apply to this section:
p.000062: Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether
p.000062: or not considered drug related.
p.000062: Life-threatening adverse event or life- threatening suspected adverse reaction. An adverse event or
p.000062: suspected adverse reaction is considered ‘‘life-threat- ening’’ if, in the view of either the in-
p.000062: vestigator or sponsor, its occurrence places the patient or subject at imme- diate risk of death. It
p.000062: does not include an adverse event or suspected adverse reaction that, had it occurred in a more
p.000062: severe form, might have caused death.
p.000062: Serious adverse event or serious sus- pected adverse reaction. An adverse event or suspected
p.000062: adverse reaction is considered ‘‘serious’’ if, in the view of either the investigator or sponsor, it
p.000062: results in any of the following out- comes: Death, a life-threatening ad- verse event,
p.000062: inpatient hospitalization or prolongation of existing hospitaliza- tion, a persistent or significant inca-
p.000062: pacity or substantial disruption of the ability to conduct normal life func- tions, or a
p.000062: congenital anomaly/birth defect. Important medical events that may not result in death, be life-threat- ening,
p.000062: or require hospitalization may be considered serious when, based upon appropriate medical judgment, they
p.000062: may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of
p.000062: the out- comes listed in this definition. Exam- ples of such medical events include al- lergic
p.000062: bronchospasm requiring inten- sive treatment in an emergency room or at home, blood dyscrasias or convul-
p.000062: sions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.
p.000062: Suspected adverse reaction means any adverse event for which there is a rea- sonable possibility
p.000062: that the drug caused the adverse event. For the pur- poses of IND safety reporting, ‘‘reason- able
p.000062: possibility’’ means there is evi- dence to suggest a causal relationship between the drug and
p.000062: the adverse event. Suspected adverse reaction im- plies a lesser degree of certainty about causality than
p.000062: adverse reaction, which
p.000063: 63
p.000063:
p.000063: means any adverse event caused by a drug.
p.000063: Unexpected adverse event or unexpected suspected adverse reaction. An adverse event or suspected adverse
p.000063: reaction is considered ‘‘unexpected’’ if it is not listed in the investigator brochure or is not listed at
p.000063: the specificity or severity that has been observed; or, if an inves- tigator brochure is not required
p.000063: or available, is not consistent with the risk information described in the gen- eral investigational
p.000063: plan or elsewhere in the current application, as amended. For example, under this definition, he- patic
p.000063: necrosis would be unexpected (by virtue of greater severity) if the inves- tigator brochure referred only
p.000063: to ele- vated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis
p.000063: would be unex- pected (by virtue of greater specificity) if the investigator brochure listed only cerebral vascular
p.000063: accidents. ‘‘Unex- pected,’’ as used in this definition, also refers to adverse events or suspected adverse
p.000063: reactions that are mentioned in the investigator brochure as occur- ring with a class of drugs or as
p.000063: antici- pated from the pharmacological prop- erties of the drug, but are not specifi- cally mentioned as
p.000063: occurring with the particular drug under investigation.
p.000063: (b) Revie of safety information. The
p.000063: sponsor must promptly review all in- formation relevant to the safety of the drug obtained or otherwise
p.000063: received by the sponsor from foreign or domestic sources, including information derived from any clinical
p.000063: or epidemiological investigations, animal or in vitro stud- ies, reports in the scientific literature, and
p.000063: unpublished scientific papers, as well as reports from foreign regulatory authorities and reports of foreign com-
p.000063: mercial marketing experience for drugs that are not marketed in the United States.
p.000063: (c)(1) IND safety reports. The sponsor must notify FDA and all participating investigators (i.e., all
p.000063: investigators to whom the sponsor is providing drug
p.000063: under its INDs or under any investiga- tor’s IND) in an IND safety report of potential serious risks,
p.000063: from clinical trials or any other source, as soon as possible, but in no case later than 15 calendar
p.000063: days after the sponsor deter- mines that the information qualifies
p.000063:
p.000063:
p.000063:
p.000063:
p.000063:
p.000063:
p.000063:
p.000063:
p.000063: § 312.32
p.000063: for reporting under paragraph (c)(1)(i), (c)(1)(ii), (c)(1)(iii), or (c)(1)(iv) of this section. In each
p.000063: IND safety report, the sponsor must identify all IND safety reports previously submitted to FDA concerning
p.000063: a similar suspected adverse reaction, and must analyze the signifi- cance of the suspected adverse reaction in
p.000063: light of previous, similar reports or any other relevant information.
p.000063: (i) Serious and unexpected suspected adverse reaction. The sponsor must re- port any suspected
p.000063: adverse reaction that is both serious and unexpected. The sponsor must report an adverse event
p.000063: as a suspected adverse reaction only if there is evidence to suggest a causal relationship between the
p.000063: drug and the adverse event, such as:
p.000063: (A) A single occurrence of an event that is uncommon and known to be strongly associated with drug
p.000063: exposure (e.g., angioedema, hepatic injury, Ste- vens-Johnson Syndrome);
p.000063: (B) One or more occurrences of an event that is not commonly associated with drug exposure, but is
p.000063: otherwise uncommon in the population exposed to the drug (e.g., tendon rupture);
p.000063: (C) An aggregate analysis of specific events observed in a clinical trial (such as known consequences of the
p.000063: under- lying disease or condition under inves- tigation or other events that com- monly occur in the
p.000063: study population independent of drug therapy) that indi- cates those events occur more fre- quently in the
p.000063: drug treatment group than in a concurrent or historical con- trol group.
p.000063: (ii) Findings from other studies. The sponsor must report any findings from epidemiological studies,
p.000063: pooled anal- ysis of multiple studies, or clinical studies (other than those reported under
p.000063: paragraph (c)(1)(i) of this sec- tion), whether or not conducted under an IND, and whether or not
p.000063: conducted by the sponsor, that suggest a signifi- cant risk in humans exposed to the drug.
p.000063: Ordinarily, such a finding would result in a safety-related change in the protocol, informed consent,
p.000063: investi- gator brochure (excluding routine up- dates of these documents), or other as- pects of the overall
p.000063: conduct of the clin- ical investigation.
p.000063: (iii) Findings from animal or in vitro
p.000063: testing. The sponsor must report any
p.000064: 64
p.000064: 21 CFR Ch. I (4–1–12 Edition)
p.000064: findings from animal or in vitro test- ing, whether or not conducted by the sponsor, that suggest a
p.000064: significant risk in humans exposed to the drug, such as reports of mutagenicity,
p.000064: teratogenicity, or carcinogenicity, or reports of significant organ toxicity at or near the expected
p.000064: human exposure. Ordinarily, any such findings would re- sult in a safety-related change in the protocol,
p.000064: informed consent, investi- gator brochure (excluding routine up- dates of these documents), or other
p.000064: as- pects of the overall conduct of the clin- ical investigation.
p.000064: (iv) Increased rate of occurrence of seri-
p.000064: ous suspected adverse reactions. The sponsor must report any clinically im- portant increase in the
p.000064: rate of a seri- ous suspected adverse reaction over that listed in the protocol or investi- gator
p.000064: brochure.
p.000064: (v) Submission of IND safety reports. The sponsor must submit each IND safety report in a
p.000064: narrative format or on FDA Form 3500A or in an electronic format that FDA can process, review, and archive.
p.000064: FDA will periodically issue guidance on how to provide the electronic submission (e.g., method of
p.000064: transmission, media, file formats, prep- aration and organization of files). The sponsor may submit foreign
p.000064: suspected adverse reactions on a Council for International Organizations of Medical Sciences (CIOMS) I
p.000064: Form instead of a FDA Form 3500A. Reports of overall findings or pooled analyses from pub- lished
p.000064: and unpublished in vitro, ani- mal, epidemiological, or clinical stud- ies must be submitted in a
p.000064: narrative format. Each notification to FDA must bear prominent identification of its contents, i.e., ‘‘IND
p.000064: Safety Report,’’ and must be transmitted to the review division in the Center for Drug Evalua- tion and
p.000064: Research or in the Center for Biologics Evaluation and Research that has responsibility for
p.000064: review of the IND. Upon request from FDA, the sponsor must submit to FDA any addi- tional data or
p.000064: information that the agency deems necessary, as soon as possible, but in no case later than 15
p.000064: calendar days after receiving the re- quest.
p.000064: (2) Unexpected fatal or life-threatening
p.000064: suspected adverse reaction reports. The sponsor must also notify FDA of any
p.000064:
p.000064:
p.000064:
p.000064:
p.000064:
p.000064:
p.000064:
p.000064: Food and Drug Administration, HHS § 312.33
p.000064:
p.000064:
p.000064: unexpected fatal or life-threatening suspected adverse reaction as soon as possible but in no case later
p.000064: than 7 cal- endar days after the sponsor’s initial receipt of the information.
p.000064: (3) Reporting format or frequency. FDA may require a sponsor to submit IND safety reports in a format or
p.000064: at a fre- quency different than that required under this paragraph. The sponsor may also propose and adopt
p.000064: a different re- porting format or frequency if the change is agreed to in advance by the director
p.000064: of the FDA review division that has responsibility for review of the IND.
p.000064: (4) Investigations of marketed drugs. A sponsor of a clinical study of a drug marketed or approved in
p.000064: the United States that is conducted under an IND is required to submit IND safety re- ports for
p.000064: suspected adverse reactions that are observed in the clinical study, at domestic or foreign study sites. The
p.000064: sponsor must also submit safety infor- mation from the clinical study as pre- scribed by the postmarketing
p.000064: safety re- porting requirements (e.g., §§ 310.305, 314.80, and 600.80 of this chapter).
p.000064: (5) Reporting study endpoints. Study endpoints (e.g., mortality or major morbidity) must be reported to
p.000064: FDA by the sponsor as described in the protocol
p.000064: and ordinarily would not be reported under paragraph (c) of this section. However, if a serious and
p.000064: unexpected adverse event occurs for which there is evidence suggesting a causal relation- ship between the drug
p.000064: and the event (e.g., death from anaphylaxis), the event must be reported under
p.000064: § 312.32(c)(1)(i) as a serious and unex- pected suspected adverse reaction even if it is a component of
p.000064: the study end- point (e.g., all-cause mortality).
p.000064: (d) Follo up. (1) The sponsor must promptly investigate all safety infor- mation it receives.
p.000064: (2) Relevant followup information to an IND safety report must be sub- mitted as soon as the
p.000064: information is available and must be identified as such, i.e., ‘‘Followup IND Safety Re- port.’’
p.000064: (3) If the results of a sponsor’s inves- tigation show that an adverse event not initially determined to
p.000064: be report- able under paragraph (c) of this section is so reportable, the sponsor must re-
p.000065: 65
p.000065:
p.000065: port such suspected adverse reaction in an IND safety report as soon as pos- sible, but in no case later
p.000065: than 15 cal- endar days after the determination is made.
p.000065: (e) Disclaimer. A safety report or other information submitted by a spon- sor under this part (and any
p.000065: release by FDA of that report or information) does not necessarily reflect a conclu- sion by the sponsor
p.000065: or FDA that the re- port or information constitutes an ad- mission that the drug caused or con- tributed to
p.000065: an adverse event. A sponsor need not admit, and may deny, that the report or information submitted by the
p.000065: sponsor constitutes an admission that the drug caused or contributed to an adverse event.
p.000065: [75 FR 59961, Sept. 29, 2010]
p.000065: § 312.33 Annual reports.
p.000065: A sponsor shall within 60 days of the anniversary date that the IND went into effect, submit a brief
p.000065: report of the progress of the investigation that in- cludes:
p.000065: (a) Individual study information. A brief summary of the status of each study in progress and each
p.000065: study com- pleted during the previous year. The summary is required to include the fol- lowing information for
p.000065: each study:
p.000065: (1) The title of the study (with any appropriate study identifiers such as protocol number), its
p.000065: purpose, a brief statement identifying the patient pop- ulation, and a statement as to whether the study is
p.000065: completed.
p.000065: (2) The total number of subjects ini- tially planned for inclusion in the study; the number
p.000065: entered into the study to date, tabulated by age group, gender, and race; the number whose
p.000065: participation in the study was com- pleted as planned; and the number who dropped out of the study for
p.000065: any rea- son.
p.000065: (3) If the study has been completed, or if interim results are known, a brief description of any available
p.000065: study re- sults.
p.000065: (b) Summary information. Information obtained during the previous year’s clinical and nonclinical
p.000065: investigations, including:
p.000065: (1) A narrative or tabular summary showing the most frequent and most
p.000065:
p.000065:
p.000065:
p.000065:
p.000065:
p.000065:
p.000065:
p.000065:
p.000065: § 312.38
p.000065: serious adverse experiences by body system.
p.000065: (2) A summary of all IND safety re- ports submitted during the past year.
p.000065: (3) A list of subjects who died during participation in the investigation, with the cause of death for each
p.000065: subject.
p.000065: (4) A list of subjects who dropped out during the course of the investigation in association with any adverse
p.000065: experi- ence, whether or not thought to be drug related.
p.000065: (5) A brief description of what, if any- thing, was obtained that is pertinent to an understanding of the drug’s
p.000065: actions, including, for example, information about dose response, information from controlled trials,
p.000065: and information about bioavailability.
p.000065: (6) A list of the preclinical studies (including animal studies) completed or in progress during the past
p.000065: year and a summary of the major preclinical findings.
p.000065: (7) A summary of any significant manufacturing or microbiological changes made during the past
p.000065: year.
p.000065: (c) A description of the general inves- tigational plan for the coming year to replace that submitted 1 year
p.000065: earlier. The general investigational plan shall contain the information required under
p.000065: § 312.23(a)(3)(iv).
p.000065: (d) If the investigator brochure has been revised, a description of the revi- sion and a copy of the new
p.000065: brochure.
p.000065: (e) A description of any significant Phase 1 protocol modifications made during the previous year and
p.000065: not pre- viously reported to the IND in a pro- tocol amendment.
p.000065: (f) A brief summary of significant foreign marketing developments with the drug during the past year,
p.000065: such as approval of marketing in any country or withdrawal or suspension from mar- keting in any country.
p.000065: (g) If desired by the sponsor, a log of any outstanding business with respect to the IND for which the
p.000065: sponsor re- quests or expects a reply, comment, or meeting.
p.000065: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000065: FR 23031, June 17, 1987; 63 FR 6862, Feb. 11,
p.000065: 1998; 67 FR 9585, Mar. 4, 2002]
p.000065:
p.000066: 66
p.000066: 21 CFR Ch. I (4–1–12 Edition)
p.000066: § 312.38 Withdrawal of an IND.
p.000066: (a) At any time a sponsor may with- draw an effective IND without preju- dice.
p.000066: (b) If an IND is withdrawn, FDA shall be so notified, all clinical investiga- tions conducted under the IND
p.000066: shall be ended, all current investigators noti- fied, and all stocks of the drug re- turned to the
p.000066: sponsor or otherwise dis- posed of at the request of the sponsor in accordance with § 312.59.
p.000066: (c) If an IND is withdrawn because of a safety reason, the sponsor shall promptly so inform FDA, all
p.000066: partici- pating investigators, and all reviewing Institutional Review Boards, together with the reasons for
p.000066: such withdrawal.
p.000066: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000066: FR 23031, June 17, 1987; 67 FR 9586, Mar. 4,
p.000066: 2002]
p.000066:
p.000066: Subpart C—Administrative Actions
p.000066: § 312.40 General requirements for use of an investigational new drug in a clinical investigation.
p.000066: (a) An investigational new drug may be used in a clinical investigation if the following conditions are met:
p.000066: (1) The sponsor of the investigation submits an IND for the drug to FDA; the IND is in effect under
p.000066: paragraph (b) of this section; and the sponsor com- plies with all applicable requirements in this part and
p.000066: parts 50 and 56 with re- spect to the conduct of the clinical in- vestigations; and
p.000066: (2) Each participating investigator conducts his or her investigation in compliance with the
p.000066: requirements of this part and parts 50 and 56.
p.000066: (b) An IND goes into effect:
p.000066: (1) Thirty days after FDA receives the IND, unless FDA notifies the spon- sor that the investigations
p.000066: described in the IND are subject to a clinical hold under § 312.42; or
p.000066: (2) On earlier notification by FDA that the clinical investigations in the IND may begin. FDA will
p.000066: notify the sponsor in writing of the date it re- ceives the IND.
p.000066: (c) A sponsor may ship an investiga- tional new drug to investigators named in the IND:
p.000066: (1) Thirty days after FDA receives the IND; or
p.000066:
p.000066:
p.000066:
p.000066:
p.000066:
p.000066:
p.000066:
p.000066: Food and Drug Administration, HHS § 312.42
p.000066:
p.000066:
p.000066: (2) On earlier FDA authorization to ship the drug.
p.000066: (d) An investigator may not admin- ister an investigational new drug to human subjects until the IND
p.000066: goes into effect under paragraph (b) of this sec- tion.
p.000066:
p.000066: § 312.41 Comment and advice on an IND.
p.000066: (a) FDA may at any time during the course of the investigation commu- nicate with the sponsor
p.000066: orally or in writing about deficiencies in the IND or about FDA’s need for more data or information.
p.000066: (b) On the sponsor’s request, FDA will provide advice on specific matters relating to an IND.
p.000066: Examples of such advice may include advice on the ade- quacy of technical data to support an
p.000066: investigational plan, on the design of a clinical trial, and on whether proposed investigations are likely to
p.000066: produce the data and information that is needed to meet requirements for a marketing ap- plication.
p.000066: (c) Unless the communication is ac- companied by a clinical hold order under § 312.42, FDA
p.000066: communications with a sponsor under this section are solely advisory and do not require any modification in
p.000066: the planned or ongoing clinical investigations or response to the agency.
p.000066: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000066: FR 23031, June 17, 1987; 67 FR 9586, Mar. 4,
p.000066: 2002]
p.000066:
p.000066: § 312.42 Clinical holds and requests for modification.
p.000066: (a) General. A clinical hold is an order issued by FDA to the sponsor to delay a proposed clinical
p.000066: investigation or to suspend an ongoing investigation. The clinical hold order may apply to one or more of the
p.000066: investigations covered by an IND. When a proposed study is placed on clinical hold, subjects may not
p.000066: be given the investigational drug. When an ongoing study is placed on clinical hold, no new subjects
p.000066: may be recruited to the study and placed on the investigational drug; patients al- ready in the study
p.000066: should be taken off therapy involving the investigational drug unless specifically permitted by FDA in the
p.000066: interest of patient safety.
p.000067: 67
p.000067:
p.000067: (b) Grounds for imposition of clinical hold—(1) Clinical hold of a Phase 1 study under an IND. FDA
p.000067: may place a pro- posed or ongoing Phase 1 investigation on clinical hold if it finds that:
p.000067: (i) Human subjects are or would be exposed to an unreasonable and signifi- cant risk of illness or injury;
p.000067: (ii) The clinical investigators named in the IND are not qualified by reason of their scientific training
p.000067: and experi- ence to conduct the investigation de- scribed in the IND;
p.000067: (iii) The investigator brochure is misleading, erroneous, or materially incomplete; or
p.000067: (iv) The IND does not contain suffi- cient information required under
p.000067: § 312.23 to assess the risks to subjects of the proposed studies.
p.000067: (v) The IND is for the study of an in- vestigational drug intended to treat a life-threatening disease or
p.000067: condition that affects both genders, and men or women with reproductive potential who have the
p.000067: disease or condition being studied are excluded from eligi- bility because of a risk or potential
p.000067: risk from use of the investigational drug of reproductive toxicity (i.e., af- fecting reproductive
p.000067: organs) or devel- opmental toxicity (i.e., affecting poten- tial offspring). The phrase ‘‘women with
p.000067: reproductive potential’’ does not include pregnant women. For purposes of this paragraph, ‘‘life-threatening
p.000067: ill- nesses or diseases’’ are defined as ‘‘dis- eases or conditions where the likeli- hood of death is high
p.000067: unless the course of the disease is interrupted.’’ The clin- ical hold would not apply under this paragraph to
p.000067: clinical studies con- ducted:
p.000067: (A) Under special circumstances, such as studies pertinent only to one gender (e.g., studies
p.000067: evaluating the ex- cretion of a drug in semen or the ef- fects on menstrual function);
p.000067: (B) Only in men or women, as long as a study that does not exclude members of the other gender with reproductive
p.000067: potential is being conducted concur- rently, has been conducted, or will take place within a
p.000067: reasonable time agreed upon by the agency; or
p.000067: (C) Only in subjects who do not suffer from the disease or condition for which the drug is being studied.
p.000067:
p.000067:
p.000067:
p.000067:
p.000067:
p.000067:
p.000067:
p.000067:
p.000067: § 312.42
p.000067: (2) Clinical hold of a Phase 2 or 3 study under an IND. FDA may place a pro- posed or ongoing Phase
p.000067: 2 or 3 inves- tigation on clinical hold if it finds that:
p.000067: (i) Any of the conditions in para- graphs (b)(1)(i) through (b)(1)(v) of this section apply; or
p.000067: (ii) The plan or protocol for the in- vestigation is clearly deficient in de- sign to meet its stated
p.000067: objectives.
p.000067: (3) Clinical hold of an expanded access IND or expanded access protocol. FDA may place an expanded
p.000067: access IND or expanded access protocol on clinical hold under the following conditions:
p.000067: (i) Final use. FDA may place a pro- posed expanded access IND or treat- ment use protocol on clinical
p.000067: hold if it is determined that:
p.000067: (A) The pertinent criteria in subpart I of this part for permitting the ex- panded access use to begin are
p.000067: not sat- isfied; or
p.000067: (B) The expanded access IND or ex- panded access protocol does not comply with the requirements for expanded ac-
p.000067: cess submissions in subpart I of this part.
p.000067: (ii) Ongoing use. FDA may place an ongoing expanded access IND or ex- panded access protocol on
p.000067: clinical hold if it is determined that the pertinent criteria in subpart I of this part for permitting
p.000067: the expanded access are no longer satisfied.
p.000067: (4) Clinical hold of any study that is
p.000067: not designed to be adequate and ell-con- trolled. FDA may place a proposed or ongoing investigation
p.000067: that is not de- signed to be adequate and well-con- trolled on clinical hold if it finds that:
p.000067: (i) Any of the conditions in para- graph (b)(1) or (b)(2) of this section apply; or
p.000067: (ii) There is reasonable evidence the investigation that is not designed to be adequate and well-controlled is
p.000067: imped- ing enrollment in, or otherwise inter- fering with the conduct or completion of, a study that is
p.000067: designed to be an adequate and well-controlled investiga- tion of the same or another investiga- tional drug;
p.000067: or
p.000067: (iii) Insufficient quantities of the in- vestigational drug exist to adequately conduct both the
p.000067: investigation that is not designed to be adequate and well- controlled and the investigations that
p.000068: 68
p.000068: 21 CFR Ch. I (4–1–12 Edition)
p.000068: are designed to be adequate and well- controlled; or
p.000068: (iv) The drug has been studied in one or more adequate and well-controlled investigations that strongly
p.000068: suggest lack of effectiveness; or
p.000068: (v) Another drug under investigation or approved for the same indication and available to the same
p.000068: patient popu- lation has demonstrated a better po- tential benefit/risk balance; or
p.000068: (vi) The drug has received marketing approval for the same indication in the same patient population; or
p.000068: (vii) The sponsor of the study that is designed to be an adequate and well- controlled investigation is not
p.000068: actively pursuing marketing approval of the in- vestigational drug with due diligence; or
p.000068: (viii) The Commissioner determines that it would not be in the public inter- est for the study to be conducted
p.000068: or continued. FDA ordinarily intends that clinical holds under paragraphs (b)(4)(ii), (b)(4)(iii) and
p.000068: (b)(4)(v) of this section would only apply to additional enrollment in nonconcurrently con- trolled
p.000068: trials rather than eliminating continued access to individuals already receiving the investigational drug.
p.000068: (5) Clinical hold of any investigation in-
p.000068: volving an exception from informed con- sent under § 50.24 of this chapter. FDA may place a proposed
p.000068: or ongoing inves- tigation involving an exception from informed consent under § 50.24 of this chapter on
p.000068: clinical hold if it is deter- mined that:
p.000068: (i) Any of the conditions in para- graphs (b)(1) or (b)(2) of this section apply; or
p.000068: (ii) The pertinent criteria in § 50.24 of this chapter for such an investigation to begin or continue are not
p.000068: submitted or not satisfied.
p.000068: (6) Clinical hold of any investigation involving an exception from informed consent under § 50.23(d) of
p.000068: this chapter. FDA may place a proposed or ongoing investigation involving an exception from informed
p.000068: consent under § 50.23(d) of this chapter on clinical hold if it is determined that:
p.000068: (i) Any of the conditions in para- graphs (b)(1) or (b)(2) of this section apply; or
p.000068: (ii) A determination by the President to waive the prior consent requirement
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068: Food and Drug Administration, HHS § 312.44
p.000068:
p.000068:
p.000068: for the administration of an investiga- tional new drug has not been made.
p.000068: (c) Discussion of deficiency. Whenever FDA concludes that a deficiency exists in a clinical investigation that
p.000068: may be grounds for the imposition of clinical hold FDA will, unless patients are ex- posed to immediate
p.000068: and serious risk, attempt to discuss and satisfactorily resolve the matter with the sponsor be- fore issuing
p.000068: the clinical hold order.
p.000068: (d) Imposition of clinical hold. The clinical hold order may be made by telephone or other
p.000068: means of rapid com- munication or in writing. The clinical hold order will identify the studies under
p.000068: the IND to which the hold ap- plies, and will briefly explain the basis for the action. The clinical
p.000068: hold order will be made by or on behalf of the Di- vision Director with responsibility for review of the IND.
p.000068: As soon as possible, and no more than 30 days after imposi- tion of the clinical hold, the Division Director
p.000068: will provide the sponsor a written explanation of the basis for the hold.
p.000068: (e) Resumption of clinical investiga- tions. An investigation may only re- sume after FDA
p.000068: (usually the Division Director, or the Director’s designee, with responsibility for review of the
p.000068: IND) has notified the sponsor that the investigation may proceed. Resump- tion of the affected
p.000068: investigation(s) will be authorized when the sponsor corrects the deficiency(ies) previously cited or
p.000068: otherwise satisfies the agency that the investigation(s) can proceed. FDA may notify a sponsor of its deter-
...
p.000068: complete re- sponse to the issue(s) identified in the clinical hold order, FDA shall respond in writing to
p.000068: the sponsor within 30-cal- endar days of receipt of the request and the complete response. FDA’s response will
p.000068: either remove or maintain the clinical hold, and will state the reasons for such determination.
p.000068: Notwith- standing the 30-calendar day response time, a sponsor may not proceed with a clinical trial on which a
p.000068: clinical hold has been imposed until the sponsor has
p.000069: 69
p.000069:
p.000069: been notified by FDA that the hold has been lifted.
p.000069: (f) Appeal. If the sponsor disagrees with the reasons cited for the clinical hold, the sponsor may
p.000069: request recon- sideration of the decision in accord- ance with § 312.48.
p.000069: (g) Conversion of IND on clinical hold to inactive status. If all investigations covered by an IND
p.000069: remain on clinical hold for 1 year or more, the IND may be placed on inactive status by FDA under §
p.000069: 312.45.
p.000069: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000069: FR 19477, May 22, 1987; 57 FR 13249, Apr. 15,
p.000069: 1992; 61 FR 51530, Oct. 2, 1996; 63 FR 68678,
p.000069: Dec. 14, 1998; 64 FR 54189, Oct. 5, 1999; 65 FR
p.000069: 34971, June 1, 2000; 74 FR 40942, Aug. 13, 2009]
p.000069:
p.000069: § 312.44 Termination.
p.000069: (a) General. This section describes the procedures under which FDA may ter- minate an IND. If an IND
p.000069: is termi- nated, the sponsor shall end all clinical investigations conducted under the IND and recall or
p.000069: otherwise provide for the disposition of all unused supplies of the drug. A termination action may be based on
p.000069: deficiencies in the IND or in the conduct of an investigation under an IND. Except as provided in
p.000069: para- graph (d) of this section, a termination shall be preceded by a proposal to ter- minate by FDA and an
p.000069: opportunity for the sponsor to respond. FDA will, in general, only initiate an action under this section
p.000069: after first attempting to resolve differences informally or, when appropriate, through the clinical hold
p.000069: procedures described in § 312.42.
p.000069: (b) Grounds for termination—(1) Phase
p.000069: 1. FDA may propose to terminate an IND during Phase 1 if it finds that:
p.000069: (i) Human subjects would be exposed to an unreasonable and significant risk of illness or unjury.
p.000069: (ii) The IND does not contain suffi- cient information required under
p.000069: § 312.23 to assess the safety to subjects of the clinical investigations.
p.000069: (iii) The methods, facilities, and con- trols used for the manufacturing, proc- essing, and packing of the
p.000069: investiga- tional drug are inadequate to establish and maintain appropriate standards of identity, strength,
p.000069: quality, and purity as needed for subject safety.
p.000069:
p.000069:
p.000069:
p.000069:
p.000069:
p.000069:
p.000069:
p.000069:
p.000069: § 312.45
p.000069: (iv) The clinical investigations are being conducted in a manner substan- tially different than that
p.000069: described in the protocols submitted in the IND.
p.000069: (v) The drug is being promoted or dis- tributed for commercial purposes not justified by the requirements of the
p.000069: in- vestigation or permitted by § 312.7.
p.000069: (vi) The IND, or any amendment or report to the IND, contains an untrue statement of a material fact
p.000069: or omits material information required by this part.
p.000069: (vii) The sponsor fails promptly to in- vestigate and inform the Food and Drug Administration and all
p.000069: investiga- tors of serious and unexpected adverse experiences in accordance with § 312.32 or fails to make
p.000069: any other report re- quired under this part.
p.000069: (viii) The sponsor fails to submit an accurate annual report of the inves- tigations in accordance with
p.000069: § 312.33.
p.000069: (ix) The sponsor fails to comply with any other applicable requirement of this part, part 50, or part 56.
p.000069: (x) The IND has remained on inactive status for 5 years or more.
p.000069: (xi) The sponsor fails to delay a pro- posed investigation under the IND or to suspend an ongoing
p.000069: investigation that has been placed on clinical hold under § 312.42(b)(4).
p.000069: (2) Phase 2 or 3. FDA may propose to terminate an IND during Phase 2 or Phase 3 if FDA finds that:
p.000069: (i) Any of the conditions in para- graphs (b)(1)(i) through (b)(1)(xi) of this section apply; or
p.000069: (ii) The investigational plan or pro- tocol(s) is not reasonable as a bona fide scientific plan to determine
p.000069: whether or not the drug is safe and effective for use; or
p.000069: (iii) There is convincing evidence that the drug is not effective for the purpose for which it
p.000069: is being inves- tigated.
p.000069: (3) FDA may propose to terminate a treatment IND if it finds that:
p.000069: (i) Any of the conditions in para- graphs (b)(1)(i) through (x) of this sec- tion apply; or
p.000069: (ii) Any of the conditions in
p.000069: § 312.42(b)(3) apply.
p.000069: (c) Opportunity for sponsor response.
p.000069: (1) If FDA proposes to terminate an IND, FDA will notify the sponsor in
p.000069:
p.000070: 70
p.000070: 21 CFR Ch. I (4–1–12 Edition)
p.000070: writing, and invite correction or expla- nation within a period of 30 days.
p.000070: (2) On such notification, the sponsor may provide a written explanation or correction or may request a
p.000070: conference with FDA to provide the requested ex- planation or correction. If the sponsor does not
p.000070: respond to the notification within the allocated time, the IND shall be terminated.
p.000070: (3) If the sponsor responds but FDA
p.000070: does not accept the explanation or cor- rection submitted, FDA shall inform the sponsor in writing of the
p.000070: reason for the nonacceptance and provide the sponsor with an opportunity for a regu- latory hearing
p.000070: before FDA under part 16 on the question of whether the IND should be terminated. The sponsor’s re- quest
p.000070: for a regulatory hearing must be made within 10 days of the sponsor’s receipt of FDA’s notification of
p.000070: non- acceptance.
p.000070: (d) Immediate termination of IND. Not-
p.000070: withstanding paragraphs (a) through
p.000070: (c) of this section, if at any time FDA concludes that continuation of the in- vestigation presents an
p.000070: immediate and substantial danger to the health of in- dividuals, the agency shall imme- diately, by
p.000070: written notice to the spon- sor from the Director of the Center for Drug Evaluation and Research or the
p.000070: Director of the Center for Biologics Evaluation and Research, terminate the IND. An IND so
p.000070: terminated is sub- ject to reinstatement by the Director on the basis of additional submissions that
p.000070: eliminate such danger. If an IND is terminated under this paragraph, the agency will afford the sponsor an
p.000070: op- portunity for a regulatory hearing under part 16 on the question of wheth- er the IND should be
p.000070: reinstated.
p.000070: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000070: FR 23031, June 17, 1987; 55 FR 11579, Mar. 29,
p.000070: 1990; 57 FR 13249, Apr. 15, 1992; 67 FR 9586,
p.000070: Mar. 4, 2002]
p.000070: § 312.45 Inactive status.
p.000070: (a) If no subjects are entered into clinical studies for a period of 2 years or more under an
p.000070: IND, or if all inves- tigations under an IND remain on clin- ical hold for 1 year or more, the IND may be
p.000070: placed by FDA on inactive sta- tus. This action may be taken by FDA either on request of the sponsor or
p.000070: on FDA’s own initiative. If FDA seeks to
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070:
p.000070: Food and Drug Administration, HHS § 312.47
p.000070:
p.000070:
p.000070: act on its own initiative under this sec- tion, it shall first notify the sponsor in writing of the proposed inactive
p.000070: status. Upon receipt of such notification, the sponsor shall have 30 days to respond as to why the IND
p.000070: should continue to remain active.
p.000070: (b) If an IND is placed on inactive status, all investigators shall be so no- tified and all stocks of the
p.000070: drug shall be returned or otherwise disposed of in accordance with § 312.59.
p.000070: (c) A sponsor is not required to sub- mit annual reports to an IND on inac- tive status. An inactive
p.000070: IND is, how- ever, still in effect for purposes of the public disclosure of data and informa- tion under
p.000070: § 312.130.
p.000070: (d) A sponsor who intends to resume clinical investigation under an IND placed on inactive status
p.000070: shall submit a protocol amendment under § 312.30 containing the proposed general inves- tigational plan
p.000070: for the coming year and appropriate protocols. If the protocol amendment relies on information pre- viously
p.000070: submitted, the plan shall ref- erence such information. Additional in- formation supporting the proposed in-
p.000070: vestigation, if any, shall be submitted in an information amendment. Not- withstanding the provisions
p.000070: of § 312.30, clinical investigations under an IND on inactive status may only resume (1) 30 days after FDA
p.000070: receives the protocol amendment, unless FDA notifies the sponsor that the investigations de- scribed
p.000070: in the amendment are subject to a clinical hold under § 312.42, or (2) on earlier notification by FDA that
p.000070: the clinical investigations described in the protocol amendment may begin.
p.000070: (e) An IND that remains on inactive
p.000070: status for 5 years or more may be ter- minated under § 312.44.
p.000070: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000070: FR 23031, June 17, 1987; 67 FR 9586, Mar. 4,
p.000070: 2002]
p.000070: § 312.47 Meetings.
p.000070: (a) General. Meetings between a spon- sor and the agency are frequently use- ful in resolving questions
p.000070: and issues raised during the course of a clinical investigation. FDA encourages such meetings to the
p.000070: extent that they aid in the evaluation of the drug and in the solution of scientific problems con-
p.000070: cerning the drug, to the extent that
p.000070:
p.000071: 71
p.000071:
p.000071: FDA’s resources permit. The general principle underlying the conduct of such meetings is that there
p.000071: should be free, full, and open communication about any scientific or medical ques- tion that may arise
p.000071: during the clinical investigation. These meetings shall be conducted and documented in accord- ance with part
p.000071: 10.
p.000071: (b) ‘‘End-of-Phase 2’’ meetings and
p.000071: meetings held before submission of a mar- keting application. At specific times during the drug
p.000071: investigation process, meetings between FDA and a sponsor can be especially helpful in minimizing wasteful
p.000071: expenditures of time and money and thus in speeding the drug development and evaluation process. In
p.000071: particular, FDA has found that meet- ings at the end of Phase 2 of an inves- tigation (end-of-Phase 2
p.000071: meetings) are of considerable assistance in planning later studies and that meetings held near completion
p.000071: of Phase 3 and before submission of a marketing application (‘‘pre-NDA’’ meetings) are helpful in
p.000071: developing methods of presentation and submission of data in the mar- keting application that
p.000071: facilitate re- view and allow timely FDA response.
p.000071: (1) End-of-Phase 2 meetings—(i) Pur-
p.000071: pose. The purpose of an end-of-phase 2 meeting is to determine the safety of proceeding to Phase 3, to
p.000071: evaluate the Phase 3 plan and protocols and the ade- quacy of current studies and plans to assess pediatric
p.000071: safety and effective- ness, and to identify any additional in- formation necessary to support a mar- keting
p.000071: application for the uses under investigation.
p.000071: (ii) Eligibility for meeting. While the end-of-Phase 2 meeting is designed pri- marily for IND’s involving
p.000071: new molec- ular entities or major new uses of mar- keted drugs, a sponsor of any IND may request and obtain an
p.000071: end-of-Phase 2 meeting.
p.000071: (iii) Timing. To be most useful to the sponsor, end-of-Phase 2 meetings should be held before
p.000071: major commit- ments of effort and resources to spe- cific Phase 3 tests are made. The sched- uling of an
p.000071: end-of-Phase 2 meeting is not, however, intended to delay the transition of an investigation from
p.000071: Phase 2 to Phase 3.
p.000071: (iv) Advance information. At least 1 month in advance of an end-of-Phase 2
p.000071:
p.000071:
p.000071:
p.000071:
p.000071:
p.000071:
p.000071:
p.000071:
p.000071: § 312.48
p.000071: meeting, the sponsor should submit background information on the spon- sor’s plan for Phase 3,
p.000071: including sum- maries of the Phase 1 and 2 investiga- tions, the specific protocols for Phase 3 clinical
p.000071: studies, plans for any addi- tional nonclinical studies, plans for pe- diatric studies, including a time
p.000071: line for protocol finalization, enrollment, completion, and data analysis, or infor- mation to support any
p.000071: planned request for waiver or deferral of pediatric stud- ies, and, if available, tentative labeling for the drug.
p.000071: The recommended con- tents of such a submission are de- scribed more fully in FDA Staff Man- ual
p.000071: Guide 4850.7 that is publicly avail- able under FDA’s public information regulations in part 20.
p.000071: (v) Conduct of meeting. Arrangements for an end-of-Phase 2 meeting are to be made with the division in FDA’s Center
p.000071: for Drug Evaluation and Research or the Center for Biologics Evaluation and Research which is
p.000071: responsible for review of the IND. The meeting will be scheduled by FDA at a time convenient to both FDA and the
p.000071: sponsor. Both the sponsor and FDA may bring consult- ants to the meeting. The meeting should be
p.000071: directed primarily at estab- lishing agreement between FDA and the sponsor of the overall plan
p.000071: for Phase 3 and the objectives and design of particular studies. The adequacy of the technical
p.000071: information to support Phase 3 studies and/or a marketing ap- plication may also be discussed. FDA will
p.000071: also provide its best judgment, at that time, of the pediatric studies that will be required for the drug
p.000071: product and whether their submission will be deferred until after approval. Agree- ments reached at the
p.000071: meeting on these matters will be recorded in minutes of the conference that will be taken by FDA in
p.000071: accordance with § 10.65 and pro- vided to the sponsor. The minutes along with any other written material
p.000071: provided to the sponsor will serve as a permanent record of any agreements reached. Barring a
p.000071: significant sci- entific development that requires oth- erwise, studies conducted in accord- ance with
p.000071: the agreement shall be pre- sumed to be sufficient in objective and design for the purpose of
p.000071: obtaining marketing approval for the drug.
p.000072: 72
p.000072: 21 CFR Ch. I (4–1–12 Edition)
p.000072: (2) ‘‘Pre-NDA’’ and ‘‘pre-BLA’’ meet- ings. FDA has found that delays associ- ated with the initial review
p.000072: of a mar- keting application may be reduced by exchanges of information about a pro- posed marketing
p.000072: application. The pri- mary purpose of this kind of exchange is to uncover any major unresolved
p.000072: problems, to identify those studies that the sponsor is relying on as adequate and well-controlled to
p.000072: establish the drug’s effectiveness, to identify the status of ongoing or needed studies adequate to
p.000072: assess pediatric safety and effectiveness, to acquaint FDA review- ers with the general information to be
p.000072: submitted in the marketing applica- tion (including technical information), to discuss appropriate methods
p.000072: for sta- tistical analysis of the data, and to dis- cuss the best approach to the presen- tation and formatting
p.000072: of data in the marketing application. Arrangements for such a meeting are to be initiated by the
p.000072: sponsor with the division re- sponsible for review of the IND. To per- mit FDA to provide the sponsor
p.000072: with the most useful advice on preparing a marketing application, the sponsor should submit to FDA’s
p.000072: reviewing divi- sion at least 1 month in advance of the meeting the following information:
p.000072: (i) A brief summary of the clinical studies to be submitted in the applica- tion.
p.000072: (ii) A proposed format for organizing the submission, including methods for presenting the data.
p.000072: (iii) Information on the status of needed or ongoing pediatric studies.
p.000072: (iv) Any other information for discus- sion at the meeting.
p.000072: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000072: FR 23031, June 17, 1987; 55 FR 11580, Mar. 29,
p.000072: 1990; 63 FR 66669, Dec. 2, 1998; 67 FR 9586, Mar.
p.000072: 4, 2002]
p.000072: § 312.48 Dispute resolution.
p.000072: (a) General. The Food and Drug Ad- ministration is committed to resolving differences between sponsors and
p.000072: FDA reviewing divisions with respect to re- quirements for IND’s as quickly and amicably as possible
p.000072: through the coop- erative exchange of information and views.
p.000072: (b) Administrative and procedural issues. When administrative or proce- dural disputes arise, the
p.000072: sponsor should
p.000072:
p.000072:
p.000072:
p.000072:
p.000072:
p.000072:
p.000072:
p.000072: Food and Drug Administration, HHS § 312.52
p.000072:
p.000072:
p.000072: first attempt to resolve the matter with the division in FDA’s Center for Drug Evaluation and
p.000072: Research or Cen- ter for Biologics Evaluation and Re- search which is responsible for review of the
p.000072: IND, beginning with the con- sumer safety officer assigned to the ap- plication. If the dispute is not
p.000072: resolved, the sponsor may raise the matter with the person designated as ombudsman, whose function shall
p.000072: be to investigate what has happened and to facilitate a timely and equitable resolution. Appro- priate issues
p.000072: to raise with the ombuds- man include resolving difficulties in scheduling meetings and obtaining
p.000072: timely replies to inquiries. Further de- tails on this procedure are contained in FDA Staff Manual Guide 4820.7
p.000072: that is publicly available under FDA’s public information regulations in part 20.
p.000072: (c) Scientific and medical disputes. (1)
p.000072: When scientific or medical disputes arise during the drug investigation process, sponsors should
p.000072: discuss the matter directly with the responsible reviewing officials. If necessary, spon- sors may
p.000072: request a meeting with the appropriate reviewing officials and management representatives in order
p.000072: to seek a resolution. Requests for such meetings shall be directed to the direc- tor of the division in
p.000072: FDA’s Center for Drug Evaluation and Research or Cen- ter for Biologics Evaluation and Re- search
p.000072: which is responsible for review of the IND. FDA will make every at- tempt to grant requests for
p.000072: meetings that involve important issues and that can be scheduled at mutually conven- ient times.
p.000072: (2) The ‘‘end-of-Phase 2’’ and ‘‘pre-
p.000072: NDA’’ meetings described in § 312.47(b) will also provide a timely forum for discussing and resolving
p.000072: scientific and medical issues on which the sponsor disagrees with the agency.
p.000072: (3) In requesting a meeting designed to resolve a scientific or medical dis- pute, applicants may suggest
p.000072: that FDA seek the advice of outside experts, in which case FDA may, in its discretion, invite to the meeting one
p.000072: or more of its advisory committee members or other consultants, as designated by the agen- cy. Applicants may
p.000072: rely on, and may bring to any meeting, their own con- sultants. For major scientific and med- ical policy
p.000072: issues not resolved by infor-
p.000073: 73
p.000073:
p.000073: mal meetings, FDA may refer the mat- ter to one of its standing advisory com- mittees for its consideration and
p.000073: rec- ommendations.
p.000073: [52 FR 8831, Mar. 19, 1987, as amended at 55
p.000073: FR 11580, Mar. 29, 1990]
p.000073:
p.000073: Subpart D—Responsibilities of Sponsors and Investigators
p.000073: § 312.50 General responsibilities of sponsors.
p.000073: Sponsors are responsibile for select- ing qualified investigators, providing them with the information
p.000073: they need to conduct an investigation properly, ensuring proper monitoring of the in- vestigation(s),
p.000073: ensuring that the inves- tigation(s) is conducted in accordance with the general investigational plan and
p.000073: protocols contained in the IND, maintaining an effective IND with re- spect to the investigations, and
p.000073: ensur- ing that FDA and all participating in- vestigators are promptly informed of significant new adverse
p.000073: effects or risks with respect to the drug. Additional specific responsibilities of sponsors are described
p.000073: elsewhere in this part.
p.000073: § 312.52 Transfer of obligations to a contract research organization.
p.000073: (a) A sponsor may transfer responsi- bility for any or all of the obligations set forth in this part
p.000073: to a contract re- search organization. Any such transfer shall be described in writing. If not all
p.000073: obligations are transferred, the writing is required to describe each of the obli- gations being assumed by the
p.000073: contract research organization. If all obligations are transferred, a general statement that all obligations
p.000073: have been trans- ferred is acceptable. Any obligation not covered by the written description shall be
p.000073: deemed not to have been trans- ferred.
p.000073: (b) A contract research organization that assumes any obligation of a spon- sor shall comply with the
p.000073: specific regu- lations in this chapter applicable to this obligation and shall be subject to the same
p.000073: regulatory action as a spon- sor for failure to comply with any obli- gation assumed under these regula-
p.000073: tions. Thus, all references to ‘‘sponsor’’ in this part apply to a contract re- search organization to
p.000073: the extent that
p.000073:
p.000073:
p.000073:
p.000073:
p.000073:
p.000073:
p.000073:
p.000073:
p.000073: § 312.53
p.000073: it assumes one or more obligations of the sponsor.
p.000073: § 312.53 Selecting investigators and monitors.
p.000073: (a) Selecting investigators. A sponsor shall select only investigators qualified by training and experience
p.000073: as appro- priate experts to investigate the drug.
p.000073: (b) Control of drug. A sponsor shall ship investigational new drugs only to investigators participating
p.000073: in the in- vestigation.
p.000073: (c) Obtaining information from the in- vestigator. Before permitting an investi- gator to begin participation
p.000073: in an in- vestigation, the sponsor shall obtain the following:
p.000073: (1) A signed investigator statement (Form FDA–1572) containing:
p.000073: (i) The name and address of the in- vestigator;
p.000073: (ii) The name and code number, if any, of the protocol(s) in the IND iden- tifying the study(ies) to be
p.000073: conducted by the investigator;
p.000073: (iii) The name and address of any medical school, hospital, or other re- search facility where the
p.000073: clinical inves- tigation(s) will be conducted;
p.000073: (iv) The name and address of any clinical laboratory facilities to be used in the study;
p.000073: (v) The name and address of the IRB that is responsible for review and ap- proval of the study(ies);
p.000073: (vi) A commitment by the investi- gator that he or she:
p.000073: (a) Will conduct the study(ies) in ac- cordance with the relevant, current protocol(s) and will only make
p.000073: changes in a protocol after notifying the spon- sor, except when necessary to protect the safety, the
p.000073: rights, or welfare of subjects;
p.000073: (b) Will comply with all requirements regarding the obligations of clinical in- vestigators and all other pertinent
p.000073: re- quirements in this part;
p.000073: (c) Will personally conduct or super- vise the described investigation(s);
p.000073: (d) Will inform any potential subjects that the drugs are being used for inves- tigational purposes and will
p.000073: ensure that the requirements relating to ob- taining informed consent (21 CFR part
p.000073: 50) and institutional review board re- view and approval (21 CFR part 56) are met;
p.000074: 74
p.000074: 21 CFR Ch. I (4–1–12 Edition)
p.000074: (e) Will report to the sponsor adverse experiences that occur in the course of the investigation(s) in accordance with
p.000074: § 312.64;
p.000074: (f) Has read and understands the in- formation in the investigator’s bro- chure, including the
p.000074: potential risks and side effects of the drug; and
p.000074: (g) Will ensure that all associates, colleagues, and employees assisting in the conduct of the
p.000074: study(ies) are in- formed about their obligations in meeting the above commitments.
p.000074: (vii) A commitment by the investi- gator that, for an investigation subject to an institutional review
p.000074: requirement under part 56, an IRB that complies with the requirements of that part will be responsible for the
p.000074: initial and con- tinuing review and approval of the clin- ical investigation and that the investi- gator will
p.000074: promptly report to the IRB all changes in the research activity and all unanticipated problems involving
p.000074: risks to human subjects or others, and will not make any changes in the re- search without IRB
p.000074: approval, except where necessary to eliminate apparent immediate hazards to the human sub- jects.
p.000074: (viii) A list of the names of the sub-
p.000074: investigators (e.g., research fellows, residents) who will be assisting the in- vestigator in the
p.000074: conduct of the inves- tigation(s).
p.000074: (2) Curriculum vitae. A curriculum vitae or other statement of qualifica- tions of the investigator
p.000074: showing the education, training, and experience that qualifies the investigator as an ex- pert in the
p.000074: clinical investigation of the drug for the use under investigation.
p.000074: (3) Clinical protocol. (i) For Phase 1 in- vestigations, a general outline of the planned investigation including
p.000074: the es- timated duration of the study and the maximum number of subjects that will be involved.
p.000074: (ii) For Phase 2 or 3 investigations, an outline of the study protocol includ- ing an approximation of the number
p.000074: of subjects to be treated with the drug and the number to be employed as con- trols, if any; the clinical
p.000074: uses to be in- vestigated; characteristics of subjects by age, sex, and condition; the kind of clinical
p.000074: observations and laboratory tests to be conducted; the estimated duration of the study; and copies or a
p.000074:
p.000074:
p.000074:
p.000074:
p.000074:
p.000074:
p.000074:
p.000074: Food and Drug Administration, HHS § 312.56
p.000074:
p.000074:
p.000074: description of case report forms to be used.
p.000074: (4) Financial disclosure information. Sufficient accurate financial informa- tion to allow the
p.000074: sponsor to submit complete and accurate certification or disclosure statements required under part 54
p.000074: of this chapter. The sponsor shall obtain a commitment from the clinical investigator to promptly
p.000074: up- date this information if any relevant changes occur during the course of the investigation and for 1
p.000074: year following the completion of the study.
p.000074: (d) Selecting monitors. A sponsor shall select a monitor qualified by training and experience to monitor the
p.000074: progress of the investigation.
p.000074: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000074: FR 23031, June 17, 1987; 61 FR 57280, Nov. 5,
p.000074: 1996; 63 FR 5252, Feb. 2, 1998; 67 FR 9586, Mar.
p.000074: 4, 2002]
p.000074:
p.000074: § 312.54 Emergency research under
p.000074: § 50.24 of this chapter.
p.000074: (a) The sponsor shall monitor the progress of all investigations involving an exception from informed
p.000074: consent under § 50.24 of this chapter. When the sponsor receives from the IRB informa- tion concerning the
p.000074: public disclosures required by § 50.24(a)(7)(ii) and (a)(7)(iii) of this chapter, the sponsor promptly shall
p.000074: submit to the IND file and to Docket Number 95S–0158 in the Divi- sion of Dockets Management
p.000074: (HFA– 305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852, copies
p.000074: of the information that was disclosed, identified by the IND number.
p.000074: (b) The sponsor also shall monitor such investigations to identify when an IRB determines that it cannot
p.000074: approve the research because it does not meet the criteria in the exception in
p.000074: § 50.24(a) of this chapter or because of other relevant ethical concerns. The sponsor promptly shall
p.000074: provide this in- formation in writing to FDA, inves- tigators who are asked to participate in this
p.000074: or a substantially equivalent clinical investigation, and other IRB’s that are asked to review this or
p.000074: a sub- stantially equivalent investigation.
p.000074: [61 FR 51530, Oct. 2, 1996, as amended at 68 FR
p.000074: 24879, May 9, 2003]
p.000074:
p.000075: 75
p.000075:
p.000075: § 312.55 Informing investigators.
p.000075: (a) Before the investigation begins, a sponsor (other than a sponsor-investi- gator) shall give each
p.000075: participating clinical investigator an investigator brochure containing the information described in §
p.000075: 312.23(a)(5).
p.000075: (b) The sponsor shall, as the overall investigation proceeds, keep each par- ticipating investigator informed
p.000075: of new observations discovered by or reported to the sponsor on the drug, particu- larly with respect
p.000075: to adverse effects and safe use. Such information may be distributed to investigators by means of
p.000075: periodically revised investigator brochures, reprints or published stud- ies, reports or letters to
p.000075: clinical inves- tigators, or other appropriate means. Important safety information is re- quired to be
p.000075: relayed to investigators in accordance with § 312.32.
p.000075: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000075: FR 23031, June 17, 1987; 67 FR 9586, Mar. 4,
p.000075: 2002]
p.000075:
p.000075: § 312.56 Review of ongoing investiga- tions.
p.000075: (a) The sponsor shall monitor the progress of all clinical investigations being conducted under its IND.
p.000075: (b) A sponsor who discovers that an investigator is not complying with the signed agreement (Form FDA–1572),
p.000075: the general investigational plan, or the re- quirements of this part or other appli- cable parts shall
p.000075: promptly either se- cure compliance or discontinue ship- ments of the investigational new drug to the
p.000075: investigator and end the inves- tigator’s participation in the investiga- tion. If the investigator’s participation
p.000075: in the investigation is ended, the spon- sor shall require that the investigator dispose of or return the
p.000075: investigational drug in accordance with the require- ments of § 312.59 and shall notify FDA.
p.000075: (c) The sponsor shall review and evaluate the evidence relating to the safety and effectiveness of
p.000075: the drug as it is obtained from the investigator. The sponsors shall make such reports to FDA
p.000075: regarding information relevant to the safety of the drug as are re- quired under § 312.32. The sponsor
p.000075: shall make annual reports on the progress of the investigation in accordance with
p.000075: § 312.33.
p.000075:
p.000075:
p.000075:
p.000075:
p.000075:
p.000075:
p.000075:
p.000075:
p.000075: § 312.57
p.000075: (d) A sponsor who determines that its investigational drug presents an unrea- sonable and significant risk to subjects
p.000075: shall discontinue those investigations that present the risk, notify FDA, all institutional review boards,
p.000075: and all in- vestigators who have at any time par- ticipated in the investigation of the
p.000075: discontinuance, assure the disposition of all stocks of the drug outstanding as required by § 312.59, and
p.000075: furnish FDA with a full report of the sponsor’s ac- tions. The sponsor shall discontinue the
p.000075: investigation as soon as possible, and in no event later than 5 working days after making the
p.000075: determination that the investigation should be dis- continued. Upon request, FDA will con- fer with a sponsor
p.000075: on the need to dis- continue an investigation.
p.000075: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000075: FR 23031, June 17, 1987; 67 FR 9586, Mar. 4,
p.000075: 2002]
p.000075:
p.000075: § 312.57 Recordkeeping and record re- tention.
p.000075: (a) A sponsor shall maintain ade- quate records showing the receipt, shipment, or other
p.000075: disposition of the investigational drug. These records are required to include, as appropriate, the name of the
p.000075: investigator to whom the drug is shipped, and the date, quantity, and batch or code mark of each such
p.000075: shipment.
p.000075: (b) A sponsor shall maintain com- plete and accurate records showing any financial interest in §
p.000075: 54.4(a)(3)(i), (a)(3)(ii), (a)(3)(iii), and (a)(3)(iv) of this chapter paid to clinical investigators by the
p.000075: sponsor of the covered study. A sponsor shall also maintain complete and accurate records concerning
p.000075: all other financial interests of investiga- tors subject to part 54 of this chapter.
p.000075: (c) A sponsor shall retain the records and reports required by this part for 2 years after a marketing
p.000075: application is approved for the drug; or, if an applica- tion is not approved for the drug, until 2 years after
p.000075: shipment and delivery of the drug for investigational use is dis- continued and FDA has been so noti-
p.000075: fied.
p.000075: (d) A sponsor shall retain reserve samples of any test article and ref- erence standard
p.000075: identified in, and used in any of the bioequivalence or bio-
p.000076: 76
p.000076: 21 CFR Ch. I (4–1–12 Edition)
p.000076: availability studies described in,
p.000076: § 320.38 or § 320.63 of this chapter, and release the reserve samples to FDA upon request, in
p.000076: accordance with, and for the period specified in § 320.38.
p.000076: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000076: FR 23031, June 17, 1987; 58 FR 25926, Apr. 28,
p.000076: 1993; 63 FR 5252, Feb. 2, 1998; 67 FR 9586, Mar.
p.000076: 4, 2002]
p.000076:
p.000076: § 312.58 Inspection of sponsor’s records and reports.
p.000076: (a) FDA inspection. A sponsor shall upon request from any properly au- thorized officer or
p.000076: employee of the Food and Drug Administration, at rea- sonable times, permit such officer or employee to
p.000076: have access to and copy and verify any records and reports re- lating to a clinical investigation con-
p.000076: ducted under this part. Upon written request by FDA, the sponsor shall sub- mit the records or reports (or
p.000076: copies of them) to FDA. The sponsor shall dis- continue shipments of the drug to any investigator who has
p.000076: failed to maintain or make available records or reports of the investigation as required by this part.
p.000076: (b) Controlled substances. If an inves- tigational new drug is a substance list- ed in any schedule of the
p.000076: Controlled Substances Act (21 U.S.C. 801; 21 CFR part 1308), records concerning ship- ment, delivery,
p.000076: receipt, and disposition of the drug, which are required to be kept under this part or other applica- ble
p.000076: parts of this chapter shall, upon the request of a properly authorized em- ployee of the Drug Enforcement
p.000076: Ad- ministration of the U.S. Department of Justice, be made available by the in- vestigator or sponsor to
p.000076: whom the re- quest is made, for inspection and copy- ing. In addition, the sponsor shall as- sure that
p.000076: adequate precautions are taken, including storage of the inves- tigational drug in a securely locked,
p.000076: substantially constructed cabinet, or other securely locked, substantially constructed enclosure, access
p.000076: to which is limited, to prevent theft or diversion of the substance into illegal channels of distribution.
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076: Food and Drug Administration, HHS § 312.64
p.000076:
p.000076:
p.000076: § 312.59 Disposition of unused supply of investigational drug.
p.000076: The sponsor shall assure the return of all unused supplies of the investiga- tional drug from each
p.000076: individual inves- tigator whose participation in the in- vestigation is discontinued or termi- nated. The
p.000076: sponsor may authorize al- ternative disposition of unused supplies of the investigational drug provided
p.000076: this alternative disposition does not expose humans to risks from the drug. The sponsor shall
p.000076: maintain written records of any disposition of the drug in accordance with § 312.57.
p.000076: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000076: FR 23031, June 17, 1987; 67 FR 9586, Mar. 4,
p.000076: 2002]
p.000076:
p.000076: § 312.60 General responsibilities of in- vestigators.
p.000076: An investigator is responsible for en- suring that an investigation is con- ducted according to the
p.000076: signed investi- gator statement, the investigational plan, and applicable regulations; for protecting
p.000076: the rights, safety, and wel- fare of subjects under the investiga- tor’s care; and for the control
p.000076: of drugs under investigation. An investigator shall, in accordance with the provi- sions of part 50
p.000076: of this chapter, obtain the informed consent of each human subject to whom the drug is adminis- tered,
p.000076: except as provided in §§ 50.23 or
p.000076: 50.24 of this chapter. Additional spe-
p.000076: cific responsibilities of clinical inves- tigators are set forth in this part and in parts 50 and 56 of this
p.000076: chapter.
p.000076: [52 FR 8831, Mar. 19, 1987, as amended at 61
p.000076: FR 51530, Oct. 2, 1996]
p.000076:
p.000076: § 312.61 Control of the investigational drug.
p.000076: An investigator shall administer the drug only to subjects under the inves- tigator’s personal supervision
p.000076: or under the supervision of a subinvestigator re- sponsible to the investigator. The in- vestigator shall not
p.000076: supply the inves- tigational drug to any person not au- thorized under this part to receive it.
p.000076: § 312.62 Investigator recordkeeping and record retention.
p.000076: (a) Disposition of drug. An investi- gator is required to maintain adequate records of the
p.000076: disposition of the drug,
p.000076:
p.000077: 77
p.000077:
p.000077: including dates, quantity, and use by subjects. If the investigation is termi- nated, suspended,
p.000077: discontinued, or completed, the investigator shall re- turn the unused supplies of the drug to the
p.000077: sponsor, or otherwise provide for disposition of the unused supplies of the drug under § 312.59.
p.000077: (b) Case histories. An investigator is required to prepare and maintain ade- quate and accurate case
p.000077: histories that record all observations and other data pertinent to the investigation on each individual
p.000077: administered the investiga- tional drug or employed as a control in the investigation. Case histories in-
p.000077: clude the case report forms and sup- porting data including, for example, signed and dated consent
p.000077: forms and medical records including, for example, progress notes of the physician, the in- dividual’s hospital
p.000077: chart(s), and the nurses’ notes. The case history for each individual shall document that in- formed
p.000077: consent was obtained prior to participation in the study.
p.000077: (c) Record retention. An investigator shall retain records required to be maintained under this part
p.000077: for a period of 2 years following the date a mar- keting application is approved for the drug for the
p.000077: indication for which it is being investigated; or, if no application is to be filed or if the application is not
p.000077: approved for such indication, until 2 years after the investigation is discon- tinued and FDA is notified.
p.000077: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000077: FR 23031, June 17, 1987; 61 FR 57280, Nov. 5,
p.000077: 1996; 67 FR 9586, Mar. 4, 2002]
p.000077: § 312.64 Investigator reports.
p.000077: (a) Progress reports. The investigator shall furnish all reports to the sponsor of the drug who is
p.000077: responsible for col- lecting and evaluating the results ob- tained. The sponsor is required under
p.000077: § 312.33 to submit annual reports to FDA on the progress of the clinical in- vestigations.
p.000077: (b) Safety reports. An investigator must immediately report to the spon- sor any serious adverse
p.000077: event, whether or not considered drug related, includ- ing those listed in the protocol or in- vestigator
p.000077: brochure and must include an assessment of whether there is a reasonable possibility that the
p.000077: drug caused the event. Study endpoints that
p.000077:
p.000077:
p.000077:
p.000077:
p.000077:
p.000077:
p.000077:
p.000077:
p.000077: § 312.66
p.000077: are serious adverse events (e.g., all- cause mortality) must be reported in accordance with the
p.000077: protocol unless there is evidence suggesting a causal relationship between the drug and the event (e.g.,
p.000077: death from anaphylaxis). In that case, the investigator must imme- diately report the event to the sponsor. The
p.000077: investigator must record non- serious adverse events and report them to the sponsor according to the
p.000077: time- table for reporting specified in the pro- tocol.
p.000077: (c) Final report. An investigator shall
p.000077: provide the sponsor with an adequate report shortly after completion of the investigator’s participation in
p.000077: the in- vestigation.
p.000077: (d) Financial disclosure reports. The clinical investigator shall provide the sponsor with sufficient
p.000077: accurate finan- cial information to allow an applicant to submit complete and accurate cer- tification or
p.000077: disclosure statements as required under part 54 of this chapter. The clinical investigator shall prompt- ly
p.000077: update this information if any rel- evant changes occur during the course of the investigation and for
p.000077: 1 year fol- lowing the completion of the study.
p.000077: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000077: FR 23031, June 17, 1987; 63 FR 5252, Feb. 2,
p.000077: 1998; 67 FR 9586, Mar. 4, 2002; 75 FR 59963,
p.000077: Sept. 29, 2010]
p.000077: § 312.66 Assurance of IRB review.
p.000077: An investigator shall assure that an IRB that complies with the require- ments set forth in part 56
p.000077: will be re- sponsible for the initial and continuing review and approval of the proposed clinical study.
p.000077: The investigator shall also assure that he or she will prompt- ly report to the IRB all changes in the
p.000077: research activity and all unanticipated problems involving risk to human sub- jects or others, and that he
p.000077: or she will not make any changes in the research without IRB approval, except where necessary to
p.000077: eliminate apparent imme- diate hazards to human subjects.
p.000077: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000077: FR 23031, June 17, 1987; 67 FR 9586, Mar. 4,
p.000077: 2002]
p.000077:
p.000077: § 312.68 Inspection of investigator’s records and reports.
p.000077: An investigator shall upon request from any properly authorized officer or
p.000077:
p.000078: 78
p.000078: 21 CFR Ch. I (4–1–12 Edition)
p.000078: employee of FDA, at reasonable times, permit such officer or employee to have access to, and copy and
p.000078: verify any records or reports made by the investi- gator pursuant to § 312.62. The investi- gator is not required
p.000078: to divulge subject names unless the records of particular individuals require a more detailed study of
p.000078: the cases, or unless there is reason to believe that the records do not represent actual case studies, or do
p.000078: not represent actual results obtained.
p.000078: § 312.69 Handling of controlled sub- stances.
p.000078: If the investigational drug is subject to the Controlled Substances Act, the investigator shall take
p.000078: adequate pre- cautions, including storage of the in- vestigational drug in a securely locked, substantially
p.000078: constructed cabinet, or other securely locked, substantially constructed enclosure, access to which is
p.000078: limited, to prevent theft or diversion of the substance into illegal channels of distribution.
p.000078: § 312.70 Disqualification of a clinical investigator.
p.000078: (a) If FDA has information indicating that an investigator (including a spon- sor-investigator) has repeatedly
p.000078: or de- liberately failed to comply with the re- quirements of this part, part 50, or part 56 of this chapter, or
p.000078: has submitted to FDA or to the sponsor false informa- tion in any required report, the Center for Drug
p.000078: Evaluation and Research or the Center for Biologics Evaluation and Research will furnish the investi-
p.000078: gator written notice of the matter complained of and offer the investi- gator an opportunity
p.000078: to explain the matter in writing, or, at the option of the investigator, in an informal con- ference.
p.000078: If an explanation is offered but not accepted by the Center for Drug Evaluation and Research or the Center for
p.000078: Biologics Evaluation and Research, the investigator will be given an oppor- tunity for a regulatory hearing
p.000078: under part 16 on the question of whether the investigator is entitled to receive in- vestigational new
p.000078: drugs.
p.000078: (b) After evaluating all available in- formation, including any explanation presented by the
p.000078: investigator, if the
p.000078:
p.000078:
p.000078:
p.000078:
p.000078:
p.000078:
p.000078:
p.000078: Food and Drug Administration, HHS § 312.80
p.000078:
p.000078:
p.000078: Commissioner determines that the in- vestigator has repeatedly or delib- erately failed to comply
p.000078: with the re- quirements of this part, part 50, or part
p.000078: 56 of this chapter, or has deliberately or repeatedly submitted false informa- tion to FDA or to the
p.000078: sponsor in any required report, the Commissioner will notify the investigator and the sponsor of any
p.000078: investigation in which the in- vestigator has been named as a partici- pant that the investigator is not
p.000078: enti- tled to receive investigational drugs. The notification will provide a state- ment of basis for such
p.000078: determination.
p.000078: (c) Each IND and each approved ap- plication submitted under part 314 con- taining data reported by an
p.000078: investi- gator who has been determined to be ineligible to receive investigational drugs will be
p.000078: examined to determine whether the investigator has submitted unreliable data that are essential to the
p.000078: continuation of the investigation or essential to the approval of any marketing application.
p.000078: (d) If the Commissioner determines, after the unreliable data submitted by the investigator are
p.000078: eliminated from consideration, that the data remaining are inadequate to support a conclusion that it is
p.000078: reasonably safe to continue the investigation, the Commissioner will notify the sponsor who shall have
p.000078: an opportunity for a regulatory hear- ing under part 16. If a danger to the public health exists, however,
p.000078: the Com- missioner shall terminate the IND im- mediately and notify the sponsor of the determination. In such
p.000078: case, the spon- sor shall have an opportunity for a reg- ulatory hearing before FDA under part 16 on the question
p.000078: of whether the IND should be reinstated.
p.000078: (e) If the Commissioner determines,
p.000078: after the unreliable data submitted by the investigator are eliminated from consideration, that the
p.000078: continued ap- proval of the drug product for which the data were submitted cannot be jus- tified, the
p.000078: Commissioner will proceed to withdraw approval of the drug prod- uct in accordance with the applicable
p.000078: provisions of the act.
p.000078: (f) An investigator who has been de- termined to be ineligible to receive in- vestigational drugs may be
p.000078: reinstated as eligible when the Commissioner de- termines that the investigator has pre-
p.000079: 79
p.000079:
p.000079: sented adequate assurances that the in- vestigator will employ investigational drugs solely in compliance
p.000079: with the provisions of this part and of parts 50 and 56.
p.000079: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000079: FR 23031, June 17, 1987; 55 FR 11580, Mar. 29,
p.000079: 1990; 62 FR 46876, Sept. 5, 1997; 67 FR 9586,
p.000079: Mar. 4, 2002]
p.000079:
p.000079: Subpart E—Drugs Intended to Treat Life-threatening and Se- verely-debilitating Illnesses
p.000079:
p.000079: AUTHORITY: 21 U.S.C. 351, 352, 353, 355, 371;
p.000079: 42 U.S.C. 262.
p.000079: SOURCE: 53 FR 41523, Oct. 21, 1988, unless
p.000079: otherwise noted.
p.000079:
p.000079: § 312.80 Purpose.
p.000079: The purpose of this section is to es- tablish procedures designed to expedite the development, evaluation,
p.000079: and mar- keting of new therapies intended to treat persons with life-threatening and
p.000079: severely-debilitating illnesses, espe- cially where no satisfactory alter- native therapy
p.000079: exists. As stated
p.000079: § 314.105(c) of this chapter, while the statutory standards of safety and effec- tiveness apply to all
p.000079: drugs, the many kinds of drugs that are subject to them, and the wide range of uses for those
p.000079: drugs, demand flexibility in ap- plying the standards. The Food and Drug Administration (FDA) has
p.000079: deter- mined that it is appropriate to exercise the broadest flexibility in applying the statutory standards, while
p.000079: preserving appropriate guarantees for safety and effectiveness. These procedures reflect the recognition that
p.000079: physicians and pa- tients are generally willing to accept greater risks or side effects from prod- ucts that
p.000079: treat life-threatening and se- verely-debilitating illnesses, than they would accept from products that treat
p.000079: less serious illnesses. These procedures also reflect the recognition that the benefits of the drug
p.000079: need to be evalu- ated in light of the severity of the dis- ease being treated. The procedure out-
p.000079: lined in this section should be inter- preted consistent with that purpose.
p.000079:
p.000079:
p.000079:
p.000079:
p.000079:
p.000079:
p.000079:
p.000079:
p.000079: § 312.81
p.000079: § 312.81 Scope.
p.000079: This section applies to new drug and biological products that are being stud- ied for their safety and
p.000079: effectiveness in treating life-threatening or severely- debilitating diseases.
p.000079: (a) For purposes of this section, the term ‘‘life-threatening’’ means:
p.000079: (1) Diseases or conditions where the likelihood of death is high unless the course of the disease is
p.000079: interrupted; and
p.000079: (2) Diseases or conditions with poten- tially fatal outcomes, where the end point of clinical trial analysis
p.000079: is sur- vival.
p.000079: (b) For purposes of this section, the term ‘‘severely debilitating’’ means diseases or conditions that
p.000079: cause major irreversible morbidity.
p.000079: (c) Sponsors are encouraged to con- sult with FDA on the applicability of these procedures to specific
p.000079: products.
p.000079: [53 FR 41523, Oct. 21, 1988, as amended at 64
p.000079: FR 401, Jan. 5, 1999]
p.000079: § 312.82 Early consultation.
p.000079: For products intended to treat life- threatening or severely-debilitating ill- nesses, sponsors may request to
p.000079: meet with FDA-reviewing officials early in the drug development process to review and reach agreement on the
p.000079: design of necessary preclinical and clinical stud- ies. Where appropriate, FDA will invite to such meetings one or
p.000079: more outside expert scientific consultants or advi- sory committee members. To the ex- tent FDA resources
p.000079: permit, agency re- viewing officials will honor requests for such meetings
p.000079: (a) Pre-investigational ne drug (IND) meetings. Prior to the submission of the initial IND, the sponsor may
p.000079: request a meeting with FDA-reviewing officials. The primary purpose of this meeting is to review and reach
p.000079: agreement on the design of animal studies needed to ini- tiate human testing. The meeting may also
p.000079: provide an opportunity for dis- cussing the scope and design of phase 1 testing, plans for studying the
p.000079: drug product in pediatric populations, and the best approach for presentation and formatting of data in the
p.000079: IND.
p.000079: (b) End-of-phase 1 meetings. When data
p.000079: from phase 1 clinical testing are avail- able, the sponsor may again request a
p.000079:
p.000080: 80
p.000080: 21 CFR Ch. I (4–1–12 Edition)
p.000080: meeting with FDA-reviewing officials. The primary purpose of this meeting is to review and reach agreement on
p.000080: the design of phase 2 controlled clinical trials, with the goal that such testing will be adequate
p.000080: to provide sufficient data on the drug’s safety and effective- ness to support a decision on its ap-
p.000080: provability for marketing, and to dis- cuss the need for, as well as the design and timing of, studies of the drug
p.000080: in pe- diatric patients. For drugs for life- threatening diseases, FDA will provide its best judgment, at
p.000080: that time, wheth- er pediatric studies will be required and whether their submission will be deferred
p.000080: until after approval. The pro- cedures outlined in § 312.47(b)(1) with respect to end-of-phase 2
p.000080: conferences, including documentation of agree- ments reached, would also be used for end-of-phase 1
p.000080: meetings.
p.000080: [53 FR 41523, Oct. 21, 1988, as amended at 63
p.000080: FR 66669, Dec. 2, 1998]
p.000080: § 312.83 Treatment protocols.
p.000080: If the preliminary analysis of phase 2 test results appears promising, FDA may ask the sponsor to submit a
p.000080: treat- ment protocol to be reviewed under the procedures and criteria listed in
p.000080: §§ 312.305 and 312.320. Such a treatment protocol, if requested and granted, would normally remain
p.000080: in effect while the complete data necessary for a mar- keting application are being assembled by the sponsor and
p.000080: reviewed by FDA (unless grounds exist for clinical hold of ongoing protocols, as provided in
p.000080: § 312.42(b)(3)(ii)).
p.000080: [53 FR 41523, Oct. 21, 1988, as amended at 76
p.000080: FR 13880, Mar. 15, 2011]
p.000080:
p.000080: § 312.84 Risk-benefit analysis in review of marketing applications for drugs to treat life-threatening and
p.000080: se- verely-debilitating illnesses.
p.000080: (a) FDA’s application of the statu- tory standards for marketing approval shall recognize the need for a
p.000080: medical risk-benefit judgment in making the final decision on approvability. As part of this evaluation,
p.000080: consistent with the statement of purpose in § 312.80, FDA will consider whether the benefits of the drug
p.000080: outweigh the known and po- tential risks of the drug and the need to answer remaining questions about
p.000080: risks and benefits of the drug, taking
p.000080:
p.000080:
p.000080:
p.000080:
p.000080:
p.000080:
p.000080:
p.000080: Food and Drug Administration, HHS § 312.110
p.000080:
p.000080:
p.000080: into consideration the severity of the disease and the absence of satisfactory alternative therapy.
p.000080: (b) In making decisions on whether to grant marketing approval for prod- ucts that have been the subject
p.000080: of an end-of-phase 1 meeting under § 312.82, FDA will usually seek the advice of outside expert
p.000080: scientific consultants or advisory committees. Upon the filing of such a marketing application under
p.000080: § 314.101 or part 601 of this chapter, FDA will notify the members of the relevant standing advisory committee of the
p.000080: ap- plication’s filing and its availability for review.
p.000080: (c) If FDA concludes that the data presented are not sufficient for mar- keting approval, FDA will issue a
p.000080: com- plete response letter under § 314.110 of this chapter or the biological product licensing procedures.
p.000080: Such letter, in describing the deficiencies in the appli- cation, will address why the results of the
p.000080: research design agreed to under
p.000080: § 312.82, or in subsequent meetings, have not provided sufficient evidence for marketing approval.
p.000080: Such letter will also describe any recommenda- tions made by the advisory committee regarding the
p.000080: application.
p.000080: (d) Marketing applications submitted under the procedures contained in this section will be subject to the
p.000080: require- ments and procedures contained in part 314 or part 600 of this chapter, as well as those in this
p.000080: subpart.
p.000080: [53 FR 41523, Oct. 21, 1988, as amended at 73
p.000080: FR 39607, July 10, 2008]
p.000080:
p.000080: § 312.85 Phase 4 studies.
p.000080: Concurrent with marketing approval, FDA may seek agreement from the sponsor to conduct certain
p.000080: post- marketing (phase 4) studies to delin- eate additional information about the drug’s risks, benefits,
p.000080: and optimal use. These studies could include, but would not be limited to, studying different doses
p.000080: or schedules of administration than were used in phase 2 studies, use of the drug in other
p.000080: patient popu- lations or other stages of the disease, or use of the drug over a longer period of time.
p.000080:
p.000081: 81
p.000081:
p.000081: § 312.86 Focused FDA regulatory re- search.
p.000081: At the discretion of the agency, FDA may undertake focused regulatory re- search on critical rate-limiting aspects
p.000081: of the preclinical, chemical/manufac- turing, and clinical phases of drug de- velopment and evaluation.
p.000081: When initi- ated, FDA will undertake such re- search efforts as a means for meeting a public health need
p.000081: in facilitating the development of therapies to treat life- threatening or severely debilitating ill- nesses.
p.000081: § 312.87 Active monitoring of conduct and evaluation of clinical trials.
p.000081: For drugs covered under this section, the Commissioner and other agency of- ficials will monitor the progress of
p.000081: the conduct and evaluation of clinical trials and be involved in facilitating their appropriate
p.000081: progress.
p.000081: § 312.88 Safeguards for patient safety.
p.000081: All of the safeguards incorporated within parts 50, 56, 312, 314, and 600 of this chapter designed
p.000081: to ensure the safety of clinical testing and the safety of products following marketing ap- proval apply
p.000081: to drugs covered by this section. This includes the requirements for informed consent (part 50 of this
p.000081: chapter) and institutional review boards (part 56 of this chapter). These safeguards further
p.000081: include the review of animal studies prior to initial human testing (§ 312.23), and the moni-
p.000081: toring of adverse drug experiences through the requirements of IND safe- ty reports (§ 312.32),
p.000081: safety update re- ports during agency review of a mar- keting application (§ 314.50 of this chap- ter), and
p.000081: postmarketing adverse reac- tion reporting (§ 314.80 of this chapter).
p.000081: Subpart F—Miscellaneous
p.000081: § 312.110 Import and export require- ments.
p.000081: (a) Imports. An investigational new drug offered for import into the United States complies with the
p.000081: requirements of this part if it is subject to an IND that is in effect for it under § 312.40 and:
p.000081: (1) The consignee in the United States is the sponsor of the IND; (2) the con- signee is a
p.000081: qualified investigator named in the IND; or (3) the consignee
p.000081:
p.000081:
p.000081:
p.000081:
p.000081:
p.000081:
p.000081:
p.000081:
p.000081: § 312.110
p.000081: is the domestic agent of a foreign spon- sor, is responsible for the control and distribution of the
p.000081: investigational drug, and the IND identifies the con- signee and describes what, if any, ac- tions the
p.000081: consignee will take with re- spect to the investigational drug.
p.000081: (b) Exports. An investigational new drug may be exported from the United States for use in a
p.000081: clinical investiga- tion under any of the following condi- tions:
p.000081: (1) An IND is in effect for the drug under § 312.40, the drug complies with the laws of the country
p.000081: to which it is being exported, and each person who receives the drug is an investigator in a study
p.000081: submitted to and allowed to proceed under the IND; or
p.000081: (2) The drug has valid marketing au- thorization in Australia, Canada, Israel, Japan, New
p.000081: Zealand, Switzer- land, South Africa, or in any country in the European Union or the European Economic Area,
p.000081: and complies with the laws of the country to which it is being exported, section 802(b)(1)(A), (f), and
p.000081: (g) of the act, and § 1.101 of this chap- ter; or
p.000081: (3) The drug is being exported to Aus- tralia, Canada, Israel, Japan, New Zea- land, Switzerland, South Africa, or
p.000081: to any country in the European Union or the European Economic Area, and com- plies with the laws of the
p.000081: country to which it is being exported, the applica- ble provisions of section 802(c), (f), and
p.000081: (g) of the act, and § 1.101 of this chap- ter. Drugs exported under this para- graph that are not
p.000081: the subject of an IND are exempt from the label require- ment in § 312.6(a); or
p.000081: (4) Except as provided in paragraph (b)(5) of this section, the person export- ing the drug sends a written
p.000081: certifi- cation to the Office of International Programs (HFG–1), Food and Drug Ad- ministration, 5600
p.000081: Fishers Lane, Rock- ville, MD 20857, at the time the drug is first exported and maintains records documenting
p.000081: compliance with this paragraph. The certification shall de- scribe the drug that is to be exported
p.000081: (i.e., trade name (if any), generic name, and dosage form), identify the country or countries to which the
p.000081: drug is to be exported, and affirm that:
p.000081: (i) The drug is intended for export;
p.000081:
p.000082: 82
p.000082: 21 CFR Ch. I (4–1–12 Edition)
p.000082: (ii) The drug is intended for inves- tigational use in a foreign country;
p.000082: (iii) The drug meets the foreign pur- chaser’s or consignee’s specifications;
p.000082: (iv) The drug is not in conflict with the importing country’s laws;
p.000082: (v) The outer shipping package is la- beled to show that the package is in- tended for export from
p.000082: the United States;
p.000082: (vi) The drug is not sold or offered for sale in the United States;
p.000082: (vii) The clinical investigation will be conducted in accordance with
p.000082: § 312.120;
p.000082: (viii) The drug is manufactured, proc- essed, packaged, and held in substan- tial conformity with current good
p.000082: man- ufacturing practices;
p.000082: (ix) The drug is not adulterated with- in the meaning of section 501(a)(1), (a)(2)(A), (a)(3), (c), or (d) of
p.000082: the act;
p.000082: (x) The drug does not present an im- minent hazard to public health, either in the United States, if
p.000082: the drug were to be reimported, or in the foreign country; and
p.000082: (xi) The drug is labeled in accordance with the foreign country’s laws.
p.000082: (5) In the event of a national emer- gency in a foreign country, where the national emergency necessitates
p.000082: expor- tation of an investigational new drug, the requirements in paragraph (b)(4) of this section apply as
p.000082: follows:
p.000082: (i) Situations here the investigational ne drug is to be stockpiled in anticipa- tion of a national
p.000082: emergency. There may be instances where exportation of an investigational new drug is needed so that the
p.000082: drug may be stockpiled and made available for use by the import- ing country if and when a
p.000082: national emergency arises. In such cases:
p.000082: (A) A person may export an inves- tigational new drug under paragraph (b)(4) of this section without
p.000082: making an affirmation with respect to any one or more of paragraphs (b)(4)(i), (b)(4)(iv),
p.000082: (b)(4)(vi), (b)(4)(vii), (b)(4)(viii), and/or (b)(4)(ix) of this sec- tion, provided that he or she:
p.000082: (1) Provides a written statement ex- plaining why compliance with each such paragraph is not
p.000082: feasible or is contrary to the best interests of the in- dividuals who may receive the inves- tigational new
p.000082: drug;
p.000082:
p.000082:
p.000082:
p.000082:
p.000082:
p.000082:
p.000082:
p.000082: Food and Drug Administration, HHS § 312.110
p.000082:
p.000082:
p.000082: (2) Provides a written statement from an authorized official of the im- porting country’s
p.000082: government. The statement must attest that the official agrees with the exporter’s statement made under
p.000082: paragraph (b)(5)(i)(A)(1) of this section; explain that the drug is to be stockpiled solely for use of the im-
p.000082: porting country in a national emer- gency; and describe the potential na- tional emergency that
p.000082: warrants expor- tation of the investigational new drug under this provision; and
p.000082: (3) Provides a written statement
p.000082: showing that the Secretary of Health and Human Services (the Secretary), or his or her designee, agrees
p.000082: with the findings of the authorized official of the importing country’s government. Persons who
p.000082: wish to obtain a written statement from the Secretary should direct their requests to Secretary’s Op- erations
p.000082: Center, Office of Emergency Operations and Security Programs, Of- fice of Public Health Emergency Pre-
p.000082: paredness, Office of the Secretary, De- partment of Health and Human Serv- ices, 200 Independence Ave.
p.000082: SW., Wash- ington, DC 20201. Requests may be also be sent by FAX: 202–619–7870 or by e- mail: HHS.SOC@hhs.gov.
p.000082: (B) Exportation may not proceed
p.000082: until FDA has authorized exportation of the investigational new drug. FDA may deny authorization if the
p.000082: state- ments provided under paragraphs (b)(5)(i)(A)(1) or (b)(5)(i)(A)(2) of this section are
p.000082: inadequate or if expor- tation is contrary to public health.
p.000082: (ii) Situations here the investigational
p.000082: ne drug is to be used for a sudden and immediate national emergency. There may be instances
p.000082: where exportation of an investigational new drug is needed so that the drug may be used in a sud- den
p.000082: and immediate national emergency that has developed or is developing. In such cases:
p.000082: (A) A person may export an inves- tigational new drug under paragraph (b)(4) of this section without
p.000082: making an affirmation with respect to any one or more of paragraphs (b)(4)(i), (b)(4)(iv),
p.000082: (b)(4)(v), (b)(4)(vi), (b)(4)(vii), (b)(4)(viii), (b)(4)(ix), and/or (b)(4)(xi), provided that he or she:
p.000082: (1) Provides a written statement ex- plaining why compliance with each such paragraph is not
p.000082: feasible or is
p.000083: 83
p.000083:
p.000083: contrary to the best interests of the in- dividuals who are expected to receive the investigational new drug and
p.000083: (2) Provides sufficient information from an authorized official of the im- porting country’s government
p.000083: to en- able the Secretary, or his or her des- ignee, to decide whether a national emergency has
p.000083: developed or is devel- oping in the importing country, wheth- er the investigational new drug will be used solely
p.000083: for that national emer- gency, and whether prompt exportation of the investigational new drug is nec-
p.000083: essary. Persons who wish to obtain a determination from the Secretary should direct their
p.000083: requests to Sec- retary’s Operations Center, Office of Emergency Operations and Security Programs,
p.000083: Office of Public Health Emergency Preparedness, Office of the Secretary, Department of Health and
p.000083: Human Services, 200 Independence Ave. SW., Washington, DC 20201. Requests may be also be sent by FAX:
p.000083: 202–619– 7870 or by e-mail: HHS.SOC@hhs.gov.
p.000083: (B) Exportation may proceed without prior FDA authorization.
p.000083: (c) Limitations. Exportation under paragraph (b) of this section may not occur if:
p.000083: (1) For drugs exported under para- graph (b)(1) of this section, the IND pertaining to the
p.000083: clinical investigation is no longer in effect;
p.000083: (2) For drugs exported under para- graph (b)(2) of this section, the require- ments in section 802(b)(1),
p.000083: (f), or (g) of the act are no longer met;
p.000083: (3) For drugs exported under para- graph (b)(3) of this section, the require- ments in section 802(c), (f),
p.000083: or (g) of the act are no longer met;
p.000083: (4) For drugs exported under para- graph (b)(4) of this section, the condi- tions underlying the
p.000083: certification or the statements submitted under para- graph (b)(5) of this section are no longer met;
p.000083: or
p.000083: (5) For any investigational new drugs under this section, the drug no longer complies with the laws of the
p.000083: import- ing country.
p.000083: (d) Insulin and antibiotics. New insulin and antibiotic drug products may be exported for investigational use
p.000083: in ac- cordance with section 801(e)(1) of the
p.000083:
p.000083:
p.000083:
p.000083:
p.000083:
p.000083:
p.000083:
p.000083:
p.000083: § 312.120
p.000083: act without complying with this sec- tion.
p.000083: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000083: FR 23031, June 17, 1987; 64 FR 401, Jan. 5, 1999;
p.000083: 67 FR 9586, Mar. 4, 2002; 70 FR 70729, Nov. 23,
p.000083: 2005]
p.000083:
p.000083: § 312.120 Foreign clinical studies not conducted under an IND.
p.000083: (a) Acceptance of studies. (1) FDA will accept as support for an IND or appli- cation for marketing
p.000083: approval (an ap- plication under section 505 of the act or section 351 of the Public Health Service Act (the PHS
p.000083: Act) (42 U.S.C. 262)) a well-designed and well-conducted for- eign clinical study not conducted under an
p.000083: IND, if the following conditions are met:
p.000083: (i) The study was conducted in ac-
p.000083: cordance with good clinical practice (GCP). For the purposes of this section, GCP is defined as a standard for
p.000083: the de- sign, conduct, performance, moni- toring, auditing, recording, analysis, and reporting of
p.000083: clinical trials in a way that provides assurance that the data and reported results are credible and accurate
p.000083: and that the rights, safety, and well-being of trial subjects are pro- tected. GCP includes review and
p.000083: ap- proval (or provision of a favorable opinion) by an independent ethics com- mittee (IEC) before
p.000083: initiating a study, continuing review of an ongoing study by an IEC, and obtaining and docu- menting
p.000083: the freely given informed con- sent of the subject (or a subject’s le- gally authorized representative, if
p.000083: the subject is unable to provide informed consent) before initiating a study. GCP does not require informed
p.000083: consent in life-threatening situations when the IEC reviewing the study finds, before initiation of the
p.000083: study, that informed consent is not feasible and either that the conditions present are consistent with
p.000083: those described in § 50.23 or
p.000083: § 50.24(a) of this chapter, or that the
p.000083: measures described in the study pro- tocol or elsewhere will protect the rights, safety, and
p.000083: well-being of sub- jects; and
p.000083: (ii) FDA is able to validate the data from the study through an onsite in- spection if the agency
p.000083: deems it nec- essary.
p.000083: (2) Although FDA will not accept as support for an IND or application for
p.000084: 84
p.000084: 21 CFR Ch. I (4–1–12 Edition)
p.000084: marketing approval a study that does not meet the conditions of paragraph (a)(1) of this section, FDA will
p.000084: examine data from such a study.
p.000084: (3) Marketing approval of a new drug based solely on foreign clinical data is governed by § 314.106 of this
p.000084: chapter.
p.000084: (b) Supporting information. A sponsor or applicant who submits data from a foreign clinical study not
p.000084: conducted under an IND as support for an IND or application for marketing approval must submit to FDA,
p.000084: in addition to in- formation required elsewhere in parts 312, 314, or 601 of this chapter, a de- scription
p.000084: of the actions the sponsor or applicant took to ensure that the re- search conformed to GCP as
p.000084: described in paragraph (a)(1)(i) of this section. The description is not required to du- plicate
p.000084: information already submitted in the IND or application for mar- keting approval. Instead, the
p.000084: descrip- tion must provide either the following information or a cross-reference to an- other section of
p.000084: the submission where the information is located:
p.000084: (1) The investigator’s qualifications;
p.000084: (2) A description of the research fa- cilities;
p.000084: (3) A detailed summary of the pro- tocol and results of the study and, should FDA request, case
p.000084: records main- tained by the investigator or addi- tional background data such as hos- pital or
p.000084: other institutional records;
p.000084: (4) A description of the drug sub- stance and drug product used in the study, including a
p.000084: description of the components, formulation, specifica- tions, and, if available, bioavailability of the
p.000084: specific drug product used in the clinical study;
p.000084: (5) If the study is intended to support the effectiveness of a drug product, in- formation showing that the
p.000084: study is adequate and well controlled under
p.000084: § 314.126 of this chapter;
p.000084: (6) The name and address of the IEC that reviewed the study and a state- ment that the IEC meets the
p.000084: definition in § 312.3 of this chapter. The sponsor or applicant must maintain records sup- porting such
p.000084: statement, including records of the names and qualifications of IEC members, and make these records
p.000084: available for agency review upon request;
p.000084:
p.000084:
p.000084:
p.000084:
p.000084:
p.000084:
p.000084:
p.000084: Food and Drug Administration, HHS § 312.140
p.000084:
p.000084:
p.000084: (7) A summary of the IEC’s decision to approve or modify and approve the study, or to provide a
p.000084: favorable opin- ion;
p.000084: (8) A description of how informed consent was obtained;
p.000084: (9) A description of what incentives, if any, were provided to subjects to participate in the study;
p.000084: (10) A description of how the spon- sor(s) monitored the study and ensured that the study was carried out
p.000084: consist- ently with the study protocol; and
p.000084: (11) A description of how investiga- tors were trained to comply with GCP (as described in paragraph
p.000084: (a)(1)(i) of this section) and to conduct the study in accordance with the study protocol, and a
p.000084: statement on whether written commitments by investigators to com- ply with GCP and the protocol were ob-
p.000084: tained. Any signed written commit- ments by investigators must be main- tained by the sponsor or
p.000084: applicant and made available for agency review upon request.
p.000084: (c) Waivers. (1) A sponsor or applicant may ask FDA to waive any applicable requirements under paragraphs
p.000084: (a)(1) and (b) of this section. A waiver re- quest may be submitted in an IND or in an information amendment
p.000084: to an IND, or in an application or in an amend- ment or supplement to an application submitted under
p.000084: part 314 or 601 of this chapter. A waiver request is required to contain at least one of the following:
p.000084: (i) An explanation why the sponsor’s or applicant’s compliance with the re- quirement is unnecessary or
p.000084: cannot be achieved;
p.000084: (ii) A description of an alternative submission or course of action that satisfies the purpose of
p.000084: the require- ment; or
p.000084: (iii) Other information justifying a waiver.
p.000084: (2) FDA may grant a waiver if it finds that doing so would be in the interest of the public health.
p.000084: (d) Records. A sponsor or applicant must retain the records required by this section for a foreign
p.000084: clinical study not conducted under an IND as follows:
p.000084: (1) If the study is submitted in sup- port of an application for marketing approval, for 2 years after
p.000084: an agency decision on that application;
p.000084:
p.000085: 85
p.000085:
p.000085: (2) If the study is submitted in sup- port of an IND but not an application for marketing approval,
p.000085: for 2 years after the submission of the IND.
p.000085: [73 FR 22815, Apr. 28, 2008]
p.000085:
p.000085: § 312.130 Availability for public disclo- sure of data and information in an IND.
p.000085: (a) The existence of an investiga- tional new drug application will not be disclosed by FDA unless it
p.000085: has pre- viously been publicly disclosed or ac- knowledged.
p.000085: (b) The availability for public disclo- sure of all data and information in an investigational new drug
p.000085: application for a new drug will be handled in ac- cordance with the provisions estab- lished in §
p.000085: 314.430 for the confidentiality of data and information in applications submitted in part 314. The availability
p.000085: for public disclosure of all data and in- formation in an investigational new drug application for a
p.000085: biological prod- uct will be governed by the provisions of §§ 601.50 and 601.51.
p.000085: (c) Notwithstanding the provisions of
p.000085: § 314.430, FDA shall disclose upon re- quest to an individual to whom an in- vestigational new drug
p.000085: has been given a copy of any IND safety report relat- ing to the use in the individual.
p.000085: (d) The availability of information required to be publicly disclosed for in- vestigations involving an
p.000085: exception from informed consent under § 50.24 of this chapter will be handled as follows: Persons wishing to
p.000085: request the publicly disclosable information in the IND that was required to be filed in Docket Number
p.000085: 95S–0158 in the Division of Dockets Management (HFA–305), Food and Drug Administration, 5630 Fishers
p.000085: Lane, rm. 1061, Rockville, MD 20852, shall submit a request under the Free- dom of Information Act.
p.000085: [52 FR 8831, Mar. 19, 1987. Redesignated at 53
p.000085: FR 41523, Oct. 21, 1988, as amended at 61 FR
p.000085: 51530, Oct. 2, 1996; 64 FR 401, Jan. 5, 1999; 68
p.000085: FR 24879, May 9, 2003]
p.000085: § 312.140 Address for correspondence.
p.000085: (a) A sponsor must send an initial IND submission to the Center for Drug Evaluation and Research (CDER)
p.000085: or to the Center for Biologics Evaluation and Research (CBER), depending on the
p.000085:
p.000085:
p.000085:
p.000085:
p.000085:
p.000085:
p.000085:
p.000085:
p.000085: § 312.145
p.000085: Center responsible for regulating the product as follows:
p.000085: (1) For drug products regulated by CDER. Send the IND submission to the Central Document Room,
p.000085: Center for Drug Evaluation and Research, Food and Drug Administration, 5901–B Ammendale Rd.,
p.000085: Beltsville, MD 20705– 1266; except send an IND submission for an in vivo bioavailability or bioequiva- lence study
p.000085: in humans to support an abbreviated new drug application to the Office of Generic Drugs (HFD–600),
p.000085: Center for Drug Evaluation and Re- search, Food and Drug Administration, Metro Park North VII, 7620
p.000085: Standish Pl., Rockville, MD 20855.
p.000085: (2) For biological products regulated by CDER. Send the IND submission to the CDER Therapeutic Biological
p.000085: Products Document Room, Center for Drug Eval- uation and Research, Food and Drug Administration, 12229
p.000085: Wilkins Ave., Rockville, MD 20852.
p.000085: (3) For biological products regulated by CBER. Send the IND submission to the Document Control Center
p.000085: (HFM–99), Center for Biologics Evaluation and Research, Food and Drug Administra- tion, 1401 Rockville
p.000085: Pike, suite 200N, Rockville, MD 20852–1448.
p.000085: (b) On receiving the IND, the respon- sible Center will inform the sponsor which one of the
p.000085: divisions in CDER or CBER is responsible for the IND. Amendments, reports, and other cor-
p.000085: respondence relating to matters cov- ered by the IND should be sent to the appropriate center at the
p.000085: address indi- cated in this section and marked to the attention of the responsible division. The outside
p.000085: wrapper of each submis- sion shall state what is contained in the submission, for example, ‘‘IND Ap-
p.000085: plication’’, ‘‘Protocol Amendment’’, etc.
p.000085: (c) All correspondence relating to ex- port of an investigational drug under
p.000085: § 312.110(b)(2) shall be submitted to the International Affairs Staff (HFY–50), Office of Health Affairs,
p.000085: Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.
p.000085: [70 FR 14981, Mar. 24, 2005, as amended at 74
p.000085: FR 13113, Mar. 26, 2009; 74 FR 55771, Oct. 29,
p.000085: 2009; 75 FR 37295, June 29, 2010]
p.000085:
p.000086: 86
p.000086: 21 CFR Ch. I (4–1–12 Edition)
p.000086: § 312.145 Guidance documents.
p.000086: (a) FDA has made available guidance documents under § 10.115 of this chapter to help you to comply with certain
p.000086: re- quirements of this part.
p.000086: (b) The Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and
p.000086: Research (CBER) maintain lists of guidance doc- uments that apply to the centers’ regu- lations. The lists are
p.000086: maintained on the Internet and are published annu- ally in the FEDERAL REGISTER. A re- quest for a
p.000086: copy of the CDER list should be directed to the Office of Training and Communications, Divi-
p.000086: sion of Drug Information, Center for Drug Evaluation and Research, Food and Drug Administration,
p.000086: 10903 New Hampshire Ave., Silver Spring, MD 20993–0002. A request for a copy of the CBER list should
p.000086: be directed to the Of- fice of Communication, Training, and Manufacturers Assistance (HFM–40), Center for
p.000086: Biologics Evaluation and Research, Food and Drug Administra- tion, 1401 Rockville Pike, Rockville, MD
p.000086: 20852–1448.
p.000086: [65 FR 56479, Sept. 19, 2000, as amended at 74
p.000086: FR 13113, Mar. 26, 2009]
p.000086:
p.000086: Subpart G—Drugs for Investiga- tional Use in Laboratory Re- search Animals or In Vitro Tests
p.000086: § 312.160 Drugs for investigational use in laboratory research animals or in vitro tests.
p.000086: (a) Authorization to ship. (1)(i) A per- son may ship a drug intended solely for tests in vitro or in
p.000086: animals used only for laboratory research purposes if it is labeled as follows:
p.000086: CAUTION: Contains a new drug for inves- tigational use only in laboratory research animals, or for tests
p.000086: in vitro. Not for use in humans.
p.000086: (ii) A person may ship a biological product for investigational in vitro di- agnostic use that
p.000086: is listed in
p.000086: § 312.2(b)(2)(ii) if it is labeled as follows:
p.000086: CAUTION: Contains a biological product for investigational in vitro diagnostic tests only.
p.000086: (2) A person shipping a drug under paragraph (a) of this section shall use
p.000086:
p.000086:
p.000086:
p.000086:
p.000086:
p.000086:
p.000086:
p.000086: Food and Drug Administration, HHS § 312.300
p.000086:
p.000086:
p.000086: due diligence to assure that the con- signee is regularly engaged in con- ducting such tests and
p.000086: that the ship- ment of the new drug will actually be used for tests in vitro or in animals used only
p.000086: for laboratory research.
p.000086: (3) A person who ships a drug under paragraph (a) of this section shall maintain adequate records
p.000086: showing the name and post office address of the ex- pert to whom the drug is shipped and the date, quantity,
p.000086: and batch or code mark of each shipment and delivery. Records of shipments under paragraph (a)(1)(i) of
p.000086: this section are to be main- tained for a period of 2 years after the shipment. Records and reports of
p.000086: data and shipments under paragraph (a)(1)(ii) of this section are to be main- tained in accordance
p.000086: with § 312.57(b). The person who ships the drug shall upon request from any properly au- thorized
p.000086: officer or employee of the Food and Drug Administration, at rea- sonable times, permit such officer
p.000086: or employee to have access to and copy and verify records required to be main- tained under this section.
p.000086: (b) Termination of authorization to
p.000086: ship. FDA may terminate authoriza- tion to ship a drug under this section if it finds that:
p.000086: (1) The sponsor of the investigation has failed to comply with any of the conditions for shipment
p.000086: established under this section; or
p.000086: (2) The continuance of the investiga- tion is unsafe or otherwise contrary to the public interest or the
p.000086: drug is used for purposes other than bona fide sci- entific investigation. FDA will notify the person
p.000086: shipping the drug of its find- ing and invite immediate correction. If correction is not immediately made, the
p.000086: person shall have an opportunity for a regulatory hearing before FDA pursuant to part 16.
p.000086: (c) Disposition of unused drug. The person who ships the drug under para- graph (a) of this section
p.000086: shall assure the return of all unused supplies of the drug from individual investigators whenever the
p.000086: investigation discon- tinues or the investigation is termi- nated. The person who ships the drug may
p.000086: authorize in writing alternative disposition of unused supplies of the drug provided this
p.000086: alternative disposi- tion does not expose humans to risks
p.000087: 87
p.000087:
p.000087: from the drug, either directly or indi- rectly (e.g., through food-producing animals). The shipper
p.000087: shall maintain records of any alternative disposition.
p.000087: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000087: FR 23031, June 17, 1987. Redesignated at 53
p.000087: FR 41523, Oct. 21, 1988; 67 FR 9586, Mar. 4,
p.000087: 2002]
p.000087:
p.000087: Subpart H [Reserved]
p.000087: Subpart I—Expanded Access to Investigational Drugs for Treat- ment Use
p.000087:
p.000087: SOURCE: 74 FR 40942, Aug. 13, 2009, unless
p.000087: otherwise noted.
p.000087:
p.000087: § 312.300 General.
p.000087: (a) Scope. This subpart contains the requirements for the use of investiga- tional new drugs and approved
p.000087: drugs where availability is limited by a risk evaluation and mitigation strategy (REMS) when the
p.000087: primary purpose is to diagnose, monitor, or treat a patient’s disease or condition. The aim of this subpart
p.000087: is to facilitate the availability of such drugs to patients with serious diseases or conditions when there is
p.000087: no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the patient’s disease or
p.000087: condition.
p.000087: (b) Definitions. The following defini- tions of terms apply to this subpart:
p.000087: Immediately life-threatening disease or condition means a stage of disease in which there is reasonable
p.000087: likelihood that death will occur within a matter of months or in which premature death is likely without early
p.000087: treatment.
p.000087: Serious disease or condition means a disease or condition associated with morbidity that has
...
p.000087: recurrent. Whether a disease or condition is seri- ous is a matter of clinical judgment, based on its
p.000087: impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left un-
p.000087: treated, will progress from a less severe condition to a more serious one.
p.000087:
p.000087:
p.000087:
p.000087:
p.000087:
p.000087:
p.000087:
p.000087:
p.000087: § 312.305
p.000087:
p.000087: § 312.305 Requirements for all ex- panded access uses.
p.000087: The criteria, submission require- ments, safeguards, and beginning treat- ment information set out in
p.000087: this sec- tion apply to all expanded access uses described in this subpart. Additional criteria,
p.000087: submission requirements, and safeguards that apply to specific types of expanded access are described
p.000087: in
p.000087: §§ 312.310 through 312.320.
p.000087: (a) Criteria. FDA must determine that:
p.000087: (1) The patient or patients to be treated have a serious or immediately life-threatening disease
p.000087: or condition, and there is no comparable or satisfac- tory alternative therapy to diagnose, monitor, or treat
p.000087: the disease or condi- tion;
p.000087: (2) The potential patient benefit jus- tifies the potential risks of the treat- ment use and those
p.000087: potential risks are not unreasonable in the context of the disease or condition to be treated; and
p.000087: (3) Providing the investigational drug for the requested use will not interfere with the initiation, conduct, or
p.000087: com- pletion of clinical investigations that could support marketing approval of the expanded access use
p.000087: or otherwise compromise the potential development of the expanded access use.
p.000087: (b) Submission. (1) An expanded access submission is required for each type of expanded access described in
p.000087: this sub- part. The submission may be a new
p.000087: IND or a protocol amendment to an ex- isting IND. Information required for a submission may be supplied by
p.000087: refer- ring to pertinent information con- tained in an existing IND if the sponsor of the existing IND
p.000087: grants a right of reference to the IND.
p.000087: (2) The expanded access submission must include:
p.000087: (i) A cover sheet (Form FDA 1571) meeting the requirements of § 312.23(a);
p.000087: (ii) The rationale for the intended use of the drug, including a list of available therapeutic options that would
p.000087: ordi- narily be tried before resorting to the investigational drug or an explanation of why the use of
p.000087: the investigational drug is preferable to the use of avail- able therapeutic options;
p.000087: (iii) The criteria for patient selection
p.000087: or, for an individual patient, a descrip- tion of the patient’s disease or condi-
p.000088: 88
p.000088: 21 CFR Ch. I (4–1–12 Edition)
p.000088: tion, including recent medical history and previous treatments of the disease or condition;
p.000088: (iv) The method of administration of the drug, dose, and duration of ther- apy;
p.000088: (v) A description of the facility where the drug will be manufactured;
p.000088: (vi) Chemistry, manufacturing, and controls information adequate to en- sure the proper identification,
p.000088: quality, purity, and strength of the investiga- tional drug;
p.000088: (vii) Pharmacology and toxicology information adequate to conclude that the drug is reasonably safe at
p.000088: the dose and duration proposed for expanded ac- cess use (ordinarily, information that would be adequate to
p.000088: permit clinical testing of the drug in a population of the size expected to be treated); and
p.000088: (viii) A description of clinical proce- dures, laboratory tests, or other moni- toring necessary to evaluate
p.000088: the effects of the drug and minimize its risks.
p.000088: (3) The expanded access submission and its mailing cover must be plainly marked ‘‘EXPANDED ACCESS SUB-
p.000088: MISSION.’’ If the expanded access sub- mission is for a treatment IND or treatment protocol, the
p.000088: applicable box on Form FDA 1571 must be checked.
p.000088: (c) Safeguards. The responsibilities of sponsors and investigators set forth in subpart D of this part are
p.000088: applicable to expanded access use under this subpart as described in this paragraph.
p.000088: (1) A licensed physician under whose immediate direction an investigational drug is administered or dispensed
p.000088: for an expanded access use under this sub- part is considered an investigator, for purposes of this part,
p.000088: and must comply with the responsibilities for investiga- tors set forth in subpart D of this part to the
p.000088: extent they are applicable to the expanded access use.
p.000088: (2) An individual or entity that sub- mits an expanded access IND or pro- tocol under this subpart is
p.000088: considered a sponsor, for purposes of this part, and must comply with the responsibilities for sponsors set
p.000088: forth in subpart D of this part to the extent they are appli- cable to the expanded access use.
p.000088: (3) A licensed physician under whose immediate direction an investigational drug is administered or dispensed,
p.000088: and
p.000088:
p.000088:
p.000088:
p.000088:
p.000088:
p.000088:
p.000088:
p.000088: Food and Drug Administration, HHS § 312.310
p.000088:
p.000088:
p.000088: who submits an IND for expanded ac- cess use under this subpart is consid- ered a sponsor-investigator,
p.000088: for purposes of this part, and must comply with the responsibilities for sponsors and inves- tigators set forth
p.000088: in subpart D of this part to the extent they are applicable to the expanded access use.
p.000088: (4) Investigators. In all cases of ex- panded access, investigators are re- sponsible for reporting
p.000088: adverse drug events to the sponsor, ensuring that the informed consent requirements of part 50 of
p.000088: this chapter are met, ensur- ing that IRB review of the expanded ac- cess use is obtained in a manner con-
p.000088: sistent with the requirements of part 56 of this chapter, and maintaining ac- curate case histories and
p.000088: drug disposi- tion records and retaining records in a manner consistent with the require- ments of §
p.000088: 312.62. Depending on the type of expanded access, other investigator responsibilities under subpart D may also
p.000088: apply.
p.000088: (5) Sponsors. In all cases of expanded
p.000088: access, sponsors are responsible for submitting IND safety reports and an- nual reports (when the IND or
p.000088: protocol continues for 1 year or longer) to FDA as required by §§ 312.32 and 312.33, en- suring that
p.000088: licensed physicians are qualified to administer the investiga- tional drug for the expanded access
p.000088: use, providing licensed physicians with the information needed to minimize the risk and maximize the
p.000088: potential benefits of the investigational drug (the investigator’s brochure must be provided if one
p.000088: exists for the drug), maintaining an effective IND for the expanded access use, and maintaining
p.000088: adequate drug disposition records and retaining records in a manner con- sistent with the
p.000088: requirements of
p.000088: § 312.57. Depending on the type of ex-
p.000088: panded access, other sponsor respon- sibilities under subpart D may also apply.
p.000088: (d) Beginning treatment—(1) INDs. An expanded access IND goes into effect 30 days after FDA receives the IND
p.000088: or on earlier notification by FDA that the expanded access use may begin.
p.000088: (2) Protocols. With the following ex- ceptions, expanded access use under a protocol submitted under an
p.000088: existing IND may begin as described in
p.000088: § 312.30(a).
p.000088:
p.000089: 89
p.000089:
p.000089: (i) Expanded access use under the emergency procedures described in
p.000089: § 312.310(d) may begin when the use is authorized by the FDA reviewing offi- cial.
p.000089: (ii) Expanded access use under
p.000089: § 312.320 may begin 30 days after FDA receives the protocol or upon earlier notification by FDA that
p.000089: use may begin.
p.000089: (3) Clinical holds. FDA may place any expanded access IND or protocol on clinical hold as described in §
p.000089: 312.42.
p.000089: § 312.310 Individual patients, includ- ing for emergency use.
p.000089: Under this section, FDA may permit an investigational drug to be used for the treatment of an individual
p.000089: patient by a licensed physician.
p.000089: (a) Criteria. The criteria in § 312.305(a) must be met; and the following deter- minations must be made:
p.000089: (1) The physician must determine that the probable risk to the person from the investigational drug
p.000089: is not greater than the probable risk from the disease or condition; and
p.000089: (2) FDA must determine that the pa- tient cannot obtain the drug under an- other IND or protocol.
p.000089: (b) Submission. The expanded access submission must include information adequate to demonstrate that the
p.000089: cri- teria in § 312.305(a) and paragraph (a) of this section have been met. The ex- panded access
p.000089: submission must meet the requirements of § 312.305(b).
p.000089: (1) If the drug is the subject of an ex- isting IND, the expanded access sub- mission may be made by the sponsor
p.000089: or by a licensed physician.
p.000089: (2) A sponsor may satisfy the submis- sion requirements by amending its ex- isting IND to include a protocol for
p.000089: in- dividual patient expanded access.
p.000089: (3) A licensed physician may satisfy the submission requirements by ob- taining from the sponsor
p.000089: permission for FDA to refer to any information in the IND that would be needed to sup- port the expanded access
p.000089: request (right of reference) and by providing any other required information not con- tained in the
p.000089: IND (usually only the in- formation specific to the individual pa- tient).
p.000089: (c) Safeguards. (1) Treatment is gen- erally limited to a single course of
p.000089:
p.000089:
p.000089:
p.000089:
p.000089:
p.000089:
p.000089:
p.000089:
p.000089: § 312.315
p.000089: therapy for a specified duration unless FDA expressly authorizes multiple courses or chronic therapy.
p.000089: (2) At the conclusion of treatment, the licensed physician or sponsor must provide FDA with a written
p.000089: summary of the results of the expanded access use, including adverse effects.
p.000089: (3) FDA may require sponsors to monitor an individual patient ex- panded access use if the
p.000089: use is for an extended duration.
p.000089: (4) When a significant number of similar individual patient expanded ac- cess requests have been
p.000089: submitted, FDA may ask the sponsor to submit an IND or protocol for the use under
p.000089: § 312.315 or § 312.320.
p.000089: (d) Emergency procedures. If there is an emergency that requires the patient to be treated before a written
p.000089: submis- sion can be made, FDA may authorize the expanded access use to begin with- out a written
p.000089: submission. The FDA re- viewing official may authorize the emergency use by telephone.
p.000089: (1) Emergency expanded access use may be requested by telephone, fac- simile, or other means
p.000089: of electronic communications. For investigational biological drug products regulated by the Center for
p.000089: Biologics Evaluation and Research, the request should be di- rected to the Office of Communication, Outreach and
p.000089: Development, Center for Biologics Evaluation and Research, 301–827–1800 or 1–800–835–4709, e-mail:
p.000089: ocod@fda.hhs.gov. For all other inves- tigational drugs, the request for au- thorization should be
p.000089: directed to the Division of Drug Information, Center for Drug Evaluation and Research, 301– 796–3400, e-mail:
p.000089: druginfo@fda.hhs.gov. After normal working hours (8 a.m. to 4:30 p.m.), the request should be di-
p.000089: rected to the FDA Emergency Call Cen- ter, 866–300–4374, e-mail: emer-
p.000089: gency.operations@fda.hhs.gov.
p.000089: (2) The licensed physician or sponsor must explain how the expanded access use will meet the
p.000089: requirements of
p.000089: §§ 312.305 and 312.310 and must agree to submit an expanded access submission within 15 working days of
p.000089: FDA’s au- thorization of the use.
p.000089: [74 FR 40942, Aug. 13, 2009, as amended at 75
p.000089: FR 32659, June 9, 2010]
p.000089:
p.000090: 90
p.000090: 21 CFR Ch. I (4–1–12 Edition)
p.000090:
p.000090: § 312.315 Intermediate-size patient populations.
p.000090: Under this section, FDA may permit an investigational drug to be used for the treatment of a patient
p.000090: population smaller than that typical of a treat- ment IND or treatment protocol. FDA may ask a sponsor
p.000090: to consolidate ex- panded access under this section when the agency has received a significant number of
p.000090: requests for individual pa- tient expanded access to an investiga- tional drug for the same use.
p.000090: (a) Need for expanded access. Expanded
p.000090: access under this section may be need- ed in the following situations:
p.000090: (1) Drug not being developed. The drug is not being developed, for example, be- cause the disease or
p.000090: condition is so rare that the sponsor is unable to re- cruit patients for a clinical trial.
p.000090: (2) Drug being developed. The drug is being studied in a clinical trial, but pa- tients requesting the drug for
p.000090: expanded access use are unable to participate in the trial. For example, patients may not be able to
p.000090: participate in the trial because they have a different disease or stage of disease than the one being
p.000090: studied or otherwise do not meet the enrollment criteria, because enroll- ment in the trial is
p.000090: closed, or because the trial site is not geographically ac- cessible.
p.000090: (3) Approved or related drug. (i) The
p.000090: drug is an approved drug product that is no longer marketed for safety rea- sons or is unavailable
p.000090: through mar- keting due to failure to meet the con- ditions of the approved application, or
p.000090: (ii) The drug contains the same ac- tive moiety as an approved drug prod- uct that is unavailable
p.000090: through mar- keting due to failure to meet the con- ditions of the approved application or a drug shortage.
p.000090: (b) Criteria. The criteria in § 312.305(a) must be met; and FDA must determine that:
p.000090: (1) There is enough evidence that the drug is safe at the dose and duration proposed for expanded access
p.000090: use to justify a clinical trial of the drug in the approximate number of patients ex- pected to receive the
p.000090: drug under ex- panded access; and
p.000090: (2) There is at least preliminary clin- ical evidence of effectiveness of the drug, or of a plausible
p.000090: pharmacologic
p.000090:
p.000090:
p.000090:
p.000090:
p.000090:
p.000090:
p.000090:
p.000090: Food and Drug Administration, HHS § 312.320
p.000090:
p.000090:
p.000090: effect of the drug to make expanded ac- cess use a reasonable therapeutic op- tion in the anticipated patient
p.000090: popu- lation.
p.000090: (c) Submission. The expanded access submission must include information adequate to satisfy FDA that the
p.000090: cri- teria in § 312.305(a) and paragraph (b) of this section have been met. The ex- panded access
p.000090: submission must meet the requirements of § 312.305(b). In addi- tion:
p.000090: (1) The expanded access submission must state whether the drug is being developed or is not being developed
p.000090: and describe the patient population to be treated.
p.000090: (2) If the drug is not being actively developed, the sponsor must explain why the drug cannot
p.000090: currently be de- veloped for the expanded access use and under what circumstances the drug could be
p.000090: developed.
p.000090: (3) If the drug is being studied in a clinical trial, the sponsor must explain why the patients to be
p.000090: treated cannot be enrolled in the clinical trial and under what circumstances the sponsor would
p.000090: conduct a clinical trial in these patients.
p.000090: (d) Safeguards. (1) Upon review of the IND annual report, FDA will determine whether it is appropriate for
p.000090: the ex- panded access to continue under this section.
p.000090: (i) If the drug is not being actively developed or if the expanded access use is not being developed (but
p.000090: another use is being developed), FDA will consider whether it is possible to conduct a clin- ical study of the
p.000090: expanded access use.
p.000090: (ii) If the drug is being actively de- veloped, FDA will consider whether providing the
p.000090: investigational drug for expanded access use is interfering with the clinical development of the drug.
p.000090: (iii) As the number of patients en- rolled increases, FDA may ask the sponsor to submit an IND or
p.000090: protocol for the use under § 312.320.
p.000090: (2) The sponsor is responsible for monitoring the expanded access pro- tocol to ensure that
p.000090: licensed physi- cians comply with the protocol and the regulations applicable to investigators.
p.000090:
p.000090: § 312.320 Treatment IND or treatment protocol.
p.000090: Under this section, FDA may permit an investigational drug to be used for widespread treatment use.
p.000090: (a) Criteria. The criteria in § 312.305(a) must be met, and FDA must determine that:
p.000090: (1) Trial status. (i) The drug is being investigated in a controlled clinical trial under an IND
p.000090: designed to support a marketing application for the ex- panded access use, or
p.000090: (ii) All clinical trials of the drug have been completed; and
p.000090: (2) Marketing status. The sponsor is actively pursuing marketing approval of the drug for the expanded access
p.000090: use with due diligence; and
p.000090: (3) Evidence. (i) When the expanded access use is for a serious disease or condition, there is
p.000090: sufficient clinical evidence of safety and effectiveness to support the expanded access use. Such evidence
p.000090: would ordinarily consist of data from phase 3 trials, but could con- sist of compelling data from completed
p.000090: phase 2 trials; or
p.000090: (ii) When the expanded access use is for an immediately life-threatening disease or condition, the
p.000090: available sci- entific evidence, taken as a whole, pro- vides a reasonable basis to conclude that the
p.000090: investigational drug may be effective for the expanded access use and would not expose patients to an
p.000090: unreasonable and significant risk of ill- ness or injury. This evidence would or- dinarily consist of clinical
p.000090: data from phase 3 or phase 2 trials, but could be based on more preliminary clinical evi- dence.
p.000090: (b) Submission. The expanded access submission must include information adequate to satisfy FDA that the
p.000090: cri- teria in § 312.305(a) and paragraph (a) of this section have been met. The ex- panded access
p.000090: submission must meet the requirements of § 312.305(b).
p.000090: (c) Safeguard. The sponsor is respon- sible for monitoring the treatment pro- tocol to ensure that
p.000090: licensed physi- cians comply with the protocol and the regulations applicable to investigators.
p.000090:
p.000091: 91
p.000091:
p.000091:
p.000091:
p.000091:
p.000091:
p.000091:
p.000091:
p.000091:
p.000091: Pt. 314
p.000091: PART 314—APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG
p.000091: Subpart A—General Provisions
p.000091: Sec.
p.000091: 314.1 Scope of this part.
p.000091: 314.2 Purpose.
p.000091: 314.3 Definitions.
p.000091: Subpart B—Applications
p.000091: 314.50 Content and format of an application.
p.000091: 314.52 Notice of certification of invalidity or noninfringement of a patent.
p.000091: 314.53 Submission of patent information.
p.000091: 314.54 Procedure for submission of an appli- cation requiring investigations for ap- proval of a new
p.000091: indication for, or other change from, a listed drug.
p.000091: 314.55 Pediatric use information.
p.000091: 314.60 Amendments to an unapproved appli- cation, supplement, or resubmission.
p.000091: 314.65 Withdrawal by the applicant of an un- approved application.
p.000091: 314.70 Supplements and other changes to an approved application.
p.000091: 314.71 Procedures for submission of a sup- plement to an approved application.
p.000091: 314.72 Change in ownership of an applica- tion.
p.000091: 314.80 Postmarketing reporting of adverse drug experiences.
p.000091: 314.81 Other postmarketing reports.
p.000091: 314.90 Waivers.
p.000091: Subpart C—Abbreviated Applications
p.000091: 314.91 Obtaining a reduction in the dis- continuance notification period.
p.000091: 314.92 Drug products for which abbreviated applications may be submitted.
p.000091: 314.93 Petition to request a change from a listed drug.
p.000091: 314.94 Content and format of an abbreviated application.
p.000091: 314.95 Notice of certification of invalidity or noninfringement of a patent.
p.000091: 314.96 Amendments to an unapproved abbre- viated application.
p.000091: 314.97 Supplements and other changes to an approved abbreviated application.
p.000091: 314.98 Postmarketing reports.
p.000091: 314.99 Other responsibilities of an applicant of an abbreviated application.
p.000091: Subpart D—FDA Action on Applications and Abbreviated Applications
p.000091: 314.100 Timeframes for reviewing applica- tions and abbreviated applications.
p.000091: 314.101 Filing an application and receiving an abbreviated new drug application.
p.000091: 314.102 Communications between FDA and applicants.
p.000091: 314.103 Dispute resolution.
p.000091:
p.000092: 92
p.000092: 21 CFR Ch. I (4–1–12 Edition)
p.000092: 314.104 Drugs with potential for abuse.
p.000092: 314.105 Approval of an application and an abbreviated application.
p.000092: 314.106 Foreign data.
p.000092: 314.107 Effective date of approval of a 505(b)(2) application or abbreviated new drug
p.000092: application under section 505(j) of the act.
...
...
Searching for indicator substance:
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p.000057: the reasons for the withdrawal.
p.000057: (iv) A brief description of the overall plan for investigating the drug product for the following year. The plan
p.000057: should include the following: (a) The rationale for the drug or the research study; (b) the indication(s) to
p.000057: be studied; (c) the general approach to be followed in evaluating the drug; (d) the kinds of
p.000057: clinical trials to be conducted in the first year following the submission (if plans are not developed
p.000057: for the entire year, the sponsor should so indicate);
p.000057: (e) the estimated number of patients to be given the drug in those studies; and
p.000057: (f) any risks of particular severity or seriousness anticipated on the basis of the toxicological data
p.000057: in animals or prior studies in humans with the drug or related drugs.
p.000057: (4) [Reserved]
p.000057: (5) Investigator’s brochure. If required under § 312.55, a copy of the investiga- tor’s brochure,
p.000057: containing the fol- lowing information:
p.000057: (i) A brief description of the drug substance and the formulation, includ- ing the structural formula,
p.000057: if known.
p.000057: (ii) A summary of the pharma- cological and toxicological effects of the drug in animals
p.000057: and, to the extent known, in humans.
p.000057: (iii) A summary of the pharmaco- kinetics and biological disposition of the drug in animals and, if
p.000057: known, in humans.
p.000057: (iv) A summary of information relat- ing to safety and effectiveness in hu- mans obtained from prior clinical
p.000057: stud- ies. (Reprints of published articles on such studies may be appended when useful.)
p.000057: (v) A description of possible risks and side effects to be anticipated on the basis of prior experience with
p.000057: the drug under investigation or with related drugs, and of precautions or special monitoring to be
p.000057: done as part of the in- vestigational use of the drug.
p.000057:
p.000057:
p.000057:
p.000057:
p.000057:
p.000057:
p.000057:
p.000057:
p.000057: § 312.23
p.000057: (6) Protocols. (i) A protocol for each planned study. (Protocols for studies not submitted initially
p.000057: in the IND should be submitted in accordance with
p.000057: § 312.30(a).) In general, protocols for Phase 1 studies may be less detailed and more flexible than
...
p.000057: to be used; and the name and address of each reviewing Institutional Review Board.
p.000057: (c) The criteria for patient selection and for exclusion of patients and an es-
p.000057:
p.000058: 58
p.000058: 21 CFR Ch. I (4–1–12 Edition)
p.000058: timate of the number of patients to be studied.
p.000058: (d) A description of the design of the study, including the kind of control group to be used, if any,
p.000058: and a descrip- tion of methods to be used to minimize bias on the part of subjects, investiga- tors, and
p.000058: analysts.
p.000058: (e) The method for determining the dose(s) to be administered, the planned maximum dosage, and the duration
p.000058: of individual patient exposure to the drug.
p.000058: (f) A description of the observations and measurements to be made to fulfill the objectives of the study.
p.000058: (g) A description of clinical proce- dures, laboratory tests, or other meas- ures to be taken to monitor
p.000058: the effects of the drug in human subjects and to minimize risk.
p.000058: (7) Chemistry, manufacturing, and con- trol information. (i) As appropriate for the particular
p.000058: investigations covered by the IND, a section describing the composition, manufacture, and control of the
p.000058: drug substance and the drug product. Although in each phase of the investigation sufficient information is
p.000058: required to be submitted to assure the proper identification, quality, purity, and strength of the
p.000058: investigational drug, the amount of information need- ed to make that assurance will vary with the phase of
p.000058: the investigation, the proposed duration of the investigation, the dosage form, and the amount of in- formation
p.000058: otherwise available. FDA recognizes that modifications to the method of preparation of the new drug
p.000058: substance and dosage form and changes in the dosage form itself are likely as the investigation
p.000058: progresses. There- fore, the emphasis in an initial Phase 1 submission should generally be placed on the
p.000058: identification and control of the raw materials and the new drug sub- stance. Final specifications for
p.000058: the drug substance and drug product are not expected until the end of the inves- tigational process.
p.000058: (ii) It should be emphasized that the
p.000058: amount of information to be submitted depends upon the scope of the proposed clinical investigation. For example, al-
p.000058: though stability data are required in all phases of the IND to demonstrate that the new drug substance
p.000058: and drug product are within acceptable chemical
p.000058:
p.000058:
p.000058:
p.000058:
p.000058:
p.000058:
p.000058:
p.000058: Food and Drug Administration, HHS § 312.23
p.000058:
p.000058:
p.000058: and physical limits for the planned du- ration of the proposed clinical inves- tigation, if very short-term
p.000058: tests are proposed, the supporting stability data can be correspondingly limited.
p.000058: (iii) As drug development proceeds and as the scale or production is changed from the
p.000058: pilot-scale produc- tion appropriate for the limited initial clinical investigations to the larger-
p.000058: scale production needed for expanded clinical trials, the sponsor should sub- mit information amendments to
p.000058: sup- plement the initial information sub- mitted on the chemistry, manufac- turing, and control
p.000058: processes with in- formation appropriate to the expanded scope of the investigation.
p.000058: (iv) Reflecting the distinctions de-
p.000058: scribed in this paragraph (a)(7), and based on the phase(s) to be studied, the submission is required to
p.000058: contain the following:
p.000058: (a) Drug substance. A description of the drug substance, including its phys- ical, chemical, or
p.000058: biological character- istics; the name and address of its man- ufacturer; the general method of prepa- ration of the
p.000058: drug substance; the ac- ceptable limits and analytical methods used to assure the identity, strength, quality,
p.000058: and purity of the drug sub- stance; and information sufficient to support stability of the drug
p.000058: substance during the toxicological studies and the planned clinical studies. Reference to the current
p.000058: edition of the United States Pharmacopeia—National For- mulary may satisfy relevant require- ments in this
p.000058: paragraph.
p.000058: (b) Drug product. A list of all compo-
p.000058: nents, which may include reasonable alternatives for inactive compounds, used in the manufacture of
p.000058: the inves- tigational drug product, including both those components intended to appear in the drug product and
p.000058: those which may not appear but which are used in the manufacturing process, and, where applicable, the
p.000058: quantitative composi- tion of the investigational drug prod- uct, including any reasonable vari- ations
p.000058: that may be expected during the investigational stage; the name and ad- dress of the drug product manufac-
p.000058: turer; a brief general description of the manufacturing and packaging proce- dure as appropriate for the product;
p.000058: the acceptable limits and analytical meth-
p.000059: 59
p.000059:
p.000059: ods used to assure the identity, strength, quality, and purity of the drug product; and
...
p.000076: availability studies described in,
p.000076: § 320.38 or § 320.63 of this chapter, and release the reserve samples to FDA upon request, in
p.000076: accordance with, and for the period specified in § 320.38.
p.000076: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000076: FR 23031, June 17, 1987; 58 FR 25926, Apr. 28,
p.000076: 1993; 63 FR 5252, Feb. 2, 1998; 67 FR 9586, Mar.
p.000076: 4, 2002]
p.000076:
p.000076: § 312.58 Inspection of sponsor’s records and reports.
p.000076: (a) FDA inspection. A sponsor shall upon request from any properly au- thorized officer or
p.000076: employee of the Food and Drug Administration, at rea- sonable times, permit such officer or employee to
p.000076: have access to and copy and verify any records and reports re- lating to a clinical investigation con-
p.000076: ducted under this part. Upon written request by FDA, the sponsor shall sub- mit the records or reports (or
p.000076: copies of them) to FDA. The sponsor shall dis- continue shipments of the drug to any investigator who has
p.000076: failed to maintain or make available records or reports of the investigation as required by this part.
p.000076: (b) Controlled substances. If an inves- tigational new drug is a substance list- ed in any schedule of the
p.000076: Controlled Substances Act (21 U.S.C. 801; 21 CFR part 1308), records concerning ship- ment, delivery,
p.000076: receipt, and disposition of the drug, which are required to be kept under this part or other applica- ble
p.000076: parts of this chapter shall, upon the request of a properly authorized em- ployee of the Drug Enforcement
p.000076: Ad- ministration of the U.S. Department of Justice, be made available by the in- vestigator or sponsor to
p.000076: whom the re- quest is made, for inspection and copy- ing. In addition, the sponsor shall as- sure that
p.000076: adequate precautions are taken, including storage of the inves- tigational drug in a securely locked,
p.000076: substantially constructed cabinet, or other securely locked, substantially constructed enclosure, access
p.000076: to which is limited, to prevent theft or diversion of the substance into illegal channels of distribution.
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076: Food and Drug Administration, HHS § 312.64
p.000076:
p.000076:
p.000076: § 312.59 Disposition of unused supply of investigational drug.
p.000076: The sponsor shall assure the return of all unused supplies of the investiga- tional drug from each
p.000076: individual inves- tigator whose participation in the in- vestigation is discontinued or termi- nated. The
p.000076: sponsor may authorize al- ternative disposition of unused supplies of the investigational drug provided
p.000076: this alternative disposition does not expose humans to risks from the drug. The sponsor shall
p.000076: maintain written records of any disposition of the drug in accordance with § 312.57.
p.000076: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000076: FR 23031, June 17, 1987; 67 FR 9586, Mar. 4,
p.000076: 2002]
p.000076:
p.000076: § 312.60 General responsibilities of in- vestigators.
...
p.000077: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000077: FR 23031, June 17, 1987; 67 FR 9586, Mar. 4,
p.000077: 2002]
p.000077:
p.000077: § 312.68 Inspection of investigator’s records and reports.
p.000077: An investigator shall upon request from any properly authorized officer or
p.000077:
p.000078: 78
p.000078: 21 CFR Ch. I (4–1–12 Edition)
p.000078: employee of FDA, at reasonable times, permit such officer or employee to have access to, and copy and
p.000078: verify any records or reports made by the investi- gator pursuant to § 312.62. The investi- gator is not required
p.000078: to divulge subject names unless the records of particular individuals require a more detailed study of
p.000078: the cases, or unless there is reason to believe that the records do not represent actual case studies, or do
p.000078: not represent actual results obtained.
p.000078: § 312.69 Handling of controlled sub- stances.
p.000078: If the investigational drug is subject to the Controlled Substances Act, the investigator shall take
p.000078: adequate pre- cautions, including storage of the in- vestigational drug in a securely locked, substantially
p.000078: constructed cabinet, or other securely locked, substantially constructed enclosure, access to which is
p.000078: limited, to prevent theft or diversion of the substance into illegal channels of distribution.
p.000078: § 312.70 Disqualification of a clinical investigator.
p.000078: (a) If FDA has information indicating that an investigator (including a spon- sor-investigator) has repeatedly
p.000078: or de- liberately failed to comply with the re- quirements of this part, part 50, or part 56 of this chapter, or
p.000078: has submitted to FDA or to the sponsor false informa- tion in any required report, the Center for Drug
p.000078: Evaluation and Research or the Center for Biologics Evaluation and Research will furnish the investi-
p.000078: gator written notice of the matter complained of and offer the investi- gator an opportunity
p.000078: to explain the matter in writing, or, at the option of the investigator, in an informal con- ference.
p.000078: If an explanation is offered but not accepted by the Center for Drug Evaluation and Research or the Center for
p.000078: Biologics Evaluation and Research, the investigator will be given an oppor- tunity for a regulatory hearing
p.000078: under part 16 on the question of whether the investigator is entitled to receive in- vestigational new
p.000078: drugs.
p.000078: (b) After evaluating all available in- formation, including any explanation presented by the
p.000078: investigator, if the
p.000078:
p.000078:
p.000078:
p.000078:
p.000078:
p.000078:
p.000078:
...
Health / Physically Disabled
Searching for indicator illness:
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p.000066: communications with a sponsor under this section are solely advisory and do not require any modification in
p.000066: the planned or ongoing clinical investigations or response to the agency.
p.000066: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000066: FR 23031, June 17, 1987; 67 FR 9586, Mar. 4,
p.000066: 2002]
p.000066:
p.000066: § 312.42 Clinical holds and requests for modification.
p.000066: (a) General. A clinical hold is an order issued by FDA to the sponsor to delay a proposed clinical
p.000066: investigation or to suspend an ongoing investigation. The clinical hold order may apply to one or more of the
p.000066: investigations covered by an IND. When a proposed study is placed on clinical hold, subjects may not
p.000066: be given the investigational drug. When an ongoing study is placed on clinical hold, no new subjects
p.000066: may be recruited to the study and placed on the investigational drug; patients al- ready in the study
p.000066: should be taken off therapy involving the investigational drug unless specifically permitted by FDA in the
p.000066: interest of patient safety.
p.000067: 67
p.000067:
p.000067: (b) Grounds for imposition of clinical hold—(1) Clinical hold of a Phase 1 study under an IND. FDA
p.000067: may place a pro- posed or ongoing Phase 1 investigation on clinical hold if it finds that:
p.000067: (i) Human subjects are or would be exposed to an unreasonable and signifi- cant risk of illness or injury;
p.000067: (ii) The clinical investigators named in the IND are not qualified by reason of their scientific training
p.000067: and experi- ence to conduct the investigation de- scribed in the IND;
p.000067: (iii) The investigator brochure is misleading, erroneous, or materially incomplete; or
p.000067: (iv) The IND does not contain suffi- cient information required under
p.000067: § 312.23 to assess the risks to subjects of the proposed studies.
p.000067: (v) The IND is for the study of an in- vestigational drug intended to treat a life-threatening disease or
p.000067: condition that affects both genders, and men or women with reproductive potential who have the
p.000067: disease or condition being studied are excluded from eligi- bility because of a risk or potential
p.000067: risk from use of the investigational drug of reproductive toxicity (i.e., af- fecting reproductive
p.000067: organs) or devel- opmental toxicity (i.e., affecting poten- tial offspring). The phrase ‘‘women with
p.000067: reproductive potential’’ does not include pregnant women. For purposes of this paragraph, ‘‘life-threatening
p.000067: ill- nesses or diseases’’ are defined as ‘‘dis- eases or conditions where the likeli- hood of death is high
...
p.000069: remain on clinical hold for 1 year or more, the IND may be placed on inactive status by FDA under §
p.000069: 312.45.
p.000069: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000069: FR 19477, May 22, 1987; 57 FR 13249, Apr. 15,
p.000069: 1992; 61 FR 51530, Oct. 2, 1996; 63 FR 68678,
p.000069: Dec. 14, 1998; 64 FR 54189, Oct. 5, 1999; 65 FR
p.000069: 34971, June 1, 2000; 74 FR 40942, Aug. 13, 2009]
p.000069:
p.000069: § 312.44 Termination.
p.000069: (a) General. This section describes the procedures under which FDA may ter- minate an IND. If an IND
p.000069: is termi- nated, the sponsor shall end all clinical investigations conducted under the IND and recall or
p.000069: otherwise provide for the disposition of all unused supplies of the drug. A termination action may be based on
p.000069: deficiencies in the IND or in the conduct of an investigation under an IND. Except as provided in
p.000069: para- graph (d) of this section, a termination shall be preceded by a proposal to ter- minate by FDA and an
p.000069: opportunity for the sponsor to respond. FDA will, in general, only initiate an action under this section
p.000069: after first attempting to resolve differences informally or, when appropriate, through the clinical hold
p.000069: procedures described in § 312.42.
p.000069: (b) Grounds for termination—(1) Phase
p.000069: 1. FDA may propose to terminate an IND during Phase 1 if it finds that:
p.000069: (i) Human subjects would be exposed to an unreasonable and significant risk of illness or unjury.
p.000069: (ii) The IND does not contain suffi- cient information required under
p.000069: § 312.23 to assess the safety to subjects of the clinical investigations.
p.000069: (iii) The methods, facilities, and con- trols used for the manufacturing, proc- essing, and packing of the
p.000069: investiga- tional drug are inadequate to establish and maintain appropriate standards of identity, strength,
p.000069: quality, and purity as needed for subject safety.
p.000069:
p.000069:
p.000069:
p.000069:
p.000069:
p.000069:
p.000069:
p.000069:
p.000069: § 312.45
p.000069: (iv) The clinical investigations are being conducted in a manner substan- tially different than that
p.000069: described in the protocols submitted in the IND.
p.000069: (v) The drug is being promoted or dis- tributed for commercial purposes not justified by the requirements of the
p.000069: in- vestigation or permitted by § 312.7.
p.000069: (vi) The IND, or any amendment or report to the IND, contains an untrue statement of a material fact
p.000069: or omits material information required by this part.
p.000069: (vii) The sponsor fails promptly to in- vestigate and inform the Food and Drug Administration and all
p.000069: investiga- tors of serious and unexpected adverse experiences in accordance with § 312.32 or fails to make
p.000069: any other report re- quired under this part.
p.000069: (viii) The sponsor fails to submit an accurate annual report of the inves- tigations in accordance with
p.000069: § 312.33.
p.000069: (ix) The sponsor fails to comply with any other applicable requirement of this part, part 50, or part 56.
...
Health / Pregnant
Searching for indicator pregnant:
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p.000067: may place a pro- posed or ongoing Phase 1 investigation on clinical hold if it finds that:
p.000067: (i) Human subjects are or would be exposed to an unreasonable and signifi- cant risk of illness or injury;
p.000067: (ii) The clinical investigators named in the IND are not qualified by reason of their scientific training
p.000067: and experi- ence to conduct the investigation de- scribed in the IND;
p.000067: (iii) The investigator brochure is misleading, erroneous, or materially incomplete; or
p.000067: (iv) The IND does not contain suffi- cient information required under
p.000067: § 312.23 to assess the risks to subjects of the proposed studies.
p.000067: (v) The IND is for the study of an in- vestigational drug intended to treat a life-threatening disease or
p.000067: condition that affects both genders, and men or women with reproductive potential who have the
p.000067: disease or condition being studied are excluded from eligi- bility because of a risk or potential
p.000067: risk from use of the investigational drug of reproductive toxicity (i.e., af- fecting reproductive
p.000067: organs) or devel- opmental toxicity (i.e., affecting poten- tial offspring). The phrase ‘‘women with
p.000067: reproductive potential’’ does not include pregnant women. For purposes of this paragraph, ‘‘life-threatening
p.000067: ill- nesses or diseases’’ are defined as ‘‘dis- eases or conditions where the likeli- hood of death is high
p.000067: unless the course of the disease is interrupted.’’ The clin- ical hold would not apply under this paragraph to
p.000067: clinical studies con- ducted:
p.000067: (A) Under special circumstances, such as studies pertinent only to one gender (e.g., studies
p.000067: evaluating the ex- cretion of a drug in semen or the ef- fects on menstrual function);
p.000067: (B) Only in men or women, as long as a study that does not exclude members of the other gender with reproductive
p.000067: potential is being conducted concur- rently, has been conducted, or will take place within a
p.000067: reasonable time agreed upon by the agency; or
p.000067: (C) Only in subjects who do not suffer from the disease or condition for which the drug is being studied.
p.000067:
p.000067:
p.000067:
p.000067:
p.000067:
p.000067:
p.000067:
p.000067:
p.000067: § 312.42
p.000067: (2) Clinical hold of a Phase 2 or 3 study under an IND. FDA may place a pro- posed or ongoing Phase
p.000067: 2 or 3 inves- tigation on clinical hold if it finds that:
p.000067: (i) Any of the conditions in para- graphs (b)(1)(i) through (b)(1)(v) of this section apply; or
...
Health / ill
Searching for indicator ill:
(return to top)
p.000067: (ii) The clinical investigators named in the IND are not qualified by reason of their scientific training
p.000067: and experi- ence to conduct the investigation de- scribed in the IND;
p.000067: (iii) The investigator brochure is misleading, erroneous, or materially incomplete; or
p.000067: (iv) The IND does not contain suffi- cient information required under
p.000067: § 312.23 to assess the risks to subjects of the proposed studies.
p.000067: (v) The IND is for the study of an in- vestigational drug intended to treat a life-threatening disease or
p.000067: condition that affects both genders, and men or women with reproductive potential who have the
p.000067: disease or condition being studied are excluded from eligi- bility because of a risk or potential
p.000067: risk from use of the investigational drug of reproductive toxicity (i.e., af- fecting reproductive
p.000067: organs) or devel- opmental toxicity (i.e., affecting poten- tial offspring). The phrase ‘‘women with
p.000067: reproductive potential’’ does not include pregnant women. For purposes of this paragraph, ‘‘life-threatening
p.000067: ill- nesses or diseases’’ are defined as ‘‘dis- eases or conditions where the likeli- hood of death is high
p.000067: unless the course of the disease is interrupted.’’ The clin- ical hold would not apply under this paragraph to
p.000067: clinical studies con- ducted:
p.000067: (A) Under special circumstances, such as studies pertinent only to one gender (e.g., studies
p.000067: evaluating the ex- cretion of a drug in semen or the ef- fects on menstrual function);
p.000067: (B) Only in men or women, as long as a study that does not exclude members of the other gender with reproductive
p.000067: potential is being conducted concur- rently, has been conducted, or will take place within a
p.000067: reasonable time agreed upon by the agency; or
p.000067: (C) Only in subjects who do not suffer from the disease or condition for which the drug is being studied.
p.000067:
p.000067:
p.000067:
p.000067:
p.000067:
p.000067:
p.000067:
p.000067:
p.000067: § 312.42
p.000067: (2) Clinical hold of a Phase 2 or 3 study under an IND. FDA may place a pro- posed or ongoing Phase
p.000067: 2 or 3 inves- tigation on clinical hold if it finds that:
p.000067: (i) Any of the conditions in para- graphs (b)(1)(i) through (b)(1)(v) of this section apply; or
p.000067: (ii) The plan or protocol for the in- vestigation is clearly deficient in de- sign to meet its stated
p.000067: objectives.
...
p.000079: treat life-threatening and se- verely-debilitating illnesses, than they would accept from products that treat
p.000079: less serious illnesses. These procedures also reflect the recognition that the benefits of the drug
p.000079: need to be evalu- ated in light of the severity of the dis- ease being treated. The procedure out-
p.000079: lined in this section should be inter- preted consistent with that purpose.
p.000079:
p.000079:
p.000079:
p.000079:
p.000079:
p.000079:
p.000079:
p.000079:
p.000079: § 312.81
p.000079: § 312.81 Scope.
p.000079: This section applies to new drug and biological products that are being stud- ied for their safety and
p.000079: effectiveness in treating life-threatening or severely- debilitating diseases.
p.000079: (a) For purposes of this section, the term ‘‘life-threatening’’ means:
p.000079: (1) Diseases or conditions where the likelihood of death is high unless the course of the disease is
p.000079: interrupted; and
p.000079: (2) Diseases or conditions with poten- tially fatal outcomes, where the end point of clinical trial analysis
p.000079: is sur- vival.
p.000079: (b) For purposes of this section, the term ‘‘severely debilitating’’ means diseases or conditions that
p.000079: cause major irreversible morbidity.
p.000079: (c) Sponsors are encouraged to con- sult with FDA on the applicability of these procedures to specific
p.000079: products.
p.000079: [53 FR 41523, Oct. 21, 1988, as amended at 64
p.000079: FR 401, Jan. 5, 1999]
p.000079: § 312.82 Early consultation.
p.000079: For products intended to treat life- threatening or severely-debilitating ill- nesses, sponsors may request to
p.000079: meet with FDA-reviewing officials early in the drug development process to review and reach agreement on the
p.000079: design of necessary preclinical and clinical stud- ies. Where appropriate, FDA will invite to such meetings one or
p.000079: more outside expert scientific consultants or advi- sory committee members. To the ex- tent FDA resources
p.000079: permit, agency re- viewing officials will honor requests for such meetings
p.000079: (a) Pre-investigational ne drug (IND) meetings. Prior to the submission of the initial IND, the sponsor may
p.000079: request a meeting with FDA-reviewing officials. The primary purpose of this meeting is to review and reach
p.000079: agreement on the design of animal studies needed to ini- tiate human testing. The meeting may also
p.000079: provide an opportunity for dis- cussing the scope and design of phase 1 testing, plans for studying the
p.000079: drug product in pediatric populations, and the best approach for presentation and formatting of data in the
p.000079: IND.
p.000079: (b) End-of-phase 1 meetings. When data
p.000079: from phase 1 clinical testing are avail- able, the sponsor may again request a
p.000079:
p.000080: 80
p.000080: 21 CFR Ch. I (4–1–12 Edition)
p.000080: meeting with FDA-reviewing officials. The primary purpose of this meeting is to review and reach agreement on
p.000080: the design of phase 2 controlled clinical trials, with the goal that such testing will be adequate
...
p.000080: (d) Marketing applications submitted under the procedures contained in this section will be subject to the
p.000080: require- ments and procedures contained in part 314 or part 600 of this chapter, as well as those in this
p.000080: subpart.
p.000080: [53 FR 41523, Oct. 21, 1988, as amended at 73
p.000080: FR 39607, July 10, 2008]
p.000080:
p.000080: § 312.85 Phase 4 studies.
p.000080: Concurrent with marketing approval, FDA may seek agreement from the sponsor to conduct certain
p.000080: post- marketing (phase 4) studies to delin- eate additional information about the drug’s risks, benefits,
p.000080: and optimal use. These studies could include, but would not be limited to, studying different doses
p.000080: or schedules of administration than were used in phase 2 studies, use of the drug in other
p.000080: patient popu- lations or other stages of the disease, or use of the drug over a longer period of time.
p.000080:
p.000081: 81
p.000081:
p.000081: § 312.86 Focused FDA regulatory re- search.
p.000081: At the discretion of the agency, FDA may undertake focused regulatory re- search on critical rate-limiting aspects
p.000081: of the preclinical, chemical/manufac- turing, and clinical phases of drug de- velopment and evaluation.
p.000081: When initi- ated, FDA will undertake such re- search efforts as a means for meeting a public health need
p.000081: in facilitating the development of therapies to treat life- threatening or severely debilitating ill- nesses.
p.000081: § 312.87 Active monitoring of conduct and evaluation of clinical trials.
p.000081: For drugs covered under this section, the Commissioner and other agency of- ficials will monitor the progress of
p.000081: the conduct and evaluation of clinical trials and be involved in facilitating their appropriate
p.000081: progress.
p.000081: § 312.88 Safeguards for patient safety.
p.000081: All of the safeguards incorporated within parts 50, 56, 312, 314, and 600 of this chapter designed
p.000081: to ensure the safety of clinical testing and the safety of products following marketing ap- proval apply
p.000081: to drugs covered by this section. This includes the requirements for informed consent (part 50 of this
p.000081: chapter) and institutional review boards (part 56 of this chapter). These safeguards further
p.000081: include the review of animal studies prior to initial human testing (§ 312.23), and the moni-
p.000081: toring of adverse drug experiences through the requirements of IND safe- ty reports (§ 312.32),
p.000081: safety update re- ports during agency review of a mar- keting application (§ 314.50 of this chap- ter), and
p.000081: postmarketing adverse reac- tion reporting (§ 314.80 of this chapter).
p.000081: Subpart F—Miscellaneous
p.000081: § 312.110 Import and export require- ments.
p.000081: (a) Imports. An investigational new drug offered for import into the United States complies with the
p.000081: requirements of this part if it is subject to an IND that is in effect for it under § 312.40 and:
...
p.000090: designed to support a marketing application for the ex- panded access use, or
p.000090: (ii) All clinical trials of the drug have been completed; and
p.000090: (2) Marketing status. The sponsor is actively pursuing marketing approval of the drug for the expanded access
p.000090: use with due diligence; and
p.000090: (3) Evidence. (i) When the expanded access use is for a serious disease or condition, there is
p.000090: sufficient clinical evidence of safety and effectiveness to support the expanded access use. Such evidence
p.000090: would ordinarily consist of data from phase 3 trials, but could con- sist of compelling data from completed
p.000090: phase 2 trials; or
p.000090: (ii) When the expanded access use is for an immediately life-threatening disease or condition, the
p.000090: available sci- entific evidence, taken as a whole, pro- vides a reasonable basis to conclude that the
p.000090: investigational drug may be effective for the expanded access use and would not expose patients to an
p.000090: unreasonable and significant risk of ill- ness or injury. This evidence would or- dinarily consist of clinical
p.000090: data from phase 3 or phase 2 trials, but could be based on more preliminary clinical evi- dence.
p.000090: (b) Submission. The expanded access submission must include information adequate to satisfy FDA that the
p.000090: cri- teria in § 312.305(a) and paragraph (a) of this section have been met. The ex- panded access
p.000090: submission must meet the requirements of § 312.305(b).
p.000090: (c) Safeguard. The sponsor is respon- sible for monitoring the treatment pro- tocol to ensure that
p.000090: licensed physi- cians comply with the protocol and the regulations applicable to investigators.
p.000090:
p.000091: 91
p.000091:
p.000091:
p.000091:
p.000091:
p.000091:
p.000091:
p.000091:
p.000091:
p.000091: Pt. 314
p.000091: PART 314—APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG
p.000091: Subpart A—General Provisions
p.000091: Sec.
p.000091: 314.1 Scope of this part.
p.000091: 314.2 Purpose.
p.000091: 314.3 Definitions.
p.000091: Subpart B—Applications
p.000091: 314.50 Content and format of an application.
p.000091: 314.52 Notice of certification of invalidity or noninfringement of a patent.
p.000091: 314.53 Submission of patent information.
p.000091: 314.54 Procedure for submission of an appli- cation requiring investigations for ap- proval of a new
p.000091: indication for, or other change from, a listed drug.
p.000091: 314.55 Pediatric use information.
p.000091: 314.60 Amendments to an unapproved appli- cation, supplement, or resubmission.
...
Social / Access to Social Goods
Searching for indicator access:
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p.000050: 312.66 Assurance of IRB review.
p.000050: 312.68 Inspection of investigator’s records and reports.
p.000050: 312.69 Handling of controlled substances.
p.000050: 312.70 Disqualification of a clinical investi- gator.
p.000050:
p.000050: Subpart E—Drugs Intended to Treat Life- threatening and Severely-debilitating Illnesses
p.000050: 312.80 Purpose.
p.000050: 312.81 Scope.
p.000050: 312.82 Early consultation.
p.000050: 312.83 Treatment protocols.
p.000050: 312.84 Risk-benefit analysis in review of marketing applications for drugs to treat life-threatening and
p.000050: severely-debilitating illnesses.
p.000050: 312.85 Phase 4 studies.
p.000050: 312.86 Focused FDA regulatory research.
p.000050: 312.87 Active monitoring of conduct and evaluation of clinical trials.
p.000050: 312.88 Safeguards for patient safety.
p.000050: Subpart F—Miscellaneous
p.000050: 312.110 Import and export requirements.
p.000050: 312.120 Foreign clinical studies not con- ducted under an IND.
p.000050: 312.130 Availability for public disclosure of data and information in an IND.
p.000050: 312.140 Address for correspondence.
p.000050: 312.145 Guidance documents.
p.000050:
p.000050: Subpart G—Drugs for Investigational Use in Laboratory Research Animals or in Vitro Tests
p.000050: 312.160 Drugs for investigational use in lab- oratory research animals or in vitro tests.
p.000050: Subpart H [Reserved]
p.000050:
p.000050:
p.000050:
p.000050:
p.000050:
p.000050:
p.000050:
p.000050: Food and Drug Administration, HHS § 312.2
p.000050:
p.000050: Subpart I—Expanded Access to Investigational Drugs for Treatment Use
p.000050: 312.300 General.
p.000050: 312.305 Requirements for all expanded ac- cess uses.
p.000050: 312.310 Individual patients, including for emergency use.
p.000050: 312.315 Intermediate-size patient popu- lations.
p.000050: 312.320 Treatment IND or treatment pro- tocol.
p.000050: AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353,
p.000050: 355, 360bbb, 371; 42 U.S.C. 262.
p.000050: SOURCE: 52 FR 8831, Mar. 19, 1987, unless
p.000050: otherwise noted.
p.000050: EDITORIAL NOTE: Nomenclature changes to part 312 can be found at 69 FR 13717, Mar. 24,
p.000050: 2004.
p.000050:
p.000050: Subpart A—General Provisions
p.000050: § 312.1 Scope.
p.000050: (a) This part contains procedures and requirements governing the use of in- vestigational new drugs, including
p.000050: pro- cedures and requirements for the sub- mission to, and review by, the Food and Drug Administration of
p.000050: investiga- tional new drug applications (IND’s). An investigational new drug for which an IND is in
p.000050: effect in accordance with this part is exempt from the premar- keting approval requirements that are
p.000050: otherwise applicable and may be shipped lawfully for the purpose of con- ducting clinical
p.000050: investigations of that drug.
p.000050: (b) References in this part to regula-
p.000050: tions in the Code of Federal Regula- tions are to chapter I of title 21, unless otherwise noted.
...
p.000052: This provision is not intended to restrict the full exchange of scientific information concerning the
p.000052: drug, in- cluding dissemination of scientific findings in scientific or lay media. Rather, its
p.000052: intent is to restrict pro- motional claims of safety or effective- ness of the drug for a use for
p.000052: which it is under investigation and to preclude commercialization of the drug before it
p.000052:
p.000053: 53
p.000053:
p.000053: is approved for commercial distribu- tion.
p.000053: (b) Commercial distribution of an inves- tigational ne drug. A sponsor or inves- tigator shall not
p.000053: commercially dis- tribute or test market an investiga- tional new drug.
p.000053: (c) Prolonging an investigation. A sponsor shall not unduly prolong an in- vestigation after finding
p.000053: that the re- sults of the investigation appear to es- tablish sufficient data to support a marketing
p.000053: application.
p.000053: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000053: FR 19476, May 22, 1987; 67 FR 9585, Mar. 4,
p.000053: 2002; 74 FR 40899, Aug. 13, 2009]
p.000053:
p.000053: § 312.8 Charging for investigational drugs under an IND.
p.000053: (a) General criteria for charging. (1) A sponsor must meet the applicable re- quirements in paragraph (b) of
p.000053: this sec- tion for charging in a clinical trial or paragraph (c) of this section for charg- ing for
p.000053: expanded access to an investiga- tional drug for treatment use under subpart I of this part, except that
p.000053: spon- sors need not fulfill the requirements in this section to charge for an ap- proved drug
p.000053: obtained from another en- tity not affiliated with the sponsor for use as part of the clinical trial
p.000053: evalua- tion (e.g., in a clinical trial of a new use of the approved drug, for use of the approved drug as an
p.000053: active control).
p.000053: (2) A sponsor must justify the
p.000053: amount to be charged in accordance with paragraph (d) of this section.
p.000053: (3) A sponsor must obtain prior writ- ten authorization from FDA to charge for an investigational drug.
p.000053: (4) FDA will withdraw authorization to charge if it determines that charg- ing is interfering with the
p.000053: development of a drug for marketing approval or that the criteria for the authorization are no longer
p.000053: being met.
p.000053: (b) Charging in a clinical trial—(1) Charging for a sponsor’s drug. A sponsor who wishes to charge
p.000053: for its investiga- tional drug, including investigational use of its approved drug, must:
p.000053: (i) Provide evidence that the drug has a potential clinical benefit that, if demonstrated in the clinical
p.000053: investiga- tions, would provide a significant ad- vantage over available products in the diagnosis,
p.000053: treatment, mitigation, or prevention of a disease or condition;
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053: § 312.8
p.000053: (ii) Demonstrate that the data to be obtained from the clinical trial would be essential to
p.000053: establishing that the drug is effective or safe for the purpose of obtaining initial approval of a drug, or
p.000053: would support a significant change in the labeling of an approved drug (e.g., new indication,
p.000053: inclusion of com- parative safety information); and
p.000053: (iii) Demonstrate that the clinical trial could not be conducted without charging because the cost of the
p.000053: drug is extraordinary to the sponsor. The cost may be extraordinary due to manufac- turing complexity,
p.000053: scarcity of a nat- ural resource, the large quantity of drug needed (e.g., due to the size or du- ration
p.000053: of the trial), or some combina- tion of these or other extraordinary circumstances (e.g., resources
p.000053: available to a sponsor).
p.000053: (2) Duration of charging in a clinical trial. Unless FDA specifies a shorter pe- riod, charging may
p.000053: continue for the length of the clinical trial.
p.000053: (c) Charging for expanded access to in- vestigational drug for treatment use. (1) A sponsor who wishes to
p.000053: charge for ex- panded access to an investigational drug for treatment use under subpart I of this part
p.000053: must provide reasonable assurance that charging will not inter- fere with developing the drug for mar- keting
p.000053: approval.
p.000053: (2) For expanded access under § 312.320 (treatment IND or treatment protocol), such assurance must include:
p.000053: (i) Evidence of sufficient enrollment in any ongoing clinical trial(s) needed for marketing approval to
p.000053: reasonably assure FDA that the trial(s) will be successfully completed as planned;
p.000053: (ii) Evidence of adequate progress in the development of the drug for mar- keting approval; and
p.000053: (iii) Information submitted under the general investigational plan (§ 312.23(a)(3)(iv))
p.000053: specifying the drug development milestones the sponsor plans to meet in the next year.
p.000053: (3) The authorization to charge is limited to the number of patients au- thorized to receive the
p.000053: drug under the treatment use, if there is a limitation.
p.000053: (4) Unless FDA specifies a shorter pe- riod, charging for expanded access to an investigational drug for
p.000053: treatment use under subpart I of this part may continue for 1 year from the time of
p.000054: 54
p.000054: 21 CFR Ch. I (4–1–12 Edition)
p.000054: FDA authorization. A sponsor may re- quest that FDA reauthorize charging for additional periods.
p.000054: (d) Costs recoverable hen charging for an investigational drug. (1) A sponsor may recover only the
p.000054: direct costs of making its investigational drug avail- able.
p.000054: (i) Direct costs are costs incurred by a sponsor that can be specifically and exclusively attributed to
p.000054: providing the drug for the investigational use for which FDA has authorized cost recov- ery. Direct
p.000054: costs include costs per unit to manufacture the drug (e.g., raw ma- terials, labor, and nonreusable supplies and
p.000054: equipment used to manufacture the quantity of drug needed for the use for which charging is authorized)
p.000054: or costs to acquire the drug from another manufacturing source, and direct costs to ship and handle
p.000054: (e.g., store) the drug.
p.000054: (ii) Indirect costs include costs in- curred primarily to produce the drug for commercial sale (e.g.,
p.000054: costs for fa- cilities and equipment used to manu- facture the supply of investigational drug, but
p.000054: that are primarily intended to produce large quantities of drug for eventual commercial sale) and research and
p.000054: development, administrative, labor, or other costs that would be in- curred even if the
p.000054: clinical trial or treatment use for which charging is au- thorized did not occur.
p.000054: (2) For expanded access to an inves- tigational drug for treatment use under §§ 312.315
p.000054: (intermediate-size pa- tient populations) and 312.320 (treat- ment IND or treatment protocol), in
p.000054: addition to the direct costs described in paragraph (d)(1)(i) of this section, a sponsor may recover the
p.000054: costs of moni- toring the expanded access IND or pro- tocol, complying with IND reporting requirements, and
p.000054: other administrative costs directly associated with the ex- panded access IND.
p.000054: (3) To support its calculation for cost recovery, a sponsor must provide sup- porting documentation to show
p.000054: that the calculation is consistent with the requirements of paragraphs (d)(1) and, if applicable, (d)(2)
p.000054: of this section. The documentation must be accompanied by a statement that an independent
p.000054:
p.000054:
p.000054:
p.000054:
p.000054:
p.000054:
p.000054:
p.000054: Food and Drug Administration, HHS § 312.21
p.000054:
p.000054:
p.000054: certified public accountant has re- viewed and approved the calculations.
p.000054: [74 FR 40899, Aug. 13, 2009]
p.000054: § 312.10 Waivers.
p.000054: (a) A sponsor may request FDA to waive applicable requirement under this part. A waiver request may be
p.000054: sub- mitted either in an IND or in an infor- mation amendment to an IND. In an emergency, a request
p.000054: may be made by telephone or other rapid communica- tion means. A waiver request is re- quired to
p.000054: contain at least one of the following:
p.000054: (1) An explanation why the sponsor’s
p.000054: compliance with the requirement is un- necessary or cannot be achieved;
p.000054: (2) A description of an alternative submission or course of action that satisfies the purpose
p.000054: of the require- ment; or
p.000054: (3) Other information justifying a waiver.
p.000054: (b) FDA may grant a waiver if it finds that the sponsor’s noncompliance would not pose a significant and
...
p.000067: unless the course of the disease is interrupted.’’ The clin- ical hold would not apply under this paragraph to
p.000067: clinical studies con- ducted:
p.000067: (A) Under special circumstances, such as studies pertinent only to one gender (e.g., studies
p.000067: evaluating the ex- cretion of a drug in semen or the ef- fects on menstrual function);
p.000067: (B) Only in men or women, as long as a study that does not exclude members of the other gender with reproductive
p.000067: potential is being conducted concur- rently, has been conducted, or will take place within a
p.000067: reasonable time agreed upon by the agency; or
p.000067: (C) Only in subjects who do not suffer from the disease or condition for which the drug is being studied.
p.000067:
p.000067:
p.000067:
p.000067:
p.000067:
p.000067:
p.000067:
p.000067:
p.000067: § 312.42
p.000067: (2) Clinical hold of a Phase 2 or 3 study under an IND. FDA may place a pro- posed or ongoing Phase
p.000067: 2 or 3 inves- tigation on clinical hold if it finds that:
p.000067: (i) Any of the conditions in para- graphs (b)(1)(i) through (b)(1)(v) of this section apply; or
p.000067: (ii) The plan or protocol for the in- vestigation is clearly deficient in de- sign to meet its stated
p.000067: objectives.
p.000067: (3) Clinical hold of an expanded access IND or expanded access protocol. FDA may place an expanded
p.000067: access IND or expanded access protocol on clinical hold under the following conditions:
p.000067: (i) Final use. FDA may place a pro- posed expanded access IND or treat- ment use protocol on clinical
p.000067: hold if it is determined that:
p.000067: (A) The pertinent criteria in subpart I of this part for permitting the ex- panded access use to begin are
p.000067: not sat- isfied; or
p.000067: (B) The expanded access IND or ex- panded access protocol does not comply with the requirements for expanded ac-
p.000067: cess submissions in subpart I of this part.
p.000067: (ii) Ongoing use. FDA may place an ongoing expanded access IND or ex- panded access protocol on
p.000067: clinical hold if it is determined that the pertinent criteria in subpart I of this part for permitting
p.000067: the expanded access are no longer satisfied.
p.000067: (4) Clinical hold of any study that is
p.000067: not designed to be adequate and ell-con- trolled. FDA may place a proposed or ongoing investigation
p.000067: that is not de- signed to be adequate and well-con- trolled on clinical hold if it finds that:
p.000067: (i) Any of the conditions in para- graph (b)(1) or (b)(2) of this section apply; or
p.000067: (ii) There is reasonable evidence the investigation that is not designed to be adequate and well-controlled is
p.000067: imped- ing enrollment in, or otherwise inter- fering with the conduct or completion of, a study that is
p.000067: designed to be an adequate and well-controlled investiga- tion of the same or another investiga- tional drug;
p.000067: or
p.000067: (iii) Insufficient quantities of the in- vestigational drug exist to adequately conduct both the
p.000067: investigation that is not designed to be adequate and well- controlled and the investigations that
p.000068: 68
p.000068: 21 CFR Ch. I (4–1–12 Edition)
p.000068: are designed to be adequate and well- controlled; or
p.000068: (iv) The drug has been studied in one or more adequate and well-controlled investigations that strongly
p.000068: suggest lack of effectiveness; or
p.000068: (v) Another drug under investigation or approved for the same indication and available to the same
p.000068: patient popu- lation has demonstrated a better po- tential benefit/risk balance; or
p.000068: (vi) The drug has received marketing approval for the same indication in the same patient population; or
p.000068: (vii) The sponsor of the study that is designed to be an adequate and well- controlled investigation is not
p.000068: actively pursuing marketing approval of the in- vestigational drug with due diligence; or
p.000068: (viii) The Commissioner determines that it would not be in the public inter- est for the study to be conducted
p.000068: or continued. FDA ordinarily intends that clinical holds under paragraphs (b)(4)(ii), (b)(4)(iii) and
p.000068: (b)(4)(v) of this section would only apply to additional enrollment in nonconcurrently con- trolled
p.000068: trials rather than eliminating continued access to individuals already receiving the investigational drug.
p.000068: (5) Clinical hold of any investigation in-
p.000068: volving an exception from informed con- sent under § 50.24 of this chapter. FDA may place a proposed
p.000068: or ongoing inves- tigation involving an exception from informed consent under § 50.24 of this chapter on
p.000068: clinical hold if it is deter- mined that:
p.000068: (i) Any of the conditions in para- graphs (b)(1) or (b)(2) of this section apply; or
p.000068: (ii) The pertinent criteria in § 50.24 of this chapter for such an investigation to begin or continue are not
p.000068: submitted or not satisfied.
p.000068: (6) Clinical hold of any investigation involving an exception from informed consent under § 50.23(d) of
p.000068: this chapter. FDA may place a proposed or ongoing investigation involving an exception from informed
p.000068: consent under § 50.23(d) of this chapter on clinical hold if it is determined that:
p.000068: (i) Any of the conditions in para- graphs (b)(1) or (b)(2) of this section apply; or
p.000068: (ii) A determination by the President to waive the prior consent requirement
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068:
p.000068: Food and Drug Administration, HHS § 312.44
p.000068:
p.000068:
...
p.000075: (c) A sponsor shall retain the records and reports required by this part for 2 years after a marketing
p.000075: application is approved for the drug; or, if an applica- tion is not approved for the drug, until 2 years after
p.000075: shipment and delivery of the drug for investigational use is dis- continued and FDA has been so noti-
p.000075: fied.
p.000075: (d) A sponsor shall retain reserve samples of any test article and ref- erence standard
p.000075: identified in, and used in any of the bioequivalence or bio-
p.000076: 76
p.000076: 21 CFR Ch. I (4–1–12 Edition)
p.000076: availability studies described in,
p.000076: § 320.38 or § 320.63 of this chapter, and release the reserve samples to FDA upon request, in
p.000076: accordance with, and for the period specified in § 320.38.
p.000076: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000076: FR 23031, June 17, 1987; 58 FR 25926, Apr. 28,
p.000076: 1993; 63 FR 5252, Feb. 2, 1998; 67 FR 9586, Mar.
p.000076: 4, 2002]
p.000076:
p.000076: § 312.58 Inspection of sponsor’s records and reports.
p.000076: (a) FDA inspection. A sponsor shall upon request from any properly au- thorized officer or
p.000076: employee of the Food and Drug Administration, at rea- sonable times, permit such officer or employee to
p.000076: have access to and copy and verify any records and reports re- lating to a clinical investigation con-
p.000076: ducted under this part. Upon written request by FDA, the sponsor shall sub- mit the records or reports (or
p.000076: copies of them) to FDA. The sponsor shall dis- continue shipments of the drug to any investigator who has
p.000076: failed to maintain or make available records or reports of the investigation as required by this part.
p.000076: (b) Controlled substances. If an inves- tigational new drug is a substance list- ed in any schedule of the
p.000076: Controlled Substances Act (21 U.S.C. 801; 21 CFR part 1308), records concerning ship- ment, delivery,
p.000076: receipt, and disposition of the drug, which are required to be kept under this part or other applica- ble
p.000076: parts of this chapter shall, upon the request of a properly authorized em- ployee of the Drug Enforcement
p.000076: Ad- ministration of the U.S. Department of Justice, be made available by the in- vestigator or sponsor to
p.000076: whom the re- quest is made, for inspection and copy- ing. In addition, the sponsor shall as- sure that
p.000076: adequate precautions are taken, including storage of the inves- tigational drug in a securely locked,
p.000076: substantially constructed cabinet, or other securely locked, substantially constructed enclosure, access
p.000076: to which is limited, to prevent theft or diversion of the substance into illegal channels of distribution.
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076:
p.000076: Food and Drug Administration, HHS § 312.64
p.000076:
p.000076:
p.000076: § 312.59 Disposition of unused supply of investigational drug.
p.000076: The sponsor shall assure the return of all unused supplies of the investiga- tional drug from each
p.000076: individual inves- tigator whose participation in the in- vestigation is discontinued or termi- nated. The
p.000076: sponsor may authorize al- ternative disposition of unused supplies of the investigational drug provided
p.000076: this alternative disposition does not expose humans to risks from the drug. The sponsor shall
p.000076: maintain written records of any disposition of the drug in accordance with § 312.57.
p.000076: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000076: FR 23031, June 17, 1987; 67 FR 9586, Mar. 4,
p.000076: 2002]
p.000076:
p.000076: § 312.60 General responsibilities of in- vestigators.
p.000076: An investigator is responsible for en- suring that an investigation is con- ducted according to the
...
p.000077: update this information if any rel- evant changes occur during the course of the investigation and for
p.000077: 1 year fol- lowing the completion of the study.
p.000077: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000077: FR 23031, June 17, 1987; 63 FR 5252, Feb. 2,
p.000077: 1998; 67 FR 9586, Mar. 4, 2002; 75 FR 59963,
p.000077: Sept. 29, 2010]
p.000077: § 312.66 Assurance of IRB review.
p.000077: An investigator shall assure that an IRB that complies with the require- ments set forth in part 56
p.000077: will be re- sponsible for the initial and continuing review and approval of the proposed clinical study.
p.000077: The investigator shall also assure that he or she will prompt- ly report to the IRB all changes in the
p.000077: research activity and all unanticipated problems involving risk to human sub- jects or others, and that he
p.000077: or she will not make any changes in the research without IRB approval, except where necessary to
p.000077: eliminate apparent imme- diate hazards to human subjects.
p.000077: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000077: FR 23031, June 17, 1987; 67 FR 9586, Mar. 4,
p.000077: 2002]
p.000077:
p.000077: § 312.68 Inspection of investigator’s records and reports.
p.000077: An investigator shall upon request from any properly authorized officer or
p.000077:
p.000078: 78
p.000078: 21 CFR Ch. I (4–1–12 Edition)
p.000078: employee of FDA, at reasonable times, permit such officer or employee to have access to, and copy and
p.000078: verify any records or reports made by the investi- gator pursuant to § 312.62. The investi- gator is not required
p.000078: to divulge subject names unless the records of particular individuals require a more detailed study of
p.000078: the cases, or unless there is reason to believe that the records do not represent actual case studies, or do
p.000078: not represent actual results obtained.
p.000078: § 312.69 Handling of controlled sub- stances.
p.000078: If the investigational drug is subject to the Controlled Substances Act, the investigator shall take
p.000078: adequate pre- cautions, including storage of the in- vestigational drug in a securely locked, substantially
p.000078: constructed cabinet, or other securely locked, substantially constructed enclosure, access to which is
p.000078: limited, to prevent theft or diversion of the substance into illegal channels of distribution.
p.000078: § 312.70 Disqualification of a clinical investigator.
p.000078: (a) If FDA has information indicating that an investigator (including a spon- sor-investigator) has repeatedly
p.000078: or de- liberately failed to comply with the re- quirements of this part, part 50, or part 56 of this chapter, or
p.000078: has submitted to FDA or to the sponsor false informa- tion in any required report, the Center for Drug
p.000078: Evaluation and Research or the Center for Biologics Evaluation and Research will furnish the investi-
p.000078: gator written notice of the matter complained of and offer the investi- gator an opportunity
p.000078: to explain the matter in writing, or, at the option of the investigator, in an informal con- ference.
p.000078: If an explanation is offered but not accepted by the Center for Drug Evaluation and Research or the Center for
p.000078: Biologics Evaluation and Research, the investigator will be given an oppor- tunity for a regulatory hearing
p.000078: under part 16 on the question of whether the investigator is entitled to receive in- vestigational new
p.000078: drugs.
p.000078: (b) After evaluating all available in- formation, including any explanation presented by the
p.000078: investigator, if the
p.000078:
p.000078:
p.000078:
p.000078:
p.000078:
p.000078:
p.000078:
...
p.000086:
p.000086:
p.000086:
p.000086:
p.000086:
p.000086:
p.000086:
p.000086: Food and Drug Administration, HHS § 312.300
p.000086:
p.000086:
p.000086: due diligence to assure that the con- signee is regularly engaged in con- ducting such tests and
p.000086: that the ship- ment of the new drug will actually be used for tests in vitro or in animals used only
p.000086: for laboratory research.
p.000086: (3) A person who ships a drug under paragraph (a) of this section shall maintain adequate records
p.000086: showing the name and post office address of the ex- pert to whom the drug is shipped and the date, quantity,
p.000086: and batch or code mark of each shipment and delivery. Records of shipments under paragraph (a)(1)(i) of
p.000086: this section are to be main- tained for a period of 2 years after the shipment. Records and reports of
p.000086: data and shipments under paragraph (a)(1)(ii) of this section are to be main- tained in accordance
p.000086: with § 312.57(b). The person who ships the drug shall upon request from any properly au- thorized
p.000086: officer or employee of the Food and Drug Administration, at rea- sonable times, permit such officer
p.000086: or employee to have access to and copy and verify records required to be main- tained under this section.
p.000086: (b) Termination of authorization to
p.000086: ship. FDA may terminate authoriza- tion to ship a drug under this section if it finds that:
p.000086: (1) The sponsor of the investigation has failed to comply with any of the conditions for shipment
p.000086: established under this section; or
p.000086: (2) The continuance of the investiga- tion is unsafe or otherwise contrary to the public interest or the
p.000086: drug is used for purposes other than bona fide sci- entific investigation. FDA will notify the person
p.000086: shipping the drug of its find- ing and invite immediate correction. If correction is not immediately made, the
p.000086: person shall have an opportunity for a regulatory hearing before FDA pursuant to part 16.
p.000086: (c) Disposition of unused drug. The person who ships the drug under para- graph (a) of this section
p.000086: shall assure the return of all unused supplies of the drug from individual investigators whenever the
p.000086: investigation discon- tinues or the investigation is termi- nated. The person who ships the drug may
p.000086: authorize in writing alternative disposition of unused supplies of the drug provided this
p.000086: alternative disposi- tion does not expose humans to risks
p.000087: 87
p.000087:
p.000087: from the drug, either directly or indi- rectly (e.g., through food-producing animals). The shipper
p.000087: shall maintain records of any alternative disposition.
p.000087: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000087: FR 23031, June 17, 1987. Redesignated at 53
p.000087: FR 41523, Oct. 21, 1988; 67 FR 9586, Mar. 4,
p.000087: 2002]
p.000087:
p.000087: Subpart H [Reserved]
p.000087: Subpart I—Expanded Access to Investigational Drugs for Treat- ment Use
p.000087:
p.000087: SOURCE: 74 FR 40942, Aug. 13, 2009, unless
p.000087: otherwise noted.
p.000087:
p.000087: § 312.300 General.
p.000087: (a) Scope. This subpart contains the requirements for the use of investiga- tional new drugs and approved
p.000087: drugs where availability is limited by a risk evaluation and mitigation strategy (REMS) when the
p.000087: primary purpose is to diagnose, monitor, or treat a patient’s disease or condition. The aim of this subpart
p.000087: is to facilitate the availability of such drugs to patients with serious diseases or conditions when there is
p.000087: no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the patient’s disease or
p.000087: condition.
p.000087: (b) Definitions. The following defini- tions of terms apply to this subpart:
p.000087: Immediately life-threatening disease or condition means a stage of disease in which there is reasonable
p.000087: likelihood that death will occur within a matter of months or in which premature death is likely without early
p.000087: treatment.
p.000087: Serious disease or condition means a disease or condition associated with morbidity that has
p.000087: substantial impact on day-to-day functioning. Short-lived and self-limiting morbidity will usu- ally not
p.000087: be sufficient, but the mor- bidity need not be irreversible, pro- vided it is persistent or
p.000087: recurrent. Whether a disease or condition is seri- ous is a matter of clinical judgment, based on its
p.000087: impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left un-
p.000087: treated, will progress from a less severe condition to a more serious one.
p.000087:
p.000087:
p.000087:
p.000087:
p.000087:
p.000087:
p.000087:
p.000087:
p.000087: § 312.305
p.000087:
p.000087: § 312.305 Requirements for all ex- panded access uses.
p.000087: The criteria, submission require- ments, safeguards, and beginning treat- ment information set out in
p.000087: this sec- tion apply to all expanded access uses described in this subpart. Additional criteria,
p.000087: submission requirements, and safeguards that apply to specific types of expanded access are described
p.000087: in
p.000087: §§ 312.310 through 312.320.
p.000087: (a) Criteria. FDA must determine that:
p.000087: (1) The patient or patients to be treated have a serious or immediately life-threatening disease
p.000087: or condition, and there is no comparable or satisfac- tory alternative therapy to diagnose, monitor, or treat
p.000087: the disease or condi- tion;
p.000087: (2) The potential patient benefit jus- tifies the potential risks of the treat- ment use and those
p.000087: potential risks are not unreasonable in the context of the disease or condition to be treated; and
p.000087: (3) Providing the investigational drug for the requested use will not interfere with the initiation, conduct, or
p.000087: com- pletion of clinical investigations that could support marketing approval of the expanded access use
p.000087: or otherwise compromise the potential development of the expanded access use.
p.000087: (b) Submission. (1) An expanded access submission is required for each type of expanded access described in
p.000087: this sub- part. The submission may be a new
p.000087: IND or a protocol amendment to an ex- isting IND. Information required for a submission may be supplied by
p.000087: refer- ring to pertinent information con- tained in an existing IND if the sponsor of the existing IND
p.000087: grants a right of reference to the IND.
p.000087: (2) The expanded access submission must include:
p.000087: (i) A cover sheet (Form FDA 1571) meeting the requirements of § 312.23(a);
p.000087: (ii) The rationale for the intended use of the drug, including a list of available therapeutic options that would
p.000087: ordi- narily be tried before resorting to the investigational drug or an explanation of why the use of
p.000087: the investigational drug is preferable to the use of avail- able therapeutic options;
p.000087: (iii) The criteria for patient selection
p.000087: or, for an individual patient, a descrip- tion of the patient’s disease or condi-
p.000088: 88
p.000088: 21 CFR Ch. I (4–1–12 Edition)
p.000088: tion, including recent medical history and previous treatments of the disease or condition;
p.000088: (iv) The method of administration of the drug, dose, and duration of ther- apy;
p.000088: (v) A description of the facility where the drug will be manufactured;
p.000088: (vi) Chemistry, manufacturing, and controls information adequate to en- sure the proper identification,
p.000088: quality, purity, and strength of the investiga- tional drug;
p.000088: (vii) Pharmacology and toxicology information adequate to conclude that the drug is reasonably safe at
p.000088: the dose and duration proposed for expanded ac- cess use (ordinarily, information that would be adequate to
p.000088: permit clinical testing of the drug in a population of the size expected to be treated); and
p.000088: (viii) A description of clinical proce- dures, laboratory tests, or other moni- toring necessary to evaluate
p.000088: the effects of the drug and minimize its risks.
p.000088: (3) The expanded access submission and its mailing cover must be plainly marked ‘‘EXPANDED ACCESS SUB-
p.000088: MISSION.’’ If the expanded access sub- mission is for a treatment IND or treatment protocol, the
p.000088: applicable box on Form FDA 1571 must be checked.
p.000088: (c) Safeguards. The responsibilities of sponsors and investigators set forth in subpart D of this part are
p.000088: applicable to expanded access use under this subpart as described in this paragraph.
p.000088: (1) A licensed physician under whose immediate direction an investigational drug is administered or dispensed
p.000088: for an expanded access use under this sub- part is considered an investigator, for purposes of this part,
p.000088: and must comply with the responsibilities for investiga- tors set forth in subpart D of this part to the
p.000088: extent they are applicable to the expanded access use.
p.000088: (2) An individual or entity that sub- mits an expanded access IND or pro- tocol under this subpart is
p.000088: considered a sponsor, for purposes of this part, and must comply with the responsibilities for sponsors set
p.000088: forth in subpart D of this part to the extent they are appli- cable to the expanded access use.
p.000088: (3) A licensed physician under whose immediate direction an investigational drug is administered or dispensed,
p.000088: and
p.000088:
p.000088:
p.000088:
p.000088:
p.000088:
p.000088:
p.000088:
p.000088: Food and Drug Administration, HHS § 312.310
p.000088:
p.000088:
p.000088: who submits an IND for expanded ac- cess use under this subpart is consid- ered a sponsor-investigator,
p.000088: for purposes of this part, and must comply with the responsibilities for sponsors and inves- tigators set forth
p.000088: in subpart D of this part to the extent they are applicable to the expanded access use.
p.000088: (4) Investigators. In all cases of ex- panded access, investigators are re- sponsible for reporting
p.000088: adverse drug events to the sponsor, ensuring that the informed consent requirements of part 50 of
p.000088: this chapter are met, ensur- ing that IRB review of the expanded ac- cess use is obtained in a manner con-
p.000088: sistent with the requirements of part 56 of this chapter, and maintaining ac- curate case histories and
p.000088: drug disposi- tion records and retaining records in a manner consistent with the require- ments of §
p.000088: 312.62. Depending on the type of expanded access, other investigator responsibilities under subpart D may also
p.000088: apply.
p.000088: (5) Sponsors. In all cases of expanded
p.000088: access, sponsors are responsible for submitting IND safety reports and an- nual reports (when the IND or
p.000088: protocol continues for 1 year or longer) to FDA as required by §§ 312.32 and 312.33, en- suring that
p.000088: licensed physicians are qualified to administer the investiga- tional drug for the expanded access
p.000088: use, providing licensed physicians with the information needed to minimize the risk and maximize the
p.000088: potential benefits of the investigational drug (the investigator’s brochure must be provided if one
p.000088: exists for the drug), maintaining an effective IND for the expanded access use, and maintaining
p.000088: adequate drug disposition records and retaining records in a manner con- sistent with the
p.000088: requirements of
p.000088: § 312.57. Depending on the type of ex-
p.000088: panded access, other sponsor respon- sibilities under subpart D may also apply.
p.000088: (d) Beginning treatment—(1) INDs. An expanded access IND goes into effect 30 days after FDA receives the IND
p.000088: or on earlier notification by FDA that the expanded access use may begin.
p.000088: (2) Protocols. With the following ex- ceptions, expanded access use under a protocol submitted under an
p.000088: existing IND may begin as described in
p.000088: § 312.30(a).
p.000088:
p.000089: 89
p.000089:
p.000089: (i) Expanded access use under the emergency procedures described in
p.000089: § 312.310(d) may begin when the use is authorized by the FDA reviewing offi- cial.
p.000089: (ii) Expanded access use under
p.000089: § 312.320 may begin 30 days after FDA receives the protocol or upon earlier notification by FDA that
p.000089: use may begin.
p.000089: (3) Clinical holds. FDA may place any expanded access IND or protocol on clinical hold as described in §
p.000089: 312.42.
p.000089: § 312.310 Individual patients, includ- ing for emergency use.
p.000089: Under this section, FDA may permit an investigational drug to be used for the treatment of an individual
p.000089: patient by a licensed physician.
p.000089: (a) Criteria. The criteria in § 312.305(a) must be met; and the following deter- minations must be made:
p.000089: (1) The physician must determine that the probable risk to the person from the investigational drug
p.000089: is not greater than the probable risk from the disease or condition; and
p.000089: (2) FDA must determine that the pa- tient cannot obtain the drug under an- other IND or protocol.
p.000089: (b) Submission. The expanded access submission must include information adequate to demonstrate that the
p.000089: cri- teria in § 312.305(a) and paragraph (a) of this section have been met. The ex- panded access
p.000089: submission must meet the requirements of § 312.305(b).
p.000089: (1) If the drug is the subject of an ex- isting IND, the expanded access sub- mission may be made by the sponsor
p.000089: or by a licensed physician.
p.000089: (2) A sponsor may satisfy the submis- sion requirements by amending its ex- isting IND to include a protocol for
p.000089: in- dividual patient expanded access.
p.000089: (3) A licensed physician may satisfy the submission requirements by ob- taining from the sponsor
p.000089: permission for FDA to refer to any information in the IND that would be needed to sup- port the expanded access
p.000089: request (right of reference) and by providing any other required information not con- tained in the
p.000089: IND (usually only the in- formation specific to the individual pa- tient).
p.000089: (c) Safeguards. (1) Treatment is gen- erally limited to a single course of
p.000089:
p.000089:
p.000089:
p.000089:
p.000089:
p.000089:
p.000089:
p.000089:
p.000089: § 312.315
p.000089: therapy for a specified duration unless FDA expressly authorizes multiple courses or chronic therapy.
p.000089: (2) At the conclusion of treatment, the licensed physician or sponsor must provide FDA with a written
p.000089: summary of the results of the expanded access use, including adverse effects.
p.000089: (3) FDA may require sponsors to monitor an individual patient ex- panded access use if the
p.000089: use is for an extended duration.
p.000089: (4) When a significant number of similar individual patient expanded ac- cess requests have been
p.000089: submitted, FDA may ask the sponsor to submit an IND or protocol for the use under
p.000089: § 312.315 or § 312.320.
p.000089: (d) Emergency procedures. If there is an emergency that requires the patient to be treated before a written
p.000089: submis- sion can be made, FDA may authorize the expanded access use to begin with- out a written
p.000089: submission. The FDA re- viewing official may authorize the emergency use by telephone.
p.000089: (1) Emergency expanded access use may be requested by telephone, fac- simile, or other means
p.000089: of electronic communications. For investigational biological drug products regulated by the Center for
p.000089: Biologics Evaluation and Research, the request should be di- rected to the Office of Communication, Outreach and
p.000089: Development, Center for Biologics Evaluation and Research, 301–827–1800 or 1–800–835–4709, e-mail:
p.000089: ocod@fda.hhs.gov. For all other inves- tigational drugs, the request for au- thorization should be
p.000089: directed to the Division of Drug Information, Center for Drug Evaluation and Research, 301– 796–3400, e-mail:
p.000089: druginfo@fda.hhs.gov. After normal working hours (8 a.m. to 4:30 p.m.), the request should be di-
p.000089: rected to the FDA Emergency Call Cen- ter, 866–300–4374, e-mail: emer-
p.000089: gency.operations@fda.hhs.gov.
p.000089: (2) The licensed physician or sponsor must explain how the expanded access use will meet the
p.000089: requirements of
p.000089: §§ 312.305 and 312.310 and must agree to submit an expanded access submission within 15 working days of
p.000089: FDA’s au- thorization of the use.
p.000089: [74 FR 40942, Aug. 13, 2009, as amended at 75
p.000089: FR 32659, June 9, 2010]
p.000089:
p.000090: 90
p.000090: 21 CFR Ch. I (4–1–12 Edition)
p.000090:
p.000090: § 312.315 Intermediate-size patient populations.
p.000090: Under this section, FDA may permit an investigational drug to be used for the treatment of a patient
p.000090: population smaller than that typical of a treat- ment IND or treatment protocol. FDA may ask a sponsor
p.000090: to consolidate ex- panded access under this section when the agency has received a significant number of
p.000090: requests for individual pa- tient expanded access to an investiga- tional drug for the same use.
p.000090: (a) Need for expanded access. Expanded
p.000090: access under this section may be need- ed in the following situations:
p.000090: (1) Drug not being developed. The drug is not being developed, for example, be- cause the disease or
p.000090: condition is so rare that the sponsor is unable to re- cruit patients for a clinical trial.
p.000090: (2) Drug being developed. The drug is being studied in a clinical trial, but pa- tients requesting the drug for
p.000090: expanded access use are unable to participate in the trial. For example, patients may not be able to
p.000090: participate in the trial because they have a different disease or stage of disease than the one being
p.000090: studied or otherwise do not meet the enrollment criteria, because enroll- ment in the trial is
p.000090: closed, or because the trial site is not geographically ac- cessible.
p.000090: (3) Approved or related drug. (i) The
p.000090: drug is an approved drug product that is no longer marketed for safety rea- sons or is unavailable
p.000090: through mar- keting due to failure to meet the con- ditions of the approved application, or
p.000090: (ii) The drug contains the same ac- tive moiety as an approved drug prod- uct that is unavailable
p.000090: through mar- keting due to failure to meet the con- ditions of the approved application or a drug shortage.
p.000090: (b) Criteria. The criteria in § 312.305(a) must be met; and FDA must determine that:
p.000090: (1) There is enough evidence that the drug is safe at the dose and duration proposed for expanded access
p.000090: use to justify a clinical trial of the drug in the approximate number of patients ex- pected to receive the
p.000090: drug under ex- panded access; and
p.000090: (2) There is at least preliminary clin- ical evidence of effectiveness of the drug, or of a plausible
p.000090: pharmacologic
p.000090:
p.000090:
p.000090:
p.000090:
p.000090:
p.000090:
p.000090:
p.000090: Food and Drug Administration, HHS § 312.320
p.000090:
p.000090:
p.000090: effect of the drug to make expanded ac- cess use a reasonable therapeutic op- tion in the anticipated patient
p.000090: popu- lation.
p.000090: (c) Submission. The expanded access submission must include information adequate to satisfy FDA that the
p.000090: cri- teria in § 312.305(a) and paragraph (b) of this section have been met. The ex- panded access
p.000090: submission must meet the requirements of § 312.305(b). In addi- tion:
p.000090: (1) The expanded access submission must state whether the drug is being developed or is not being developed
p.000090: and describe the patient population to be treated.
p.000090: (2) If the drug is not being actively developed, the sponsor must explain why the drug cannot
p.000090: currently be de- veloped for the expanded access use and under what circumstances the drug could be
p.000090: developed.
p.000090: (3) If the drug is being studied in a clinical trial, the sponsor must explain why the patients to be
p.000090: treated cannot be enrolled in the clinical trial and under what circumstances the sponsor would
p.000090: conduct a clinical trial in these patients.
p.000090: (d) Safeguards. (1) Upon review of the IND annual report, FDA will determine whether it is appropriate for
p.000090: the ex- panded access to continue under this section.
p.000090: (i) If the drug is not being actively developed or if the expanded access use is not being developed (but
p.000090: another use is being developed), FDA will consider whether it is possible to conduct a clin- ical study of the
p.000090: expanded access use.
p.000090: (ii) If the drug is being actively de- veloped, FDA will consider whether providing the
p.000090: investigational drug for expanded access use is interfering with the clinical development of the drug.
p.000090: (iii) As the number of patients en- rolled increases, FDA may ask the sponsor to submit an IND or
p.000090: protocol for the use under § 312.320.
p.000090: (2) The sponsor is responsible for monitoring the expanded access pro- tocol to ensure that
p.000090: licensed physi- cians comply with the protocol and the regulations applicable to investigators.
p.000090:
p.000090: § 312.320 Treatment IND or treatment protocol.
p.000090: Under this section, FDA may permit an investigational drug to be used for widespread treatment use.
p.000090: (a) Criteria. The criteria in § 312.305(a) must be met, and FDA must determine that:
p.000090: (1) Trial status. (i) The drug is being investigated in a controlled clinical trial under an IND
p.000090: designed to support a marketing application for the ex- panded access use, or
p.000090: (ii) All clinical trials of the drug have been completed; and
p.000090: (2) Marketing status. The sponsor is actively pursuing marketing approval of the drug for the expanded access
p.000090: use with due diligence; and
p.000090: (3) Evidence. (i) When the expanded access use is for a serious disease or condition, there is
p.000090: sufficient clinical evidence of safety and effectiveness to support the expanded access use. Such evidence
p.000090: would ordinarily consist of data from phase 3 trials, but could con- sist of compelling data from completed
p.000090: phase 2 trials; or
p.000090: (ii) When the expanded access use is for an immediately life-threatening disease or condition, the
p.000090: available sci- entific evidence, taken as a whole, pro- vides a reasonable basis to conclude that the
p.000090: investigational drug may be effective for the expanded access use and would not expose patients to an
p.000090: unreasonable and significant risk of ill- ness or injury. This evidence would or- dinarily consist of clinical
p.000090: data from phase 3 or phase 2 trials, but could be based on more preliminary clinical evi- dence.
p.000090: (b) Submission. The expanded access submission must include information adequate to satisfy FDA that the
p.000090: cri- teria in § 312.305(a) and paragraph (a) of this section have been met. The ex- panded access
p.000090: submission must meet the requirements of § 312.305(b).
p.000090: (c) Safeguard. The sponsor is respon- sible for monitoring the treatment pro- tocol to ensure that
p.000090: licensed physi- cians comply with the protocol and the regulations applicable to investigators.
p.000090:
p.000091: 91
p.000091:
p.000091:
p.000091:
p.000091:
p.000091:
p.000091:
p.000091:
p.000091:
p.000091: Pt. 314
p.000091: PART 314—APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG
p.000091: Subpart A—General Provisions
p.000091: Sec.
p.000091: 314.1 Scope of this part.
p.000091: 314.2 Purpose.
p.000091: 314.3 Definitions.
p.000091: Subpart B—Applications
p.000091: 314.50 Content and format of an application.
p.000091: 314.52 Notice of certification of invalidity or noninfringement of a patent.
p.000091: 314.53 Submission of patent information.
p.000091: 314.54 Procedure for submission of an appli- cation requiring investigations for ap- proval of a new
p.000091: indication for, or other change from, a listed drug.
p.000091: 314.55 Pediatric use information.
p.000091: 314.60 Amendments to an unapproved appli- cation, supplement, or resubmission.
p.000091: 314.65 Withdrawal by the applicant of an un- approved application.
p.000091: 314.70 Supplements and other changes to an approved application.
p.000091: 314.71 Procedures for submission of a sup- plement to an approved application.
p.000091: 314.72 Change in ownership of an applica- tion.
p.000091: 314.80 Postmarketing reporting of adverse drug experiences.
p.000091: 314.81 Other postmarketing reports.
p.000091: 314.90 Waivers.
p.000091: Subpart C—Abbreviated Applications
...
Social / Age
Searching for indicator age:
(return to top)
p.000050: investigations of that drug.
p.000050: (b) References in this part to regula-
p.000050: tions in the Code of Federal Regula- tions are to chapter I of title 21, unless otherwise noted.
p.000050: § 312.2 Applicability.
p.000050: (a) Applicability. Except as provided in this section, this part applies to all clinical investigations of
p.000050: products that are subject to section 505 of the Federal Food, Drug, and Cosmetic Act or to the licensing provisions
p.000050: of the Public Health Service Act (58 Stat. 632, as amended (42 U.S.C. 201 et seq.)).
p.000050: (b) Exemptions. (1) The clinical inves- tigation of a drug product that is law- fully marketed in the
p.000050: United States is exempt from the requirements of this part if all the following apply:
p.000050: (i) The investigation is not intended to be reported to FDA as a well-con- trolled study in support of
p.000050: a new indi-
p.000051: 51
p.000051:
p.000051: cation for use nor intended to be used to support any other significant change in the labeling for the drug;
p.000051: (ii) If the drug that is undergoing in- vestigation is lawfully marketed as a prescription drug product, the
p.000051: inves- tigation is not intended to support a significant change in the advertising for the product;
p.000051: (iii) The investigation does not in- volve a route of administration or dos- age level or use in a patient
p.000051: population or other factor that significantly in- creases the risks (or decreases the ac- ceptability of
p.000051: the risks) associated with the use of the drug product;
p.000051: (iv) The investigation is conducted in compliance with the requirements for institutional review set forth in part
p.000051: 56 and with the requirements for informed consent set forth in part 50; and
p.000051: (v) The investigation is conducted in compliance with the requirements of
p.000051: § 312.7.
p.000051: (2)(i) A clinical investigation involv- ing an in vitro diagnostic biological product listed in
p.000051: paragraph (b)(2)(ii) of this section is exempt from the re- quirements of this part if (a) it is
p.000051: in- tended to be used in a diagnostic proce- dure that confirms the diagnosis made by another, medically
p.000051: established, di- agnostic product or procedure and (b) it is shipped in compliance with § 312.160.
p.000051: (ii) In accordance with paragraph (b)(2)(i) of this section, the following products are exempt from
p.000051: the require- ments of this part: (a) blood grouping serum; (b) reagent red blood cells; and
p.000051: (c) anti-human globulin.
p.000051: (3) A drug intended solely for tests in vitro or in laboratory research animals is exempt from the requirements
p.000051: of this part if shipped in accordance with
p.000051: § 312.160.
p.000051: (4) FDA will not accept an applica- tion for an investigation that is ex- empt under the provisions
p.000051: of paragraph (b)(1) of this section.
...
p.000065: than 15 cal- endar days after the determination is made.
p.000065: (e) Disclaimer. A safety report or other information submitted by a spon- sor under this part (and any
p.000065: release by FDA of that report or information) does not necessarily reflect a conclu- sion by the sponsor
p.000065: or FDA that the re- port or information constitutes an ad- mission that the drug caused or con- tributed to
p.000065: an adverse event. A sponsor need not admit, and may deny, that the report or information submitted by the
p.000065: sponsor constitutes an admission that the drug caused or contributed to an adverse event.
p.000065: [75 FR 59961, Sept. 29, 2010]
p.000065: § 312.33 Annual reports.
p.000065: A sponsor shall within 60 days of the anniversary date that the IND went into effect, submit a brief
p.000065: report of the progress of the investigation that in- cludes:
p.000065: (a) Individual study information. A brief summary of the status of each study in progress and each
p.000065: study com- pleted during the previous year. The summary is required to include the fol- lowing information for
p.000065: each study:
p.000065: (1) The title of the study (with any appropriate study identifiers such as protocol number), its
p.000065: purpose, a brief statement identifying the patient pop- ulation, and a statement as to whether the study is
p.000065: completed.
p.000065: (2) The total number of subjects ini- tially planned for inclusion in the study; the number
p.000065: entered into the study to date, tabulated by age group, gender, and race; the number whose
p.000065: participation in the study was com- pleted as planned; and the number who dropped out of the study for
p.000065: any rea- son.
p.000065: (3) If the study has been completed, or if interim results are known, a brief description of any available
p.000065: study re- sults.
p.000065: (b) Summary information. Information obtained during the previous year’s clinical and nonclinical
p.000065: investigations, including:
p.000065: (1) A narrative or tabular summary showing the most frequent and most
p.000065:
p.000065:
p.000065:
p.000065:
p.000065:
p.000065:
p.000065:
p.000065:
p.000065: § 312.38
p.000065: serious adverse experiences by body system.
p.000065: (2) A summary of all IND safety re- ports submitted during the past year.
p.000065: (3) A list of subjects who died during participation in the investigation, with the cause of death for each
p.000065: subject.
p.000065: (4) A list of subjects who dropped out during the course of the investigation in association with any adverse
p.000065: experi- ence, whether or not thought to be drug related.
p.000065: (5) A brief description of what, if any- thing, was obtained that is pertinent to an understanding of the drug’s
p.000065: actions, including, for example, information about dose response, information from controlled trials,
p.000065: and information about bioavailability.
p.000065: (6) A list of the preclinical studies (including animal studies) completed or in progress during the past
...
p.000074: initial and con- tinuing review and approval of the clin- ical investigation and that the investi- gator will
p.000074: promptly report to the IRB all changes in the research activity and all unanticipated problems involving
p.000074: risks to human subjects or others, and will not make any changes in the re- search without IRB
p.000074: approval, except where necessary to eliminate apparent immediate hazards to the human sub- jects.
p.000074: (viii) A list of the names of the sub-
p.000074: investigators (e.g., research fellows, residents) who will be assisting the in- vestigator in the
p.000074: conduct of the inves- tigation(s).
p.000074: (2) Curriculum vitae. A curriculum vitae or other statement of qualifica- tions of the investigator
p.000074: showing the education, training, and experience that qualifies the investigator as an ex- pert in the
p.000074: clinical investigation of the drug for the use under investigation.
p.000074: (3) Clinical protocol. (i) For Phase 1 in- vestigations, a general outline of the planned investigation including
p.000074: the es- timated duration of the study and the maximum number of subjects that will be involved.
p.000074: (ii) For Phase 2 or 3 investigations, an outline of the study protocol includ- ing an approximation of the number
p.000074: of subjects to be treated with the drug and the number to be employed as con- trols, if any; the clinical
p.000074: uses to be in- vestigated; characteristics of subjects by age, sex, and condition; the kind of clinical
p.000074: observations and laboratory tests to be conducted; the estimated duration of the study; and copies or a
p.000074:
p.000074:
p.000074:
p.000074:
p.000074:
p.000074:
p.000074:
p.000074: Food and Drug Administration, HHS § 312.56
p.000074:
p.000074:
p.000074: description of case report forms to be used.
p.000074: (4) Financial disclosure information. Sufficient accurate financial informa- tion to allow the
p.000074: sponsor to submit complete and accurate certification or disclosure statements required under part 54
p.000074: of this chapter. The sponsor shall obtain a commitment from the clinical investigator to promptly
p.000074: up- date this information if any relevant changes occur during the course of the investigation and for 1
p.000074: year following the completion of the study.
p.000074: (d) Selecting monitors. A sponsor shall select a monitor qualified by training and experience to monitor the
p.000074: progress of the investigation.
p.000074: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000074: FR 23031, June 17, 1987; 61 FR 57280, Nov. 5,
p.000074: 1996; 63 FR 5252, Feb. 2, 1998; 67 FR 9586, Mar.
p.000074: 4, 2002]
p.000074:
p.000074: § 312.54 Emergency research under
p.000074: § 50.24 of this chapter.
p.000074: (a) The sponsor shall monitor the progress of all investigations involving an exception from informed
p.000074: consent under § 50.24 of this chapter. When the sponsor receives from the IRB informa- tion concerning the
...
Social / Fetus/Neonate
Searching for indicator fetus:
(return to top)
p.000059: of the individuals who evaluated the results of such stud- ies and concluded that it is reasonably safe to
p.000059: begin the proposed investiga- tions and a statement of where the in- vestigations were conducted and
p.000059: where the records are available for inspec- tion. As drug development proceeds, the sponsor is
p.000059: required to submit infor- mational amendments, as appropriate, with additional information pertinent to safety.
p.000059: (i) Pharmacology and drug disposition.
p.000059: A section describing the pharma- cological effects and mechanism(s) of action of the drug in
p.000059: animals, and in- formation on the absorption, distribu- tion, metabolism, and excretion of the drug, if
p.000059: known.
p.000059: (ii) Toxicology. (a) An integrated sum- mary of the toxicological effects of the drug in animals and in vitro.
p.000059: Depend- ing on the nature of the drug and the
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059: § 312.23
p.000059: phase of the investigation, the descrip- tion is to include the results of acute, subacute, and chronic
p.000059: toxicity tests; tests of the drug’s effects on reproduc- tion and the developing fetus; any spe- cial
p.000059: toxicity test related to the drug’s particular mode of administration or conditions of use (e.g.,
p.000059: inhalation, der- mal, or ocular toxicology); and any in vitro studies intended to evaluate drug toxicity.
p.000059: (b) For each toxicology study that is intended primarily to support the safe- ty of the proposed clinical
p.000059: investiga- tion, a full tabulation of data suitable for detailed review.
p.000059: (iii) For each nonclinical laboratory study subject to the good laboratory practice regulations under part
p.000059: 58, a statement that the study was con- ducted in compliance with the good laboratory practice
p.000059: regulations in part 58, or, if the study was not conducted in compliance with those regulations, a brief
p.000059: statement of the reason for the noncompliance.
p.000059: (9) Previous human experience ith the investigational drug. A summary of pre- vious human experience
p.000059: known to the applicant, if any, with the investiga- tional drug. The information is re- quired to
p.000059: include the following:
p.000059: (i) If the investigational drug has been investigated or marketed pre- viously, either in the
p.000059: United States or other countries, detailed information about such experience that is relevant to the
p.000059: safety of the proposed investiga- tion or to the investigation’s rationale. If the drug has been the subject of con-
...
Social / Linguistic Proficiency
Searching for indicator language:
(return to top)
p.000060: organs upon administration to a human subject. Phase 1 studies of ra- dioactive drugs must include
p.000060: studies which will obtain sufficient data for dosimetry calculations.
p.000060: (iii) Pediatric studies. Plans for assess- ing pediatric safety and effectiveness.
p.000060: (iv) Other information. A brief state- ment of any other information that would aid evaluation of
p.000060: the proposed clinical investigations with respect to their safety or their design and poten- tial as
p.000060: controlled clinical trials to sup- port marketing of the drug.
p.000060: (11) Relevant information. If requested by FDA, any other relevant informa- tion needed for review of the
p.000060: applica- tion.
p.000060: (b) Information previously submitted. The sponsor ordinarily is not required to resubmit information
p.000060: previously submitted, but may incorporate the in- formation by reference. A reference to information submitted
p.000060: previously must identify the file by name, reference number, volume, and page number where the
p.000060: information can be found. A
p.000060:
p.000060:
p.000060:
p.000060:
p.000060:
p.000060:
p.000060:
p.000060: Food and Drug Administration, HHS § 312.30
p.000060:
p.000060:
p.000060: reference to information submitted to the agency by a person other than the sponsor is required to
p.000060: contain a writ- ten statement that authorizes the ref- erence and that is signed by the person who submitted the
p.000060: information.
p.000060: (c) Material in a foreign language. The sponsor shall submit an accurate and complete English translation
p.000060: of each part of the IND that is not in English. The sponsor shall also submit a copy of each original
p.000060: literature publication for which an English translation is sub- mitted.
p.000060: (d) Number of copies. The sponsor shall submit an original and two copies of all submissions to the
p.000060: IND file, in- cluding the original submission and all amendments and reports.
p.000060: (e) Numbering of IND submissions. Each submission relating to an IND is required to be numbered
p.000060: serially using a single, three-digit serial number. The initial IND is required to be numbered 000; each
p.000060: subsequent submission (e.g., amendment, report, or correspondence) is required to be numbered chrono-
p.000060: logically in sequence.
p.000060: (f) Identification of exception from in- formed consent. If the investigation in- volves an exception from
p.000060: informed con- sent under § 50.24 of this chapter, the sponsor shall prominently identify on the cover sheet
p.000060: that the investigation is subject to the requirements in § 50.24 of this chapter.
p.000060: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000060: FR 23031, June 17, 1987; 53 FR 1918, Jan. 25,
p.000060: 1988; 61 FR 51529, Oct. 2, 1996; 62 FR 40599,
p.000060: July 29, 1997; 63 FR 66669, Dec. 2, 1998; 65 FR
p.000060: 56479, Sept. 19, 2000; 67 FR 9585, Mar. 4, 2002]
p.000060:
p.000060: § 312.30 Protocol amendments.
p.000060: Once an IND is in effect, a sponsor shall amend it as needed to ensure that the clinical investigations
...
Social / Marital Status
Searching for indicator single:
(return to top)
p.000060: applica- tion.
p.000060: (b) Information previously submitted. The sponsor ordinarily is not required to resubmit information
p.000060: previously submitted, but may incorporate the in- formation by reference. A reference to information submitted
p.000060: previously must identify the file by name, reference number, volume, and page number where the
p.000060: information can be found. A
p.000060:
p.000060:
p.000060:
p.000060:
p.000060:
p.000060:
p.000060:
p.000060: Food and Drug Administration, HHS § 312.30
p.000060:
p.000060:
p.000060: reference to information submitted to the agency by a person other than the sponsor is required to
p.000060: contain a writ- ten statement that authorizes the ref- erence and that is signed by the person who submitted the
p.000060: information.
p.000060: (c) Material in a foreign language. The sponsor shall submit an accurate and complete English translation
p.000060: of each part of the IND that is not in English. The sponsor shall also submit a copy of each original
p.000060: literature publication for which an English translation is sub- mitted.
p.000060: (d) Number of copies. The sponsor shall submit an original and two copies of all submissions to the
p.000060: IND file, in- cluding the original submission and all amendments and reports.
p.000060: (e) Numbering of IND submissions. Each submission relating to an IND is required to be numbered
p.000060: serially using a single, three-digit serial number. The initial IND is required to be numbered 000; each
p.000060: subsequent submission (e.g., amendment, report, or correspondence) is required to be numbered chrono-
p.000060: logically in sequence.
p.000060: (f) Identification of exception from in- formed consent. If the investigation in- volves an exception from
p.000060: informed con- sent under § 50.24 of this chapter, the sponsor shall prominently identify on the cover sheet
p.000060: that the investigation is subject to the requirements in § 50.24 of this chapter.
p.000060: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000060: FR 23031, June 17, 1987; 53 FR 1918, Jan. 25,
p.000060: 1988; 61 FR 51529, Oct. 2, 1996; 62 FR 40599,
p.000060: July 29, 1997; 63 FR 66669, Dec. 2, 1998; 65 FR
p.000060: 56479, Sept. 19, 2000; 67 FR 9585, Mar. 4, 2002]
p.000060:
p.000060: § 312.30 Protocol amendments.
p.000060: Once an IND is in effect, a sponsor shall amend it as needed to ensure that the clinical investigations
p.000060: are con- ducted according to protocols included in the application. This section sets forth the
p.000060: provisions under which new protocols may be submitted and changes in previously submitted proto-
p.000060: cols may be made. Whenever a sponsor intends to conduct a clinical investiga- tion with an exception from
p.000060: informed consent for emergency research as set forth in § 50.24 of this chapter, the spon- sor shall submit
p.000060: a separate IND for such investigation.
p.000061: 61
p.000061:
...
p.000061: number) to the submission that contained the pro- tocol.
p.000061: (iii) In the case of a new investigator, the investigator’s name, the qualifica- tions to conduct the
p.000061: investigation, ref- erence to the previously submitted pro- tocol, and all additional information about the
p.000061: investigator’s study as is re- quired under § 312.23(a)(6)(iii)(b).
p.000061: (2) Reference, if necessary, to specific technical information in the IND or in a concurrently submitted
p.000061: information amendment to the IND that the spon- sor relies on to support any clinically significant
p.000061: change in the new or amended protocol. If the reference is made to supporting information al-
p.000061: ready in the IND, the sponsor shall identify by name, reference number, volume, and page number
p.000061: the location of the information.
p.000061: (3) If the sponsor desires FDA to com- ment on the submission, a request for such comment and the specific
p.000061: ques- tions FDA’s response should address.
p.000061:
p.000062: 62
p.000062: 21 CFR Ch. I (4–1–12 Edition)
p.000062: (e) When submitted. A sponsor shall submit a protocol amendment for a new protocol or a change in
p.000062: protocol before its implementation. Protocol amendments to add a new investigator or to provide
p.000062: additional information about investigators may be grouped and submitted at 30-day intervals. When
p.000062: several submissions of new proto- cols or protocol changes are antici- pated during a short period, the
p.000062: spon- sor is encouraged, to the extent fea- sible, to include these all in a single submission.
p.000062: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000062: FR 23031, June 17, 1987; 53 FR 1918, Jan. 25,
p.000062: 1988; 61 FR 51530, Oct. 2, 1996; 67 FR 9585, Mar.
p.000062: 4, 2002; 74 FR 40942, Aug. 13, 2009]
p.000062:
p.000062: § 312.31 Information amendments.
p.000062: (a) Requirement for information amend- ment. A sponsor shall report in an in- formation amendment essential
p.000062: infor- mation on the IND that is not within the scope of a protocol amendment, IND safety reports,
p.000062: or annual report. Examples of information requiring an information amendment include:
p.000062: (1) New toxicology, chemistry, or other technical information; or
p.000062: (2) A report regarding the discontinu- ance of a clinical investigation.
p.000062: (b) Content and format of an informa- tion amendment. An information amend- ment is required to bear
p.000062: prominent identification of its contents (e.g., ‘‘In- formation Amendment: Chemistry, Manufacturing, and
p.000062: Control’’, ‘‘Infor- mation Amendment: Pharmacology- Toxicology’’, ‘‘Information Amend- ment:
p.000062: Clinical’’), and to contain the following:
p.000062: (1) A statement of the nature and purpose of the amendment.
p.000062: (2) An organized submission of the data in a format appropriate for sci- entific review.
p.000062: (3) If the sponsor desires FDA to com- ment on an information amendment, a request for such comment.
p.000062: (c) When submitted. Information amendments to the IND should be sub- mitted as necessary but,
p.000062: to the extent feasible, not more than every 30 days.
p.000062: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000062: FR 23031, June 17, 1987; 53 FR 1918, Jan. 25,
p.000062: 1988; 67 FR 9585, Mar. 4, 2002]
...
p.000063: mercial marketing experience for drugs that are not marketed in the United States.
p.000063: (c)(1) IND safety reports. The sponsor must notify FDA and all participating investigators (i.e., all
p.000063: investigators to whom the sponsor is providing drug
p.000063: under its INDs or under any investiga- tor’s IND) in an IND safety report of potential serious risks,
p.000063: from clinical trials or any other source, as soon as possible, but in no case later than 15 calendar
p.000063: days after the sponsor deter- mines that the information qualifies
p.000063:
p.000063:
p.000063:
p.000063:
p.000063:
p.000063:
p.000063:
p.000063:
p.000063: § 312.32
p.000063: for reporting under paragraph (c)(1)(i), (c)(1)(ii), (c)(1)(iii), or (c)(1)(iv) of this section. In each
p.000063: IND safety report, the sponsor must identify all IND safety reports previously submitted to FDA concerning
p.000063: a similar suspected adverse reaction, and must analyze the signifi- cance of the suspected adverse reaction in
p.000063: light of previous, similar reports or any other relevant information.
p.000063: (i) Serious and unexpected suspected adverse reaction. The sponsor must re- port any suspected
p.000063: adverse reaction that is both serious and unexpected. The sponsor must report an adverse event
p.000063: as a suspected adverse reaction only if there is evidence to suggest a causal relationship between the
p.000063: drug and the adverse event, such as:
p.000063: (A) A single occurrence of an event that is uncommon and known to be strongly associated with drug
p.000063: exposure (e.g., angioedema, hepatic injury, Ste- vens-Johnson Syndrome);
p.000063: (B) One or more occurrences of an event that is not commonly associated with drug exposure, but is
p.000063: otherwise uncommon in the population exposed to the drug (e.g., tendon rupture);
p.000063: (C) An aggregate analysis of specific events observed in a clinical trial (such as known consequences of the
p.000063: under- lying disease or condition under inves- tigation or other events that com- monly occur in the
p.000063: study population independent of drug therapy) that indi- cates those events occur more fre- quently in the
p.000063: drug treatment group than in a concurrent or historical con- trol group.
p.000063: (ii) Findings from other studies. The sponsor must report any findings from epidemiological studies,
p.000063: pooled anal- ysis of multiple studies, or clinical studies (other than those reported under
p.000063: paragraph (c)(1)(i) of this sec- tion), whether or not conducted under an IND, and whether or not
p.000063: conducted by the sponsor, that suggest a signifi- cant risk in humans exposed to the drug.
...
p.000089: is not greater than the probable risk from the disease or condition; and
p.000089: (2) FDA must determine that the pa- tient cannot obtain the drug under an- other IND or protocol.
p.000089: (b) Submission. The expanded access submission must include information adequate to demonstrate that the
p.000089: cri- teria in § 312.305(a) and paragraph (a) of this section have been met. The ex- panded access
p.000089: submission must meet the requirements of § 312.305(b).
p.000089: (1) If the drug is the subject of an ex- isting IND, the expanded access sub- mission may be made by the sponsor
p.000089: or by a licensed physician.
p.000089: (2) A sponsor may satisfy the submis- sion requirements by amending its ex- isting IND to include a protocol for
p.000089: in- dividual patient expanded access.
p.000089: (3) A licensed physician may satisfy the submission requirements by ob- taining from the sponsor
p.000089: permission for FDA to refer to any information in the IND that would be needed to sup- port the expanded access
p.000089: request (right of reference) and by providing any other required information not con- tained in the
p.000089: IND (usually only the in- formation specific to the individual pa- tient).
p.000089: (c) Safeguards. (1) Treatment is gen- erally limited to a single course of
p.000089:
p.000089:
p.000089:
p.000089:
p.000089:
p.000089:
p.000089:
p.000089:
p.000089: § 312.315
p.000089: therapy for a specified duration unless FDA expressly authorizes multiple courses or chronic therapy.
p.000089: (2) At the conclusion of treatment, the licensed physician or sponsor must provide FDA with a written
p.000089: summary of the results of the expanded access use, including adverse effects.
p.000089: (3) FDA may require sponsors to monitor an individual patient ex- panded access use if the
p.000089: use is for an extended duration.
p.000089: (4) When a significant number of similar individual patient expanded ac- cess requests have been
p.000089: submitted, FDA may ask the sponsor to submit an IND or protocol for the use under
p.000089: § 312.315 or § 312.320.
p.000089: (d) Emergency procedures. If there is an emergency that requires the patient to be treated before a written
p.000089: submis- sion can be made, FDA may authorize the expanded access use to begin with- out a written
p.000089: submission. The FDA re- viewing official may authorize the emergency use by telephone.
p.000089: (1) Emergency expanded access use may be requested by telephone, fac- simile, or other means
...
Social / Police Officer
Searching for indicator officer:
(return to top)
p.000072: (i) A brief summary of the clinical studies to be submitted in the applica- tion.
p.000072: (ii) A proposed format for organizing the submission, including methods for presenting the data.
p.000072: (iii) Information on the status of needed or ongoing pediatric studies.
p.000072: (iv) Any other information for discus- sion at the meeting.
p.000072: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000072: FR 23031, June 17, 1987; 55 FR 11580, Mar. 29,
p.000072: 1990; 63 FR 66669, Dec. 2, 1998; 67 FR 9586, Mar.
p.000072: 4, 2002]
p.000072: § 312.48 Dispute resolution.
p.000072: (a) General. The Food and Drug Ad- ministration is committed to resolving differences between sponsors and
p.000072: FDA reviewing divisions with respect to re- quirements for IND’s as quickly and amicably as possible
p.000072: through the coop- erative exchange of information and views.
p.000072: (b) Administrative and procedural issues. When administrative or proce- dural disputes arise, the
p.000072: sponsor should
p.000072:
p.000072:
p.000072:
p.000072:
p.000072:
p.000072:
p.000072:
p.000072: Food and Drug Administration, HHS § 312.52
p.000072:
p.000072:
p.000072: first attempt to resolve the matter with the division in FDA’s Center for Drug Evaluation and
p.000072: Research or Cen- ter for Biologics Evaluation and Re- search which is responsible for review of the
p.000072: IND, beginning with the con- sumer safety officer assigned to the ap- plication. If the dispute is not
p.000072: resolved, the sponsor may raise the matter with the person designated as ombudsman, whose function shall
p.000072: be to investigate what has happened and to facilitate a timely and equitable resolution. Appro- priate issues
p.000072: to raise with the ombuds- man include resolving difficulties in scheduling meetings and obtaining
p.000072: timely replies to inquiries. Further de- tails on this procedure are contained in FDA Staff Manual Guide 4820.7
p.000072: that is publicly available under FDA’s public information regulations in part 20.
p.000072: (c) Scientific and medical disputes. (1)
p.000072: When scientific or medical disputes arise during the drug investigation process, sponsors should
p.000072: discuss the matter directly with the responsible reviewing officials. If necessary, spon- sors may
p.000072: request a meeting with the appropriate reviewing officials and management representatives in order
p.000072: to seek a resolution. Requests for such meetings shall be directed to the direc- tor of the division in
p.000072: FDA’s Center for Drug Evaluation and Research or Cen- ter for Biologics Evaluation and Re- search
p.000072: which is responsible for review of the IND. FDA will make every at- tempt to grant requests for
p.000072: meetings that involve important issues and that can be scheduled at mutually conven- ient times.
p.000072: (2) The ‘‘end-of-Phase 2’’ and ‘‘pre-
p.000072: NDA’’ meetings described in § 312.47(b) will also provide a timely forum for discussing and resolving
...
p.000075: 54.4(a)(3)(i), (a)(3)(ii), (a)(3)(iii), and (a)(3)(iv) of this chapter paid to clinical investigators by the
p.000075: sponsor of the covered study. A sponsor shall also maintain complete and accurate records concerning
p.000075: all other financial interests of investiga- tors subject to part 54 of this chapter.
p.000075: (c) A sponsor shall retain the records and reports required by this part for 2 years after a marketing
p.000075: application is approved for the drug; or, if an applica- tion is not approved for the drug, until 2 years after
p.000075: shipment and delivery of the drug for investigational use is dis- continued and FDA has been so noti-
p.000075: fied.
p.000075: (d) A sponsor shall retain reserve samples of any test article and ref- erence standard
p.000075: identified in, and used in any of the bioequivalence or bio-
p.000076: 76
p.000076: 21 CFR Ch. I (4–1–12 Edition)
p.000076: availability studies described in,
p.000076: § 320.38 or § 320.63 of this chapter, and release the reserve samples to FDA upon request, in
p.000076: accordance with, and for the period specified in § 320.38.
p.000076: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000076: FR 23031, June 17, 1987; 58 FR 25926, Apr. 28,
p.000076: 1993; 63 FR 5252, Feb. 2, 1998; 67 FR 9586, Mar.
p.000076: 4, 2002]
p.000076:
p.000076: § 312.58 Inspection of sponsor’s records and reports.
p.000076: (a) FDA inspection. A sponsor shall upon request from any properly au- thorized officer or
p.000076: employee of the Food and Drug Administration, at rea- sonable times, permit such officer or employee to
p.000076: have access to and copy and verify any records and reports re- lating to a clinical investigation con-
p.000076: ducted under this part. Upon written request by FDA, the sponsor shall sub- mit the records or reports (or
p.000076: copies of them) to FDA. The sponsor shall dis- continue shipments of the drug to any investigator who has
p.000076: failed to maintain or make available records or reports of the investigation as required by this part.
p.000076: (b) Controlled substances. If an inves- tigational new drug is a substance list- ed in any schedule of the
p.000076: Controlled Substances Act (21 U.S.C. 801; 21 CFR part 1308), records concerning ship- ment, delivery,
p.000076: receipt, and disposition of the drug, which are required to be kept under this part or other applica- ble
p.000076: parts of this chapter shall, upon the request of a properly authorized em- ployee of the Drug Enforcement
p.000076: Ad- ministration of the U.S. Department of Justice, be made available by the in- vestigator or sponsor to
p.000076: whom the re- quest is made, for inspection and copy- ing. In addition, the sponsor shall as- sure that
p.000076: adequate precautions are taken, including storage of the inves- tigational drug in a securely locked,
...
p.000077: accurate finan- cial information to allow an applicant to submit complete and accurate cer- tification or
p.000077: disclosure statements as required under part 54 of this chapter. The clinical investigator shall prompt- ly
p.000077: update this information if any rel- evant changes occur during the course of the investigation and for
p.000077: 1 year fol- lowing the completion of the study.
p.000077: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000077: FR 23031, June 17, 1987; 63 FR 5252, Feb. 2,
p.000077: 1998; 67 FR 9586, Mar. 4, 2002; 75 FR 59963,
p.000077: Sept. 29, 2010]
p.000077: § 312.66 Assurance of IRB review.
p.000077: An investigator shall assure that an IRB that complies with the require- ments set forth in part 56
p.000077: will be re- sponsible for the initial and continuing review and approval of the proposed clinical study.
p.000077: The investigator shall also assure that he or she will prompt- ly report to the IRB all changes in the
p.000077: research activity and all unanticipated problems involving risk to human sub- jects or others, and that he
p.000077: or she will not make any changes in the research without IRB approval, except where necessary to
p.000077: eliminate apparent imme- diate hazards to human subjects.
p.000077: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000077: FR 23031, June 17, 1987; 67 FR 9586, Mar. 4,
p.000077: 2002]
p.000077:
p.000077: § 312.68 Inspection of investigator’s records and reports.
p.000077: An investigator shall upon request from any properly authorized officer or
p.000077:
p.000078: 78
p.000078: 21 CFR Ch. I (4–1–12 Edition)
p.000078: employee of FDA, at reasonable times, permit such officer or employee to have access to, and copy and
p.000078: verify any records or reports made by the investi- gator pursuant to § 312.62. The investi- gator is not required
p.000078: to divulge subject names unless the records of particular individuals require a more detailed study of
p.000078: the cases, or unless there is reason to believe that the records do not represent actual case studies, or do
p.000078: not represent actual results obtained.
p.000078: § 312.69 Handling of controlled sub- stances.
p.000078: If the investigational drug is subject to the Controlled Substances Act, the investigator shall take
p.000078: adequate pre- cautions, including storage of the in- vestigational drug in a securely locked, substantially
p.000078: constructed cabinet, or other securely locked, substantially constructed enclosure, access to which is
p.000078: limited, to prevent theft or diversion of the substance into illegal channels of distribution.
p.000078: § 312.70 Disqualification of a clinical investigator.
p.000078: (a) If FDA has information indicating that an investigator (including a spon- sor-investigator) has repeatedly
p.000078: or de- liberately failed to comply with the re- quirements of this part, part 50, or part 56 of this chapter, or
p.000078: has submitted to FDA or to the sponsor false informa- tion in any required report, the Center for Drug
...
p.000086: § 312.2(b)(2)(ii) if it is labeled as follows:
p.000086: CAUTION: Contains a biological product for investigational in vitro diagnostic tests only.
p.000086: (2) A person shipping a drug under paragraph (a) of this section shall use
p.000086:
p.000086:
p.000086:
p.000086:
p.000086:
p.000086:
p.000086:
p.000086: Food and Drug Administration, HHS § 312.300
p.000086:
p.000086:
p.000086: due diligence to assure that the con- signee is regularly engaged in con- ducting such tests and
p.000086: that the ship- ment of the new drug will actually be used for tests in vitro or in animals used only
p.000086: for laboratory research.
p.000086: (3) A person who ships a drug under paragraph (a) of this section shall maintain adequate records
p.000086: showing the name and post office address of the ex- pert to whom the drug is shipped and the date, quantity,
p.000086: and batch or code mark of each shipment and delivery. Records of shipments under paragraph (a)(1)(i) of
p.000086: this section are to be main- tained for a period of 2 years after the shipment. Records and reports of
p.000086: data and shipments under paragraph (a)(1)(ii) of this section are to be main- tained in accordance
p.000086: with § 312.57(b). The person who ships the drug shall upon request from any properly au- thorized
p.000086: officer or employee of the Food and Drug Administration, at rea- sonable times, permit such officer
p.000086: or employee to have access to and copy and verify records required to be main- tained under this section.
p.000086: (b) Termination of authorization to
p.000086: ship. FDA may terminate authoriza- tion to ship a drug under this section if it finds that:
p.000086: (1) The sponsor of the investigation has failed to comply with any of the conditions for shipment
p.000086: established under this section; or
p.000086: (2) The continuance of the investiga- tion is unsafe or otherwise contrary to the public interest or the
p.000086: drug is used for purposes other than bona fide sci- entific investigation. FDA will notify the person
p.000086: shipping the drug of its find- ing and invite immediate correction. If correction is not immediately made, the
p.000086: person shall have an opportunity for a regulatory hearing before FDA pursuant to part 16.
p.000086: (c) Disposition of unused drug. The person who ships the drug under para- graph (a) of this section
p.000086: shall assure the return of all unused supplies of the drug from individual investigators whenever the
p.000086: investigation discon- tinues or the investigation is termi- nated. The person who ships the drug may
...
Social / Property Ownership
Searching for indicator home:
(return to top)
p.000062: suspected adverse reaction is considered ‘‘life-threat- ening’’ if, in the view of either the in-
p.000062: vestigator or sponsor, its occurrence places the patient or subject at imme- diate risk of death. It
p.000062: does not include an adverse event or suspected adverse reaction that, had it occurred in a more
p.000062: severe form, might have caused death.
p.000062: Serious adverse event or serious sus- pected adverse reaction. An adverse event or suspected
p.000062: adverse reaction is considered ‘‘serious’’ if, in the view of either the investigator or sponsor, it
p.000062: results in any of the following out- comes: Death, a life-threatening ad- verse event,
p.000062: inpatient hospitalization or prolongation of existing hospitaliza- tion, a persistent or significant inca-
p.000062: pacity or substantial disruption of the ability to conduct normal life func- tions, or a
p.000062: congenital anomaly/birth defect. Important medical events that may not result in death, be life-threat- ening,
p.000062: or require hospitalization may be considered serious when, based upon appropriate medical judgment, they
p.000062: may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of
p.000062: the out- comes listed in this definition. Exam- ples of such medical events include al- lergic
p.000062: bronchospasm requiring inten- sive treatment in an emergency room or at home, blood dyscrasias or convul-
p.000062: sions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.
p.000062: Suspected adverse reaction means any adverse event for which there is a rea- sonable possibility
p.000062: that the drug caused the adverse event. For the pur- poses of IND safety reporting, ‘‘reason- able
p.000062: possibility’’ means there is evi- dence to suggest a causal relationship between the drug and
p.000062: the adverse event. Suspected adverse reaction im- plies a lesser degree of certainty about causality than
p.000062: adverse reaction, which
p.000063: 63
p.000063:
p.000063: means any adverse event caused by a drug.
p.000063: Unexpected adverse event or unexpected suspected adverse reaction. An adverse event or suspected adverse
p.000063: reaction is considered ‘‘unexpected’’ if it is not listed in the investigator brochure or is not listed at
p.000063: the specificity or severity that has been observed; or, if an inves- tigator brochure is not required
p.000063: or available, is not consistent with the risk information described in the gen- eral investigational
p.000063: plan or elsewhere in the current application, as amended. For example, under this definition, he- patic
...
Social / Racial Minority
Searching for indicator race:
(return to top)
p.000065: (e) Disclaimer. A safety report or other information submitted by a spon- sor under this part (and any
p.000065: release by FDA of that report or information) does not necessarily reflect a conclu- sion by the sponsor
p.000065: or FDA that the re- port or information constitutes an ad- mission that the drug caused or con- tributed to
p.000065: an adverse event. A sponsor need not admit, and may deny, that the report or information submitted by the
p.000065: sponsor constitutes an admission that the drug caused or contributed to an adverse event.
p.000065: [75 FR 59961, Sept. 29, 2010]
p.000065: § 312.33 Annual reports.
p.000065: A sponsor shall within 60 days of the anniversary date that the IND went into effect, submit a brief
p.000065: report of the progress of the investigation that in- cludes:
p.000065: (a) Individual study information. A brief summary of the status of each study in progress and each
p.000065: study com- pleted during the previous year. The summary is required to include the fol- lowing information for
p.000065: each study:
p.000065: (1) The title of the study (with any appropriate study identifiers such as protocol number), its
p.000065: purpose, a brief statement identifying the patient pop- ulation, and a statement as to whether the study is
p.000065: completed.
p.000065: (2) The total number of subjects ini- tially planned for inclusion in the study; the number
p.000065: entered into the study to date, tabulated by age group, gender, and race; the number whose
p.000065: participation in the study was com- pleted as planned; and the number who dropped out of the study for
p.000065: any rea- son.
p.000065: (3) If the study has been completed, or if interim results are known, a brief description of any available
p.000065: study re- sults.
p.000065: (b) Summary information. Information obtained during the previous year’s clinical and nonclinical
p.000065: investigations, including:
p.000065: (1) A narrative or tabular summary showing the most frequent and most
p.000065:
p.000065:
p.000065:
p.000065:
p.000065:
p.000065:
p.000065:
p.000065:
p.000065: § 312.38
p.000065: serious adverse experiences by body system.
p.000065: (2) A summary of all IND safety re- ports submitted during the past year.
p.000065: (3) A list of subjects who died during participation in the investigation, with the cause of death for each
p.000065: subject.
p.000065: (4) A list of subjects who dropped out during the course of the investigation in association with any adverse
p.000065: experi- ence, whether or not thought to be drug related.
p.000065: (5) A brief description of what, if any- thing, was obtained that is pertinent to an understanding of the drug’s
p.000065: actions, including, for example, information about dose response, information from controlled trials,
p.000065: and information about bioavailability.
p.000065: (6) A list of the preclinical studies (including animal studies) completed or in progress during the past
p.000065: year and a summary of the major preclinical findings.
p.000065: (7) A summary of any significant manufacturing or microbiological changes made during the past
...
Social / Threat of Stigma
Searching for indicator threat:
(return to top)
p.000062: prominent identification of its contents (e.g., ‘‘In- formation Amendment: Chemistry, Manufacturing, and
p.000062: Control’’, ‘‘Infor- mation Amendment: Pharmacology- Toxicology’’, ‘‘Information Amend- ment:
p.000062: Clinical’’), and to contain the following:
p.000062: (1) A statement of the nature and purpose of the amendment.
p.000062: (2) An organized submission of the data in a format appropriate for sci- entific review.
p.000062: (3) If the sponsor desires FDA to com- ment on an information amendment, a request for such comment.
p.000062: (c) When submitted. Information amendments to the IND should be sub- mitted as necessary but,
p.000062: to the extent feasible, not more than every 30 days.
p.000062: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000062: FR 23031, June 17, 1987; 53 FR 1918, Jan. 25,
p.000062: 1988; 67 FR 9585, Mar. 4, 2002]
p.000062:
p.000062:
p.000062:
p.000062:
p.000062:
p.000062:
p.000062:
p.000062: Food and Drug Administration, HHS § 312.32
p.000062:
p.000062:
p.000062: § 312.32 IND safety reporting.
p.000062: (a) Definitions. The following defini- tions of terms apply to this section:
p.000062: Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether
p.000062: or not considered drug related.
p.000062: Life-threatening adverse event or life- threatening suspected adverse reaction. An adverse event or
p.000062: suspected adverse reaction is considered ‘‘life-threat- ening’’ if, in the view of either the in-
p.000062: vestigator or sponsor, its occurrence places the patient or subject at imme- diate risk of death. It
p.000062: does not include an adverse event or suspected adverse reaction that, had it occurred in a more
p.000062: severe form, might have caused death.
p.000062: Serious adverse event or serious sus- pected adverse reaction. An adverse event or suspected
p.000062: adverse reaction is considered ‘‘serious’’ if, in the view of either the investigator or sponsor, it
p.000062: results in any of the following out- comes: Death, a life-threatening ad- verse event,
p.000062: inpatient hospitalization or prolongation of existing hospitaliza- tion, a persistent or significant inca-
p.000062: pacity or substantial disruption of the ability to conduct normal life func- tions, or a
p.000062: congenital anomaly/birth defect. Important medical events that may not result in death, be life-threat- ening,
p.000062: or require hospitalization may be considered serious when, based upon appropriate medical judgment, they
p.000062: may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of
p.000062: the out- comes listed in this definition. Exam- ples of such medical events include al- lergic
p.000062: bronchospasm requiring inten- sive treatment in an emergency room or at home, blood dyscrasias or convul-
p.000062: sions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.
p.000062: Suspected adverse reaction means any adverse event for which there is a rea- sonable possibility
p.000062: that the drug caused the adverse event. For the pur- poses of IND safety reporting, ‘‘reason- able
p.000062: possibility’’ means there is evi- dence to suggest a causal relationship between the drug and
p.000062: the adverse event. Suspected adverse reaction im- plies a lesser degree of certainty about causality than
p.000062: adverse reaction, which
p.000063: 63
p.000063:
p.000063: means any adverse event caused by a drug.
p.000063: Unexpected adverse event or unexpected suspected adverse reaction. An adverse event or suspected adverse
...
Social / Trade Union Membership
Searching for indicator union:
(return to top)
p.000081: (1) The consignee in the United States is the sponsor of the IND; (2) the con- signee is a
p.000081: qualified investigator named in the IND; or (3) the consignee
p.000081:
p.000081:
p.000081:
p.000081:
p.000081:
p.000081:
p.000081:
p.000081:
p.000081: § 312.110
p.000081: is the domestic agent of a foreign spon- sor, is responsible for the control and distribution of the
p.000081: investigational drug, and the IND identifies the con- signee and describes what, if any, ac- tions the
p.000081: consignee will take with re- spect to the investigational drug.
p.000081: (b) Exports. An investigational new drug may be exported from the United States for use in a
p.000081: clinical investiga- tion under any of the following condi- tions:
p.000081: (1) An IND is in effect for the drug under § 312.40, the drug complies with the laws of the country
p.000081: to which it is being exported, and each person who receives the drug is an investigator in a study
p.000081: submitted to and allowed to proceed under the IND; or
p.000081: (2) The drug has valid marketing au- thorization in Australia, Canada, Israel, Japan, New
p.000081: Zealand, Switzer- land, South Africa, or in any country in the European Union or the European Economic Area,
p.000081: and complies with the laws of the country to which it is being exported, section 802(b)(1)(A), (f), and
p.000081: (g) of the act, and § 1.101 of this chap- ter; or
p.000081: (3) The drug is being exported to Aus- tralia, Canada, Israel, Japan, New Zea- land, Switzerland, South Africa, or
p.000081: to any country in the European Union or the European Economic Area, and com- plies with the laws of the
p.000081: country to which it is being exported, the applica- ble provisions of section 802(c), (f), and
p.000081: (g) of the act, and § 1.101 of this chap- ter. Drugs exported under this para- graph that are not
p.000081: the subject of an IND are exempt from the label require- ment in § 312.6(a); or
p.000081: (4) Except as provided in paragraph (b)(5) of this section, the person export- ing the drug sends a written
p.000081: certifi- cation to the Office of International Programs (HFG–1), Food and Drug Ad- ministration, 5600
p.000081: Fishers Lane, Rock- ville, MD 20857, at the time the drug is first exported and maintains records documenting
p.000081: compliance with this paragraph. The certification shall de- scribe the drug that is to be exported
p.000081: (i.e., trade name (if any), generic name, and dosage form), identify the country or countries to which the
p.000081: drug is to be exported, and affirm that:
p.000081: (i) The drug is intended for export;
p.000081:
p.000082: 82
p.000082: 21 CFR Ch. I (4–1–12 Edition)
p.000082: (ii) The drug is intended for inves- tigational use in a foreign country;
p.000082: (iii) The drug meets the foreign pur- chaser’s or consignee’s specifications;
...
Social / Victim of Abuse
Searching for indicator abuse:
(return to top)
p.000059: (ii) If the drug is a combination of
p.000059: drugs previously investigated or mar- keted, the information required under paragraph (a)(9)(i) of
p.000059: this section should be provided for each active drug component. However, if any component in such combination is
p.000059: subject to an
p.000060: 60
p.000060: 21 CFR Ch. I (4–1–12 Edition)
p.000060: approved marketing application or is otherwise lawfully marketed in the United States, the sponsor is
p.000060: not re- quired to submit published material concerning that active drug component unless such material relates
p.000060: directly to the proposed investigational use (in- cluding publications relevant to com- ponent-component
p.000060: interaction).
p.000060: (iii) If the drug has been marketed outside the United States, a list of the countries in which the
p.000060: drug has been marketed and a list of the countries in which the drug has been withdrawn from marketing for
p.000060: reasons potentially related to safety or effectiveness.
p.000060: (10) Additional information. In certain applications, as described below, infor- mation on special topics
p.000060: may be need- ed. Such information shall be sub- mitted in this section as follows:
p.000060: (i) Drug dependence and abuse poten- tial. If the drug is a psychotropic sub- stance or otherwise has
p.000060: abuse poten- tial, a section describing relevant clin- ical studies and experience and studies in test animals.
p.000060: (ii) Radioactive drugs. If the drug is a radioactive drug, sufficient data from animal or human
p.000060: studies to allow a reasonable calculation of radiation-ab- sorbed dose to the whole body and crit- ical
p.000060: organs upon administration to a human subject. Phase 1 studies of ra- dioactive drugs must include
p.000060: studies which will obtain sufficient data for dosimetry calculations.
p.000060: (iii) Pediatric studies. Plans for assess- ing pediatric safety and effectiveness.
p.000060: (iv) Other information. A brief state- ment of any other information that would aid evaluation of
p.000060: the proposed clinical investigations with respect to their safety or their design and poten- tial as
p.000060: controlled clinical trials to sup- port marketing of the drug.
p.000060: (11) Relevant information. If requested by FDA, any other relevant informa- tion needed for review of the
p.000060: applica- tion.
p.000060: (b) Information previously submitted. The sponsor ordinarily is not required to resubmit information
p.000060: previously submitted, but may incorporate the in- formation by reference. A reference to information submitted
p.000060: previously must identify the file by name, reference number, volume, and page number where the
p.000060: information can be found. A
p.000060:
p.000060:
p.000060:
p.000060:
p.000060:
p.000060:
p.000060:
...
p.000062: does not include an adverse event or suspected adverse reaction that, had it occurred in a more
p.000062: severe form, might have caused death.
p.000062: Serious adverse event or serious sus- pected adverse reaction. An adverse event or suspected
p.000062: adverse reaction is considered ‘‘serious’’ if, in the view of either the investigator or sponsor, it
p.000062: results in any of the following out- comes: Death, a life-threatening ad- verse event,
p.000062: inpatient hospitalization or prolongation of existing hospitaliza- tion, a persistent or significant inca-
p.000062: pacity or substantial disruption of the ability to conduct normal life func- tions, or a
p.000062: congenital anomaly/birth defect. Important medical events that may not result in death, be life-threat- ening,
p.000062: or require hospitalization may be considered serious when, based upon appropriate medical judgment, they
p.000062: may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of
p.000062: the out- comes listed in this definition. Exam- ples of such medical events include al- lergic
p.000062: bronchospasm requiring inten- sive treatment in an emergency room or at home, blood dyscrasias or convul-
p.000062: sions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.
p.000062: Suspected adverse reaction means any adverse event for which there is a rea- sonable possibility
p.000062: that the drug caused the adverse event. For the pur- poses of IND safety reporting, ‘‘reason- able
p.000062: possibility’’ means there is evi- dence to suggest a causal relationship between the drug and
p.000062: the adverse event. Suspected adverse reaction im- plies a lesser degree of certainty about causality than
p.000062: adverse reaction, which
p.000063: 63
p.000063:
p.000063: means any adverse event caused by a drug.
p.000063: Unexpected adverse event or unexpected suspected adverse reaction. An adverse event or suspected adverse
p.000063: reaction is considered ‘‘unexpected’’ if it is not listed in the investigator brochure or is not listed at
p.000063: the specificity or severity that has been observed; or, if an inves- tigator brochure is not required
p.000063: or available, is not consistent with the risk information described in the gen- eral investigational
p.000063: plan or elsewhere in the current application, as amended. For example, under this definition, he- patic
p.000063: necrosis would be unexpected (by virtue of greater severity) if the inves- tigator brochure referred only
p.000063: to ele- vated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis
p.000063: would be unex- pected (by virtue of greater specificity) if the investigator brochure listed only cerebral vascular
...
p.000091: 314.71 Procedures for submission of a sup- plement to an approved application.
p.000091: 314.72 Change in ownership of an applica- tion.
p.000091: 314.80 Postmarketing reporting of adverse drug experiences.
p.000091: 314.81 Other postmarketing reports.
p.000091: 314.90 Waivers.
p.000091: Subpart C—Abbreviated Applications
p.000091: 314.91 Obtaining a reduction in the dis- continuance notification period.
p.000091: 314.92 Drug products for which abbreviated applications may be submitted.
p.000091: 314.93 Petition to request a change from a listed drug.
p.000091: 314.94 Content and format of an abbreviated application.
p.000091: 314.95 Notice of certification of invalidity or noninfringement of a patent.
p.000091: 314.96 Amendments to an unapproved abbre- viated application.
p.000091: 314.97 Supplements and other changes to an approved abbreviated application.
p.000091: 314.98 Postmarketing reports.
p.000091: 314.99 Other responsibilities of an applicant of an abbreviated application.
p.000091: Subpart D—FDA Action on Applications and Abbreviated Applications
p.000091: 314.100 Timeframes for reviewing applica- tions and abbreviated applications.
p.000091: 314.101 Filing an application and receiving an abbreviated new drug application.
p.000091: 314.102 Communications between FDA and applicants.
p.000091: 314.103 Dispute resolution.
p.000091:
p.000092: 92
p.000092: 21 CFR Ch. I (4–1–12 Edition)
p.000092: 314.104 Drugs with potential for abuse.
p.000092: 314.105 Approval of an application and an abbreviated application.
p.000092: 314.106 Foreign data.
p.000092: 314.107 Effective date of approval of a 505(b)(2) application or abbreviated new drug
p.000092: application under section 505(j) of the act.
p.000092: 314.108 New drug product exclusivity.
p.000092: 314.110 Complete response letter to the ap- plicant.
p.000092: 314.120 [Reserved]
p.000092: 314.122 Submitting an abbreviated applica- tion for, or a 505(j)(2)(C) petition that re- lies on, a listed
p.000092: drug that is no longer marketed.
p.000092: 314.125 Refusal to approve an application.
p.000092: 314.126 Adequate and well-controlled stud- ies.
p.000092: 314.127 Refusal to approve an abbreviated new drug application.
p.000092: 314.150 Withdrawal of approval of an appli- cation or abbreviated application.
p.000092: 314.151 Withdrawal of approval of an abbre- viated new drug application under sec- tion 505(j)(5) of the
p.000092: act.
p.000092: 314.152 Notice of withdrawal of approval of an application or abbreviated application for a new drug.
p.000092: 314.153 Suspension of approval of an abbre- viated new drug application.
p.000092: 314.160 Approval of an application or abbre- viated application for which approval was previously
p.000092: refused, suspended, or withdrawn.
...
Social / Women
Searching for indicator women:
(return to top)
p.000066: be given the investigational drug. When an ongoing study is placed on clinical hold, no new subjects
p.000066: may be recruited to the study and placed on the investigational drug; patients al- ready in the study
p.000066: should be taken off therapy involving the investigational drug unless specifically permitted by FDA in the
p.000066: interest of patient safety.
p.000067: 67
p.000067:
p.000067: (b) Grounds for imposition of clinical hold—(1) Clinical hold of a Phase 1 study under an IND. FDA
p.000067: may place a pro- posed or ongoing Phase 1 investigation on clinical hold if it finds that:
p.000067: (i) Human subjects are or would be exposed to an unreasonable and signifi- cant risk of illness or injury;
p.000067: (ii) The clinical investigators named in the IND are not qualified by reason of their scientific training
p.000067: and experi- ence to conduct the investigation de- scribed in the IND;
p.000067: (iii) The investigator brochure is misleading, erroneous, or materially incomplete; or
p.000067: (iv) The IND does not contain suffi- cient information required under
p.000067: § 312.23 to assess the risks to subjects of the proposed studies.
p.000067: (v) The IND is for the study of an in- vestigational drug intended to treat a life-threatening disease or
p.000067: condition that affects both genders, and men or women with reproductive potential who have the
p.000067: disease or condition being studied are excluded from eligi- bility because of a risk or potential
p.000067: risk from use of the investigational drug of reproductive toxicity (i.e., af- fecting reproductive
p.000067: organs) or devel- opmental toxicity (i.e., affecting poten- tial offspring). The phrase ‘‘women with
p.000067: reproductive potential’’ does not include pregnant women. For purposes of this paragraph, ‘‘life-threatening
p.000067: ill- nesses or diseases’’ are defined as ‘‘dis- eases or conditions where the likeli- hood of death is high
p.000067: unless the course of the disease is interrupted.’’ The clin- ical hold would not apply under this paragraph to
p.000067: clinical studies con- ducted:
p.000067: (A) Under special circumstances, such as studies pertinent only to one gender (e.g., studies
p.000067: evaluating the ex- cretion of a drug in semen or the ef- fects on menstrual function);
p.000067: (B) Only in men or women, as long as a study that does not exclude members of the other gender with reproductive
p.000067: potential is being conducted concur- rently, has been conducted, or will take place within a
p.000067: reasonable time agreed upon by the agency; or
p.000067: (C) Only in subjects who do not suffer from the disease or condition for which the drug is being studied.
p.000067:
p.000067:
p.000067:
p.000067:
p.000067:
p.000067:
p.000067:
p.000067:
p.000067: § 312.42
p.000067: (2) Clinical hold of a Phase 2 or 3 study under an IND. FDA may place a pro- posed or ongoing Phase
p.000067: 2 or 3 inves- tigation on clinical hold if it finds that:
p.000067: (i) Any of the conditions in para- graphs (b)(1)(i) through (b)(1)(v) of this section apply; or
p.000067: (ii) The plan or protocol for the in- vestigation is clearly deficient in de- sign to meet its stated
p.000067: objectives.
p.000067: (3) Clinical hold of an expanded access IND or expanded access protocol. FDA may place an expanded
p.000067: access IND or expanded access protocol on clinical hold under the following conditions:
p.000067: (i) Final use. FDA may place a pro- posed expanded access IND or treat- ment use protocol on clinical
p.000067: hold if it is determined that:
...
Social / education
Searching for indicator education:
(return to top)
p.000074: 74
p.000074: 21 CFR Ch. I (4–1–12 Edition)
p.000074: (e) Will report to the sponsor adverse experiences that occur in the course of the investigation(s) in accordance with
p.000074: § 312.64;
p.000074: (f) Has read and understands the in- formation in the investigator’s bro- chure, including the
p.000074: potential risks and side effects of the drug; and
p.000074: (g) Will ensure that all associates, colleagues, and employees assisting in the conduct of the
p.000074: study(ies) are in- formed about their obligations in meeting the above commitments.
p.000074: (vii) A commitment by the investi- gator that, for an investigation subject to an institutional review
p.000074: requirement under part 56, an IRB that complies with the requirements of that part will be responsible for the
p.000074: initial and con- tinuing review and approval of the clin- ical investigation and that the investi- gator will
p.000074: promptly report to the IRB all changes in the research activity and all unanticipated problems involving
p.000074: risks to human subjects or others, and will not make any changes in the re- search without IRB
p.000074: approval, except where necessary to eliminate apparent immediate hazards to the human sub- jects.
p.000074: (viii) A list of the names of the sub-
p.000074: investigators (e.g., research fellows, residents) who will be assisting the in- vestigator in the
p.000074: conduct of the inves- tigation(s).
p.000074: (2) Curriculum vitae. A curriculum vitae or other statement of qualifica- tions of the investigator
p.000074: showing the education, training, and experience that qualifies the investigator as an ex- pert in the
p.000074: clinical investigation of the drug for the use under investigation.
p.000074: (3) Clinical protocol. (i) For Phase 1 in- vestigations, a general outline of the planned investigation including
p.000074: the es- timated duration of the study and the maximum number of subjects that will be involved.
p.000074: (ii) For Phase 2 or 3 investigations, an outline of the study protocol includ- ing an approximation of the number
p.000074: of subjects to be treated with the drug and the number to be employed as con- trols, if any; the clinical
p.000074: uses to be in- vestigated; characteristics of subjects by age, sex, and condition; the kind of clinical
p.000074: observations and laboratory tests to be conducted; the estimated duration of the study; and copies or a
p.000074:
p.000074:
p.000074:
p.000074:
p.000074:
p.000074:
p.000074:
p.000074: Food and Drug Administration, HHS § 312.56
p.000074:
p.000074:
p.000074: description of case report forms to be used.
p.000074: (4) Financial disclosure information. Sufficient accurate financial informa- tion to allow the
p.000074: sponsor to submit complete and accurate certification or disclosure statements required under part 54
p.000074: of this chapter. The sponsor shall obtain a commitment from the clinical investigator to promptly
p.000074: up- date this information if any relevant changes occur during the course of the investigation and for 1
...
Social / employees
Searching for indicator employees:
(return to top)
p.000052: The term also includes a biological product that is used in vitro for diagnostic purposes. The terms
p.000052: ‘‘investigational drug’’ and ‘‘investigational new drug’’ are deemed to be synonymous for purposes of this
p.000052: part.
p.000052: Investigator means an individual who actually conducts a clinical investiga- tion (i.e., under whose immediate
p.000052: direc- tion the drug is administered or dis- pensed to a subject). In the event an in- vestigation is conducted
p.000052: by a team of individuals, the investigator is the re- sponsible leader of the team. ‘‘Sub-
p.000052: investigator’’ includes any other indi- vidual member of that team.
p.000052: Marketing application means an appli- cation for a new drug submitted under section 505(b) of the act or
p.000052: a biologics license application for a biological product submitted under the Public Health Service
p.000052: Act.
p.000052: Sponsor means a person who takes re- sponsibility for and initiates a clinical investigation. The sponsor may
p.000052: be an individual or pharmaceutical company, governmental agency, academic insti- tution, private organization,
p.000052: or other organization. The sponsor does not ac- tually conduct the investigation unless the sponsor is a
p.000052: sponsor-investigator. A person other than an individual that uses one or more of its own employees to
p.000052: conduct an investigation that it has initiated is a sponsor, not a sponsor-in- vestigator, and the employees are
p.000052: in- vestigators.
p.000052: Sponsor-Investigator means an indi-
p.000052: vidual who both initiates and conducts an investigation, and under whose im- mediate direction the
p.000052: investigational drug is administered or dispensed. The term does not include any person other than an
p.000052: individual. The requirements applicable to a sponsor-investigator under this part include both those
p.000052: ap- plicable to an investigator and a spon- sor.
p.000052:
p.000052:
p.000052:
p.000052:
p.000052:
p.000052:
p.000052:
p.000052: Food and Drug Administration, HHS § 312.8
p.000052:
p.000052:
p.000052: Subject means a human who partici- pates in an investigation, either as a recipient of the
p.000052: investigational new drug or as a control. A subject may be a healthy human or a patient with a
p.000052: disease.
p.000052: [52 FR 8831, Mar. 19, 1987, as amended at 64
p.000052: FR 401, Jan. 5, 1999; 64 FR 56449, Oct. 20, 1999;
p.000052: 73 FR 22815, Apr. 28, 2008]
p.000052:
p.000052: § 312.6 Labeling of an investigational new drug.
p.000052: (a) The immediate package of an in- vestigational new drug intended for human use shall bear a label
p.000052: with the statement ‘‘Caution: New Drug—Lim- ited by Federal (or United States) law to investigational use.’’
...
p.000073: (v) The name and address of the IRB that is responsible for review and ap- proval of the study(ies);
p.000073: (vi) A commitment by the investi- gator that he or she:
p.000073: (a) Will conduct the study(ies) in ac- cordance with the relevant, current protocol(s) and will only make
p.000073: changes in a protocol after notifying the spon- sor, except when necessary to protect the safety, the
p.000073: rights, or welfare of subjects;
p.000073: (b) Will comply with all requirements regarding the obligations of clinical in- vestigators and all other pertinent
p.000073: re- quirements in this part;
p.000073: (c) Will personally conduct or super- vise the described investigation(s);
p.000073: (d) Will inform any potential subjects that the drugs are being used for inves- tigational purposes and will
p.000073: ensure that the requirements relating to ob- taining informed consent (21 CFR part
p.000073: 50) and institutional review board re- view and approval (21 CFR part 56) are met;
p.000074: 74
p.000074: 21 CFR Ch. I (4–1–12 Edition)
p.000074: (e) Will report to the sponsor adverse experiences that occur in the course of the investigation(s) in accordance with
p.000074: § 312.64;
p.000074: (f) Has read and understands the in- formation in the investigator’s bro- chure, including the
p.000074: potential risks and side effects of the drug; and
p.000074: (g) Will ensure that all associates, colleagues, and employees assisting in the conduct of the
p.000074: study(ies) are in- formed about their obligations in meeting the above commitments.
p.000074: (vii) A commitment by the investi- gator that, for an investigation subject to an institutional review
p.000074: requirement under part 56, an IRB that complies with the requirements of that part will be responsible for the
p.000074: initial and con- tinuing review and approval of the clin- ical investigation and that the investi- gator will
p.000074: promptly report to the IRB all changes in the research activity and all unanticipated problems involving
p.000074: risks to human subjects or others, and will not make any changes in the re- search without IRB
p.000074: approval, except where necessary to eliminate apparent immediate hazards to the human sub- jects.
p.000074: (viii) A list of the names of the sub-
p.000074: investigators (e.g., research fellows, residents) who will be assisting the in- vestigator in the
p.000074: conduct of the inves- tigation(s).
p.000074: (2) Curriculum vitae. A curriculum vitae or other statement of qualifica- tions of the investigator
p.000074: showing the education, training, and experience that qualifies the investigator as an ex- pert in the
p.000074: clinical investigation of the drug for the use under investigation.
p.000074: (3) Clinical protocol. (i) For Phase 1 in- vestigations, a general outline of the planned investigation including
p.000074: the es- timated duration of the study and the maximum number of subjects that will be involved.
p.000074: (ii) For Phase 2 or 3 investigations, an outline of the study protocol includ- ing an approximation of the number
...
Social / gender
Searching for indicator gender:
(return to top)
p.000065: than 15 cal- endar days after the determination is made.
p.000065: (e) Disclaimer. A safety report or other information submitted by a spon- sor under this part (and any
p.000065: release by FDA of that report or information) does not necessarily reflect a conclu- sion by the sponsor
p.000065: or FDA that the re- port or information constitutes an ad- mission that the drug caused or con- tributed to
p.000065: an adverse event. A sponsor need not admit, and may deny, that the report or information submitted by the
p.000065: sponsor constitutes an admission that the drug caused or contributed to an adverse event.
p.000065: [75 FR 59961, Sept. 29, 2010]
p.000065: § 312.33 Annual reports.
p.000065: A sponsor shall within 60 days of the anniversary date that the IND went into effect, submit a brief
p.000065: report of the progress of the investigation that in- cludes:
p.000065: (a) Individual study information. A brief summary of the status of each study in progress and each
p.000065: study com- pleted during the previous year. The summary is required to include the fol- lowing information for
p.000065: each study:
p.000065: (1) The title of the study (with any appropriate study identifiers such as protocol number), its
p.000065: purpose, a brief statement identifying the patient pop- ulation, and a statement as to whether the study is
p.000065: completed.
p.000065: (2) The total number of subjects ini- tially planned for inclusion in the study; the number
p.000065: entered into the study to date, tabulated by age group, gender, and race; the number whose
p.000065: participation in the study was com- pleted as planned; and the number who dropped out of the study for
p.000065: any rea- son.
p.000065: (3) If the study has been completed, or if interim results are known, a brief description of any available
p.000065: study re- sults.
p.000065: (b) Summary information. Information obtained during the previous year’s clinical and nonclinical
p.000065: investigations, including:
p.000065: (1) A narrative or tabular summary showing the most frequent and most
p.000065:
p.000065:
p.000065:
p.000065:
p.000065:
p.000065:
p.000065:
p.000065:
p.000065: § 312.38
p.000065: serious adverse experiences by body system.
p.000065: (2) A summary of all IND safety re- ports submitted during the past year.
p.000065: (3) A list of subjects who died during participation in the investigation, with the cause of death for each
p.000065: subject.
p.000065: (4) A list of subjects who dropped out during the course of the investigation in association with any adverse
p.000065: experi- ence, whether or not thought to be drug related.
p.000065: (5) A brief description of what, if any- thing, was obtained that is pertinent to an understanding of the drug’s
p.000065: actions, including, for example, information about dose response, information from controlled trials,
p.000065: and information about bioavailability.
p.000065: (6) A list of the preclinical studies (including animal studies) completed or in progress during the past
p.000065: year and a summary of the major preclinical findings.
...
p.000067: (iv) The IND does not contain suffi- cient information required under
p.000067: § 312.23 to assess the risks to subjects of the proposed studies.
p.000067: (v) The IND is for the study of an in- vestigational drug intended to treat a life-threatening disease or
p.000067: condition that affects both genders, and men or women with reproductive potential who have the
p.000067: disease or condition being studied are excluded from eligi- bility because of a risk or potential
p.000067: risk from use of the investigational drug of reproductive toxicity (i.e., af- fecting reproductive
p.000067: organs) or devel- opmental toxicity (i.e., affecting poten- tial offspring). The phrase ‘‘women with
p.000067: reproductive potential’’ does not include pregnant women. For purposes of this paragraph, ‘‘life-threatening
p.000067: ill- nesses or diseases’’ are defined as ‘‘dis- eases or conditions where the likeli- hood of death is high
p.000067: unless the course of the disease is interrupted.’’ The clin- ical hold would not apply under this paragraph to
p.000067: clinical studies con- ducted:
p.000067: (A) Under special circumstances, such as studies pertinent only to one gender (e.g., studies
p.000067: evaluating the ex- cretion of a drug in semen or the ef- fects on menstrual function);
p.000067: (B) Only in men or women, as long as a study that does not exclude members of the other gender with reproductive
p.000067: potential is being conducted concur- rently, has been conducted, or will take place within a
p.000067: reasonable time agreed upon by the agency; or
p.000067: (C) Only in subjects who do not suffer from the disease or condition for which the drug is being studied.
p.000067:
p.000067:
p.000067:
p.000067:
p.000067:
p.000067:
p.000067:
p.000067:
p.000067: § 312.42
p.000067: (2) Clinical hold of a Phase 2 or 3 study under an IND. FDA may place a pro- posed or ongoing Phase
p.000067: 2 or 3 inves- tigation on clinical hold if it finds that:
p.000067: (i) Any of the conditions in para- graphs (b)(1)(i) through (b)(1)(v) of this section apply; or
p.000067: (ii) The plan or protocol for the in- vestigation is clearly deficient in de- sign to meet its stated
p.000067: objectives.
p.000067: (3) Clinical hold of an expanded access IND or expanded access protocol. FDA may place an expanded
p.000067: access IND or expanded access protocol on clinical hold under the following conditions:
p.000067: (i) Final use. FDA may place a pro- posed expanded access IND or treat- ment use protocol on clinical
p.000067: hold if it is determined that:
p.000067: (A) The pertinent criteria in subpart I of this part for permitting the ex- panded access use to begin are
p.000067: not sat- isfied; or
...
Social / philosophical differences/differences of opinion
Searching for indicator opinion:
(return to top)
p.000083: import- ing country.
p.000083: (d) Insulin and antibiotics. New insulin and antibiotic drug products may be exported for investigational use
p.000083: in ac- cordance with section 801(e)(1) of the
p.000083:
p.000083:
p.000083:
p.000083:
p.000083:
p.000083:
p.000083:
p.000083:
p.000083: § 312.120
p.000083: act without complying with this sec- tion.
p.000083: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000083: FR 23031, June 17, 1987; 64 FR 401, Jan. 5, 1999;
p.000083: 67 FR 9586, Mar. 4, 2002; 70 FR 70729, Nov. 23,
p.000083: 2005]
p.000083:
p.000083: § 312.120 Foreign clinical studies not conducted under an IND.
p.000083: (a) Acceptance of studies. (1) FDA will accept as support for an IND or appli- cation for marketing
p.000083: approval (an ap- plication under section 505 of the act or section 351 of the Public Health Service Act (the PHS
p.000083: Act) (42 U.S.C. 262)) a well-designed and well-conducted for- eign clinical study not conducted under an
p.000083: IND, if the following conditions are met:
p.000083: (i) The study was conducted in ac-
p.000083: cordance with good clinical practice (GCP). For the purposes of this section, GCP is defined as a standard for
p.000083: the de- sign, conduct, performance, moni- toring, auditing, recording, analysis, and reporting of
p.000083: clinical trials in a way that provides assurance that the data and reported results are credible and accurate
p.000083: and that the rights, safety, and well-being of trial subjects are pro- tected. GCP includes review and
p.000083: ap- proval (or provision of a favorable opinion) by an independent ethics com- mittee (IEC) before
p.000083: initiating a study, continuing review of an ongoing study by an IEC, and obtaining and docu- menting
p.000083: the freely given informed con- sent of the subject (or a subject’s le- gally authorized representative, if
p.000083: the subject is unable to provide informed consent) before initiating a study. GCP does not require informed
p.000083: consent in life-threatening situations when the IEC reviewing the study finds, before initiation of the
p.000083: study, that informed consent is not feasible and either that the conditions present are consistent with
p.000083: those described in § 50.23 or
p.000083: § 50.24(a) of this chapter, or that the
p.000083: measures described in the study pro- tocol or elsewhere will protect the rights, safety, and
p.000083: well-being of sub- jects; and
p.000083: (ii) FDA is able to validate the data from the study through an onsite in- spection if the agency
p.000083: deems it nec- essary.
p.000083: (2) Although FDA will not accept as support for an IND or application for
p.000084: 84
p.000084: 21 CFR Ch. I (4–1–12 Edition)
p.000084: marketing approval a study that does not meet the conditions of paragraph (a)(1) of this section, FDA will
p.000084: examine data from such a study.
p.000084: (3) Marketing approval of a new drug based solely on foreign clinical data is governed by § 314.106 of this
p.000084: chapter.
...
General/Other / Natural Hazards
Searching for indicator hazard:
(return to top)
p.000061: pro- tocol that significantly affects the safety of subjects or any change in a Phase 2 or 3
p.000061: protocol that significantly affects the safety of subjects, the scope of the investigation, or the scientific
p.000061: quality of the study. Examples of changes requiring an amendment under this paragraph include:
p.000061: (i) Any increase in drug dosage or du- ration of exposure of individual sub- jects to the drug beyond
p.000061: that in the current protocol, or any significant in- crease in the number of subjects under study.
p.000061: (ii) Any significant change in the de- sign of a protocol (such as the addition or dropping of a control group).
p.000061: (iii) The addition of a new test or procedure that is intended to improve monitoring for, or reduce the
p.000061: risk of, a side effect or adverse event; or the dropping of a test intended to monitor safety.
p.000061: (2)(i) A protocol change under para- graph (b)(1) of this section may be made provided two
p.000061: conditions are met:
p.000061: (a) The sponsor has submitted the change to FDA for its review; and
p.000061: (b) The change has been approved by the IRB with responsibility for review and approval of the study. The
p.000061: sponsor may comply with these two conditions in either order.
p.000061: (ii) Notwithstanding paragraph (b)(2)(i) of this section, a protocol change intended to
p.000061: eliminate an appar- ent immediate hazard to subjects may be implemented immediately provided FDA is
p.000061: subsequently notified by pro- tocol amendment and the reviewing
p.000061:
p.000061:
p.000061:
p.000061:
p.000061:
p.000061:
p.000061:
p.000061:
p.000061: § 312.31
p.000061: IRB is notified in accordance with
p.000061: § 56.104(c).
p.000061: (c) Ne investigator. A sponsor shall submit a protocol amendment when a new investigator is added to
p.000061: carry out a previously submitted protocol, except that a protocol amendment is not re- quired when a licensed
p.000061: practitioner is added in the case of a treatment pro- tocol under § 312.315 or § 312.320. Once the
p.000061: investigator is added to the study, the investigational drug may be shipped to the investigator
p.000061: and the in- vestigator may begin participating in the study. The sponsor shall notify FDA of the
p.000061: new investigator within 30 days of the investigator being added.
p.000061: (d) Content and format. A protocol amendment is required to be promi- nently identified as such
p.000061: (i.e., ‘‘Pro- tocol Amendment: New Protocol’’, ‘‘Protocol Amendment: Change in Pro- tocol’’, or
p.000061: ‘‘Protocol Amendment: New Investigator’’), and to contain the fol- lowing:
p.000061: (1)(i) In the case of a new protocol, a copy of the new protocol and a brief de- scription of the most
p.000061: clinically signifi- cant differences between it and pre- vious protocols.
p.000061: (ii) In the case of a change in pro- tocol, a brief description of the change and reference (date and
p.000061: number) to the submission that contained the pro- tocol.
...
p.000081: (i.e., trade name (if any), generic name, and dosage form), identify the country or countries to which the
p.000081: drug is to be exported, and affirm that:
p.000081: (i) The drug is intended for export;
p.000081:
p.000082: 82
p.000082: 21 CFR Ch. I (4–1–12 Edition)
p.000082: (ii) The drug is intended for inves- tigational use in a foreign country;
p.000082: (iii) The drug meets the foreign pur- chaser’s or consignee’s specifications;
p.000082: (iv) The drug is not in conflict with the importing country’s laws;
p.000082: (v) The outer shipping package is la- beled to show that the package is in- tended for export from
p.000082: the United States;
p.000082: (vi) The drug is not sold or offered for sale in the United States;
p.000082: (vii) The clinical investigation will be conducted in accordance with
p.000082: § 312.120;
p.000082: (viii) The drug is manufactured, proc- essed, packaged, and held in substan- tial conformity with current good
p.000082: man- ufacturing practices;
p.000082: (ix) The drug is not adulterated with- in the meaning of section 501(a)(1), (a)(2)(A), (a)(3), (c), or (d) of
p.000082: the act;
p.000082: (x) The drug does not present an im- minent hazard to public health, either in the United States, if
p.000082: the drug were to be reimported, or in the foreign country; and
p.000082: (xi) The drug is labeled in accordance with the foreign country’s laws.
p.000082: (5) In the event of a national emer- gency in a foreign country, where the national emergency necessitates
p.000082: expor- tation of an investigational new drug, the requirements in paragraph (b)(4) of this section apply as
p.000082: follows:
p.000082: (i) Situations here the investigational ne drug is to be stockpiled in anticipa- tion of a national
p.000082: emergency. There may be instances where exportation of an investigational new drug is needed so that the
p.000082: drug may be stockpiled and made available for use by the import- ing country if and when a
p.000082: national emergency arises. In such cases:
p.000082: (A) A person may export an inves- tigational new drug under paragraph (b)(4) of this section without
p.000082: making an affirmation with respect to any one or more of paragraphs (b)(4)(i), (b)(4)(iv),
...
General/Other / Other Country
Searching for indicator foreign country:
(return to top)
p.000081: to any country in the European Union or the European Economic Area, and com- plies with the laws of the
p.000081: country to which it is being exported, the applica- ble provisions of section 802(c), (f), and
p.000081: (g) of the act, and § 1.101 of this chap- ter. Drugs exported under this para- graph that are not
p.000081: the subject of an IND are exempt from the label require- ment in § 312.6(a); or
p.000081: (4) Except as provided in paragraph (b)(5) of this section, the person export- ing the drug sends a written
p.000081: certifi- cation to the Office of International Programs (HFG–1), Food and Drug Ad- ministration, 5600
p.000081: Fishers Lane, Rock- ville, MD 20857, at the time the drug is first exported and maintains records documenting
p.000081: compliance with this paragraph. The certification shall de- scribe the drug that is to be exported
p.000081: (i.e., trade name (if any), generic name, and dosage form), identify the country or countries to which the
p.000081: drug is to be exported, and affirm that:
p.000081: (i) The drug is intended for export;
p.000081:
p.000082: 82
p.000082: 21 CFR Ch. I (4–1–12 Edition)
p.000082: (ii) The drug is intended for inves- tigational use in a foreign country;
p.000082: (iii) The drug meets the foreign pur- chaser’s or consignee’s specifications;
p.000082: (iv) The drug is not in conflict with the importing country’s laws;
p.000082: (v) The outer shipping package is la- beled to show that the package is in- tended for export from
p.000082: the United States;
p.000082: (vi) The drug is not sold or offered for sale in the United States;
p.000082: (vii) The clinical investigation will be conducted in accordance with
p.000082: § 312.120;
p.000082: (viii) The drug is manufactured, proc- essed, packaged, and held in substan- tial conformity with current good
p.000082: man- ufacturing practices;
p.000082: (ix) The drug is not adulterated with- in the meaning of section 501(a)(1), (a)(2)(A), (a)(3), (c), or (d) of
p.000082: the act;
p.000082: (x) The drug does not present an im- minent hazard to public health, either in the United States, if
p.000082: the drug were to be reimported, or in the foreign country; and
p.000082: (xi) The drug is labeled in accordance with the foreign country’s laws.
p.000082: (5) In the event of a national emer- gency in a foreign country, where the national emergency necessitates
p.000082: expor- tation of an investigational new drug, the requirements in paragraph (b)(4) of this section apply as
p.000082: follows:
p.000082: (i) Situations here the investigational ne drug is to be stockpiled in anticipa- tion of a national
p.000082: emergency. There may be instances where exportation of an investigational new drug is needed so that the
p.000082: drug may be stockpiled and made available for use by the import- ing country if and when a
p.000082: national emergency arises. In such cases:
p.000082: (A) A person may export an inves- tigational new drug under paragraph (b)(4) of this section without
p.000082: making an affirmation with respect to any one or more of paragraphs (b)(4)(i), (b)(4)(iv),
p.000082: (b)(4)(vi), (b)(4)(vii), (b)(4)(viii), and/or (b)(4)(ix) of this sec- tion, provided that he or she:
p.000082: (1) Provides a written statement ex- plaining why compliance with each such paragraph is not
p.000082: feasible or is contrary to the best interests of the in- dividuals who may receive the inves- tigational new
p.000082: drug;
p.000082:
p.000082:
p.000082:
p.000082:
p.000082:
p.000082:
p.000082:
...
General/Other / Public Emergency
Searching for indicator emergency:
(return to top)
p.000050: Subpart A—General Provisions
p.000050: Sec.
p.000050: 312.1 Scope.
p.000050: 312.2 Applicability.
p.000050: 312.3 Definitions and interpretations.
p.000050: 312.6 Labeling of an investigational new drug.
p.000050: 312.7 Promotion of investigational drugs.
p.000050: 312.8 Charging for investigational drugs under an IND.
p.000050: 312.10 Waivers.
p.000050:
p.000050: Subpart B—Investigational New Drug Application (IND)
p.000050: 312.20 Requirement for an IND.
p.000050: 312.21 Phases of an investigation.
p.000050: 312.22 General principles of the IND submis- sion.
p.000050: 312.23 IND content and format.
p.000050: 312.30 Protocol amendments.
p.000050: 312.31 Information amendments.
p.000050: 312.32 IND safety reporting.
p.000050: 312.33 Annual reports.
p.000050: 312.38 Withdrawal of an IND.
p.000050: Subpart C—Administrative Actions
p.000050: 312.40 General requirements for use of an in- vestigational new drug in a clinical in- vestigation.
p.000050: 312.41 Comment and advice on an IND.
p.000050: 312.42 Clinical holds and requests for modi- fication.
p.000050: 312.44 Termination.
p.000050: 312.45 Inactive status.
p.000050: 312.47 Meetings.
p.000050: 312.48 Dispute resolution.
p.000050:
p.000050: 50
p.000050:
p.000050: 21 CFR Ch. I (4–1–12 Edition)
p.000050: Subpart D—Responsibilities of Sponsors and Investigators
p.000050: 312.50 General responsibilities of sponsors.
p.000050: 312.52 Transfer of obligations to a contract research organization.
p.000050: 312.53 Selecting investigators and monitors.
p.000050: 312.54 Emergency research under § 50.24 of this chapter.
p.000050: 312.55 Informing investigators.
p.000050: 312.56 Review of ongoing investigations.
p.000050: 312.57 Recordkeeping and record retention.
p.000050: 312.58 Inspection of sponsor’s records and reports.
p.000050: 312.59 Disposition of unused supply of inves- tigational drug.
p.000050: 312.60 General responsibilities of investiga- tors.
p.000050: 312.61 Control of the investigational drug.
p.000050: 312.62 Investigator recordkeeping and record retention.
p.000050: 312.64 Investigator reports.
p.000050: 312.66 Assurance of IRB review.
p.000050: 312.68 Inspection of investigator’s records and reports.
p.000050: 312.69 Handling of controlled substances.
p.000050: 312.70 Disqualification of a clinical investi- gator.
p.000050:
p.000050: Subpart E—Drugs Intended to Treat Life- threatening and Severely-debilitating Illnesses
p.000050: 312.80 Purpose.
p.000050: 312.81 Scope.
p.000050: 312.82 Early consultation.
p.000050: 312.83 Treatment protocols.
p.000050: 312.84 Risk-benefit analysis in review of marketing applications for drugs to treat life-threatening and
p.000050: severely-debilitating illnesses.
p.000050: 312.85 Phase 4 studies.
p.000050: 312.86 Focused FDA regulatory research.
p.000050: 312.87 Active monitoring of conduct and evaluation of clinical trials.
p.000050: 312.88 Safeguards for patient safety.
p.000050: Subpart F—Miscellaneous
p.000050: 312.110 Import and export requirements.
p.000050: 312.120 Foreign clinical studies not con- ducted under an IND.
p.000050: 312.130 Availability for public disclosure of data and information in an IND.
p.000050: 312.140 Address for correspondence.
p.000050: 312.145 Guidance documents.
p.000050:
p.000050: Subpart G—Drugs for Investigational Use in Laboratory Research Animals or in Vitro Tests
p.000050: 312.160 Drugs for investigational use in lab- oratory research animals or in vitro tests.
p.000050: Subpart H [Reserved]
p.000050:
p.000050:
p.000050:
p.000050:
p.000050:
p.000050:
p.000050:
p.000050: Food and Drug Administration, HHS § 312.2
p.000050:
p.000050: Subpart I—Expanded Access to Investigational Drugs for Treatment Use
p.000050: 312.300 General.
p.000050: 312.305 Requirements for all expanded ac- cess uses.
p.000050: 312.310 Individual patients, including for emergency use.
p.000050: 312.315 Intermediate-size patient popu- lations.
p.000050: 312.320 Treatment IND or treatment pro- tocol.
p.000050: AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353,
p.000050: 355, 360bbb, 371; 42 U.S.C. 262.
p.000050: SOURCE: 52 FR 8831, Mar. 19, 1987, unless
p.000050: otherwise noted.
p.000050: EDITORIAL NOTE: Nomenclature changes to part 312 can be found at 69 FR 13717, Mar. 24,
p.000050: 2004.
p.000050:
p.000050: Subpart A—General Provisions
p.000050: § 312.1 Scope.
p.000050: (a) This part contains procedures and requirements governing the use of in- vestigational new drugs, including
p.000050: pro- cedures and requirements for the sub- mission to, and review by, the Food and Drug Administration of
p.000050: investiga- tional new drug applications (IND’s). An investigational new drug for which an IND is in
p.000050: effect in accordance with this part is exempt from the premar- keting approval requirements that are
p.000050: otherwise applicable and may be shipped lawfully for the purpose of con- ducting clinical
p.000050: investigations of that drug.
p.000050: (b) References in this part to regula-
p.000050: tions in the Code of Federal Regula- tions are to chapter I of title 21, unless otherwise noted.
p.000050: § 312.2 Applicability.
p.000050: (a) Applicability. Except as provided in this section, this part applies to all clinical investigations of
...
p.000054: (2) For expanded access to an inves- tigational drug for treatment use under §§ 312.315
p.000054: (intermediate-size pa- tient populations) and 312.320 (treat- ment IND or treatment protocol), in
p.000054: addition to the direct costs described in paragraph (d)(1)(i) of this section, a sponsor may recover the
p.000054: costs of moni- toring the expanded access IND or pro- tocol, complying with IND reporting requirements, and
p.000054: other administrative costs directly associated with the ex- panded access IND.
p.000054: (3) To support its calculation for cost recovery, a sponsor must provide sup- porting documentation to show
p.000054: that the calculation is consistent with the requirements of paragraphs (d)(1) and, if applicable, (d)(2)
p.000054: of this section. The documentation must be accompanied by a statement that an independent
p.000054:
p.000054:
p.000054:
p.000054:
p.000054:
p.000054:
p.000054:
p.000054: Food and Drug Administration, HHS § 312.21
p.000054:
p.000054:
p.000054: certified public accountant has re- viewed and approved the calculations.
p.000054: [74 FR 40899, Aug. 13, 2009]
p.000054: § 312.10 Waivers.
p.000054: (a) A sponsor may request FDA to waive applicable requirement under this part. A waiver request may be
p.000054: sub- mitted either in an IND or in an infor- mation amendment to an IND. In an emergency, a request
p.000054: may be made by telephone or other rapid communica- tion means. A waiver request is re- quired to
p.000054: contain at least one of the following:
p.000054: (1) An explanation why the sponsor’s
p.000054: compliance with the requirement is un- necessary or cannot be achieved;
p.000054: (2) A description of an alternative submission or course of action that satisfies the purpose
p.000054: of the require- ment; or
p.000054: (3) Other information justifying a waiver.
p.000054: (b) FDA may grant a waiver if it finds that the sponsor’s noncompliance would not pose a significant and
p.000054: unrea- sonable risk to human subjects of the investigation and that one of the fol- lowing is met:
p.000054: (1) The sponsor’s compliance with the requirement is unnecessary for the agency to evaluate the
p.000054: application, or compliance cannot be achieved;
p.000054: (2) The sponsor’s proposed alter- native satisfies the requirement; or
p.000054: (3) The applicant’s submission other- wise justifies a waiver.
p.000054: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000054: FR 23031, June 17, 1987; 67 FR 9585, Mar. 4,
p.000054: 2002]
p.000054:
p.000054: Subpart B—Investigational New Drug Application (IND)
p.000054: § 312.20 Requirement for an IND.
p.000054: (a) A sponsor shall submit an IND to FDA if the sponsor intends to conduct a clinical investigation
p.000054: with an inves- tigational new drug that is subject to
p.000054: § 312.2(a).
...
p.000060: (e) Numbering of IND submissions. Each submission relating to an IND is required to be numbered
p.000060: serially using a single, three-digit serial number. The initial IND is required to be numbered 000; each
p.000060: subsequent submission (e.g., amendment, report, or correspondence) is required to be numbered chrono-
p.000060: logically in sequence.
p.000060: (f) Identification of exception from in- formed consent. If the investigation in- volves an exception from
p.000060: informed con- sent under § 50.24 of this chapter, the sponsor shall prominently identify on the cover sheet
p.000060: that the investigation is subject to the requirements in § 50.24 of this chapter.
p.000060: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000060: FR 23031, June 17, 1987; 53 FR 1918, Jan. 25,
p.000060: 1988; 61 FR 51529, Oct. 2, 1996; 62 FR 40599,
p.000060: July 29, 1997; 63 FR 66669, Dec. 2, 1998; 65 FR
p.000060: 56479, Sept. 19, 2000; 67 FR 9585, Mar. 4, 2002]
p.000060:
p.000060: § 312.30 Protocol amendments.
p.000060: Once an IND is in effect, a sponsor shall amend it as needed to ensure that the clinical investigations
p.000060: are con- ducted according to protocols included in the application. This section sets forth the
p.000060: provisions under which new protocols may be submitted and changes in previously submitted proto-
p.000060: cols may be made. Whenever a sponsor intends to conduct a clinical investiga- tion with an exception from
p.000060: informed consent for emergency research as set forth in § 50.24 of this chapter, the spon- sor shall submit
p.000060: a separate IND for such investigation.
p.000061: 61
p.000061:
p.000061: (a) Ne protocol. Whenever a sponsor intends to conduct a study that is not covered by a protocol
p.000061: already con- tained in the IND, the sponsor shall submit to FDA a protocol amendment containing the
p.000061: protocol for the study. Such study may begin provided two conditions are met: (1) The sponsor has
p.000061: submitted the protocol to FDA for its review; and (2) the protocol has been approved by the
p.000061: Institutional Review Board (IRB) with responsibility for re- view and approval of the study in ac-
p.000061: cordance with the requirements of part
p.000061: 56. The sponsor may comply with these
p.000061: two conditions in either order.
p.000061: (b) Changes in a protocol. (1) A sponsor shall submit a protocol amendment de- scribing any change in a Phase 1
p.000061: pro- tocol that significantly affects the safety of subjects or any change in a Phase 2 or 3
p.000061: protocol that significantly affects the safety of subjects, the scope of the investigation, or the scientific
p.000061: quality of the study. Examples of changes requiring an amendment under this paragraph include:
p.000061: (i) Any increase in drug dosage or du- ration of exposure of individual sub- jects to the drug beyond
p.000061: that in the current protocol, or any significant in- crease in the number of subjects under study.
p.000061: (ii) Any significant change in the de- sign of a protocol (such as the addition or dropping of a control group).
...
p.000062: suspected adverse reaction is considered ‘‘life-threat- ening’’ if, in the view of either the in-
p.000062: vestigator or sponsor, its occurrence places the patient or subject at imme- diate risk of death. It
p.000062: does not include an adverse event or suspected adverse reaction that, had it occurred in a more
p.000062: severe form, might have caused death.
p.000062: Serious adverse event or serious sus- pected adverse reaction. An adverse event or suspected
p.000062: adverse reaction is considered ‘‘serious’’ if, in the view of either the investigator or sponsor, it
p.000062: results in any of the following out- comes: Death, a life-threatening ad- verse event,
p.000062: inpatient hospitalization or prolongation of existing hospitaliza- tion, a persistent or significant inca-
p.000062: pacity or substantial disruption of the ability to conduct normal life func- tions, or a
p.000062: congenital anomaly/birth defect. Important medical events that may not result in death, be life-threat- ening,
p.000062: or require hospitalization may be considered serious when, based upon appropriate medical judgment, they
p.000062: may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of
p.000062: the out- comes listed in this definition. Exam- ples of such medical events include al- lergic
p.000062: bronchospasm requiring inten- sive treatment in an emergency room or at home, blood dyscrasias or convul-
p.000062: sions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.
p.000062: Suspected adverse reaction means any adverse event for which there is a rea- sonable possibility
p.000062: that the drug caused the adverse event. For the pur- poses of IND safety reporting, ‘‘reason- able
p.000062: possibility’’ means there is evi- dence to suggest a causal relationship between the drug and
p.000062: the adverse event. Suspected adverse reaction im- plies a lesser degree of certainty about causality than
p.000062: adverse reaction, which
p.000063: 63
p.000063:
p.000063: means any adverse event caused by a drug.
p.000063: Unexpected adverse event or unexpected suspected adverse reaction. An adverse event or suspected adverse
p.000063: reaction is considered ‘‘unexpected’’ if it is not listed in the investigator brochure or is not listed at
p.000063: the specificity or severity that has been observed; or, if an inves- tigator brochure is not required
p.000063: or available, is not consistent with the risk information described in the gen- eral investigational
p.000063: plan or elsewhere in the current application, as amended. For example, under this definition, he- patic
...
p.000074: of subjects to be treated with the drug and the number to be employed as con- trols, if any; the clinical
p.000074: uses to be in- vestigated; characteristics of subjects by age, sex, and condition; the kind of clinical
p.000074: observations and laboratory tests to be conducted; the estimated duration of the study; and copies or a
p.000074:
p.000074:
p.000074:
p.000074:
p.000074:
p.000074:
p.000074:
p.000074: Food and Drug Administration, HHS § 312.56
p.000074:
p.000074:
p.000074: description of case report forms to be used.
p.000074: (4) Financial disclosure information. Sufficient accurate financial informa- tion to allow the
p.000074: sponsor to submit complete and accurate certification or disclosure statements required under part 54
p.000074: of this chapter. The sponsor shall obtain a commitment from the clinical investigator to promptly
p.000074: up- date this information if any relevant changes occur during the course of the investigation and for 1
p.000074: year following the completion of the study.
p.000074: (d) Selecting monitors. A sponsor shall select a monitor qualified by training and experience to monitor the
p.000074: progress of the investigation.
p.000074: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000074: FR 23031, June 17, 1987; 61 FR 57280, Nov. 5,
p.000074: 1996; 63 FR 5252, Feb. 2, 1998; 67 FR 9586, Mar.
p.000074: 4, 2002]
p.000074:
p.000074: § 312.54 Emergency research under
p.000074: § 50.24 of this chapter.
p.000074: (a) The sponsor shall monitor the progress of all investigations involving an exception from informed
p.000074: consent under § 50.24 of this chapter. When the sponsor receives from the IRB informa- tion concerning the
p.000074: public disclosures required by § 50.24(a)(7)(ii) and (a)(7)(iii) of this chapter, the sponsor promptly shall
p.000074: submit to the IND file and to Docket Number 95S–0158 in the Divi- sion of Dockets Management
p.000074: (HFA– 305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852, copies
p.000074: of the information that was disclosed, identified by the IND number.
p.000074: (b) The sponsor also shall monitor such investigations to identify when an IRB determines that it cannot
p.000074: approve the research because it does not meet the criteria in the exception in
p.000074: § 50.24(a) of this chapter or because of other relevant ethical concerns. The sponsor promptly shall
p.000074: provide this in- formation in writing to FDA, inves- tigators who are asked to participate in this
p.000074: or a substantially equivalent clinical investigation, and other IRB’s that are asked to review this or
p.000074: a sub- stantially equivalent investigation.
p.000074: [61 FR 51530, Oct. 2, 1996, as amended at 68 FR
p.000074: 24879, May 9, 2003]
p.000074:
p.000075: 75
p.000075:
p.000075: § 312.55 Informing investigators.
p.000075: (a) Before the investigation begins, a sponsor (other than a sponsor-investi- gator) shall give each
...
p.000082: (iii) The drug meets the foreign pur- chaser’s or consignee’s specifications;
p.000082: (iv) The drug is not in conflict with the importing country’s laws;
p.000082: (v) The outer shipping package is la- beled to show that the package is in- tended for export from
p.000082: the United States;
p.000082: (vi) The drug is not sold or offered for sale in the United States;
p.000082: (vii) The clinical investigation will be conducted in accordance with
p.000082: § 312.120;
p.000082: (viii) The drug is manufactured, proc- essed, packaged, and held in substan- tial conformity with current good
p.000082: man- ufacturing practices;
p.000082: (ix) The drug is not adulterated with- in the meaning of section 501(a)(1), (a)(2)(A), (a)(3), (c), or (d) of
p.000082: the act;
p.000082: (x) The drug does not present an im- minent hazard to public health, either in the United States, if
p.000082: the drug were to be reimported, or in the foreign country; and
p.000082: (xi) The drug is labeled in accordance with the foreign country’s laws.
p.000082: (5) In the event of a national emer- gency in a foreign country, where the national emergency necessitates
p.000082: expor- tation of an investigational new drug, the requirements in paragraph (b)(4) of this section apply as
p.000082: follows:
p.000082: (i) Situations here the investigational ne drug is to be stockpiled in anticipa- tion of a national
p.000082: emergency. There may be instances where exportation of an investigational new drug is needed so that the
p.000082: drug may be stockpiled and made available for use by the import- ing country if and when a
p.000082: national emergency arises. In such cases:
p.000082: (A) A person may export an inves- tigational new drug under paragraph (b)(4) of this section without
p.000082: making an affirmation with respect to any one or more of paragraphs (b)(4)(i), (b)(4)(iv),
p.000082: (b)(4)(vi), (b)(4)(vii), (b)(4)(viii), and/or (b)(4)(ix) of this sec- tion, provided that he or she:
p.000082: (1) Provides a written statement ex- plaining why compliance with each such paragraph is not
p.000082: feasible or is contrary to the best interests of the in- dividuals who may receive the inves- tigational new
p.000082: drug;
p.000082:
p.000082:
p.000082:
p.000082:
p.000082:
p.000082:
p.000082:
p.000082: Food and Drug Administration, HHS § 312.110
p.000082:
p.000082:
p.000082: (2) Provides a written statement from an authorized official of the im- porting country’s
p.000082: government. The statement must attest that the official agrees with the exporter’s statement made under
p.000082: paragraph (b)(5)(i)(A)(1) of this section; explain that the drug is to be stockpiled solely for use of the im-
p.000082: porting country in a national emer- gency; and describe the potential na- tional emergency that
p.000082: warrants expor- tation of the investigational new drug under this provision; and
p.000082: (3) Provides a written statement
p.000082: showing that the Secretary of Health and Human Services (the Secretary), or his or her designee, agrees
p.000082: with the findings of the authorized official of the importing country’s government. Persons who
p.000082: wish to obtain a written statement from the Secretary should direct their requests to Secretary’s Op- erations
p.000082: Center, Office of Emergency Operations and Security Programs, Of- fice of Public Health Emergency Pre-
p.000082: paredness, Office of the Secretary, De- partment of Health and Human Serv- ices, 200 Independence Ave.
p.000082: SW., Wash- ington, DC 20201. Requests may be also be sent by FAX: 202–619–7870 or by e- mail: HHS.SOC@hhs.gov.
p.000082: (B) Exportation may not proceed
p.000082: until FDA has authorized exportation of the investigational new drug. FDA may deny authorization if the
p.000082: state- ments provided under paragraphs (b)(5)(i)(A)(1) or (b)(5)(i)(A)(2) of this section are
p.000082: inadequate or if expor- tation is contrary to public health.
p.000082: (ii) Situations here the investigational
p.000082: ne drug is to be used for a sudden and immediate national emergency. There may be instances
p.000082: where exportation of an investigational new drug is needed so that the drug may be used in a sud- den
p.000082: and immediate national emergency that has developed or is developing. In such cases:
p.000082: (A) A person may export an inves- tigational new drug under paragraph (b)(4) of this section without
p.000082: making an affirmation with respect to any one or more of paragraphs (b)(4)(i), (b)(4)(iv),
p.000082: (b)(4)(v), (b)(4)(vi), (b)(4)(vii), (b)(4)(viii), (b)(4)(ix), and/or (b)(4)(xi), provided that he or she:
p.000082: (1) Provides a written statement ex- plaining why compliance with each such paragraph is not
p.000082: feasible or is
p.000083: 83
p.000083:
p.000083: contrary to the best interests of the in- dividuals who are expected to receive the investigational new drug and
p.000083: (2) Provides sufficient information from an authorized official of the im- porting country’s government
p.000083: to en- able the Secretary, or his or her des- ignee, to decide whether a national emergency has
p.000083: developed or is devel- oping in the importing country, wheth- er the investigational new drug will be used solely
p.000083: for that national emer- gency, and whether prompt exportation of the investigational new drug is nec-
p.000083: essary. Persons who wish to obtain a determination from the Secretary should direct their
p.000083: requests to Sec- retary’s Operations Center, Office of Emergency Operations and Security Programs,
p.000083: Office of Public Health Emergency Preparedness, Office of the Secretary, Department of Health and
p.000083: Human Services, 200 Independence Ave. SW., Washington, DC 20201. Requests may be also be sent by FAX:
p.000083: 202–619– 7870 or by e-mail: HHS.SOC@hhs.gov.
p.000083: (B) Exportation may proceed without prior FDA authorization.
p.000083: (c) Limitations. Exportation under paragraph (b) of this section may not occur if:
p.000083: (1) For drugs exported under para- graph (b)(1) of this section, the IND pertaining to the
p.000083: clinical investigation is no longer in effect;
p.000083: (2) For drugs exported under para- graph (b)(2) of this section, the require- ments in section 802(b)(1),
p.000083: (f), or (g) of the act are no longer met;
p.000083: (3) For drugs exported under para- graph (b)(3) of this section, the require- ments in section 802(c), (f),
p.000083: or (g) of the act are no longer met;
p.000083: (4) For drugs exported under para- graph (b)(4) of this section, the condi- tions underlying the
p.000083: certification or the statements submitted under para- graph (b)(5) of this section are no longer met;
p.000083: or
p.000083: (5) For any investigational new drugs under this section, the drug no longer complies with the laws of the
p.000083: import- ing country.
p.000083: (d) Insulin and antibiotics. New insulin and antibiotic drug products may be exported for investigational use
p.000083: in ac- cordance with section 801(e)(1) of the
p.000083:
p.000083:
p.000083:
p.000083:
p.000083:
p.000083:
p.000083:
p.000083:
p.000083: § 312.120
p.000083: act without complying with this sec- tion.
p.000083: [52 FR 8831, Mar. 19, 1987, as amended at 52
...
p.000088: use, providing licensed physicians with the information needed to minimize the risk and maximize the
p.000088: potential benefits of the investigational drug (the investigator’s brochure must be provided if one
p.000088: exists for the drug), maintaining an effective IND for the expanded access use, and maintaining
p.000088: adequate drug disposition records and retaining records in a manner con- sistent with the
p.000088: requirements of
p.000088: § 312.57. Depending on the type of ex-
p.000088: panded access, other sponsor respon- sibilities under subpart D may also apply.
p.000088: (d) Beginning treatment—(1) INDs. An expanded access IND goes into effect 30 days after FDA receives the IND
p.000088: or on earlier notification by FDA that the expanded access use may begin.
p.000088: (2) Protocols. With the following ex- ceptions, expanded access use under a protocol submitted under an
p.000088: existing IND may begin as described in
p.000088: § 312.30(a).
p.000088:
p.000089: 89
p.000089:
p.000089: (i) Expanded access use under the emergency procedures described in
p.000089: § 312.310(d) may begin when the use is authorized by the FDA reviewing offi- cial.
p.000089: (ii) Expanded access use under
p.000089: § 312.320 may begin 30 days after FDA receives the protocol or upon earlier notification by FDA that
p.000089: use may begin.
p.000089: (3) Clinical holds. FDA may place any expanded access IND or protocol on clinical hold as described in §
p.000089: 312.42.
p.000089: § 312.310 Individual patients, includ- ing for emergency use.
p.000089: Under this section, FDA may permit an investigational drug to be used for the treatment of an individual
p.000089: patient by a licensed physician.
p.000089: (a) Criteria. The criteria in § 312.305(a) must be met; and the following deter- minations must be made:
p.000089: (1) The physician must determine that the probable risk to the person from the investigational drug
p.000089: is not greater than the probable risk from the disease or condition; and
p.000089: (2) FDA must determine that the pa- tient cannot obtain the drug under an- other IND or protocol.
p.000089: (b) Submission. The expanded access submission must include information adequate to demonstrate that the
p.000089: cri- teria in § 312.305(a) and paragraph (a) of this section have been met. The ex- panded access
p.000089: submission must meet the requirements of § 312.305(b).
p.000089: (1) If the drug is the subject of an ex- isting IND, the expanded access sub- mission may be made by the sponsor
p.000089: or by a licensed physician.
p.000089: (2) A sponsor may satisfy the submis- sion requirements by amending its ex- isting IND to include a protocol for
p.000089: in- dividual patient expanded access.
p.000089: (3) A licensed physician may satisfy the submission requirements by ob- taining from the sponsor
p.000089: permission for FDA to refer to any information in the IND that would be needed to sup- port the expanded access
p.000089: request (right of reference) and by providing any other required information not con- tained in the
p.000089: IND (usually only the in- formation specific to the individual pa- tient).
p.000089: (c) Safeguards. (1) Treatment is gen- erally limited to a single course of
p.000089:
p.000089:
p.000089:
p.000089:
p.000089:
p.000089:
p.000089:
p.000089:
p.000089: § 312.315
p.000089: therapy for a specified duration unless FDA expressly authorizes multiple courses or chronic therapy.
p.000089: (2) At the conclusion of treatment, the licensed physician or sponsor must provide FDA with a written
p.000089: summary of the results of the expanded access use, including adverse effects.
p.000089: (3) FDA may require sponsors to monitor an individual patient ex- panded access use if the
p.000089: use is for an extended duration.
p.000089: (4) When a significant number of similar individual patient expanded ac- cess requests have been
p.000089: submitted, FDA may ask the sponsor to submit an IND or protocol for the use under
p.000089: § 312.315 or § 312.320.
p.000089: (d) Emergency procedures. If there is an emergency that requires the patient to be treated before a written
p.000089: submis- sion can be made, FDA may authorize the expanded access use to begin with- out a written
p.000089: submission. The FDA re- viewing official may authorize the emergency use by telephone.
p.000089: (1) Emergency expanded access use may be requested by telephone, fac- simile, or other means
p.000089: of electronic communications. For investigational biological drug products regulated by the Center for
p.000089: Biologics Evaluation and Research, the request should be di- rected to the Office of Communication, Outreach and
p.000089: Development, Center for Biologics Evaluation and Research, 301–827–1800 or 1–800–835–4709, e-mail:
p.000089: ocod@fda.hhs.gov. For all other inves- tigational drugs, the request for au- thorization should be
p.000089: directed to the Division of Drug Information, Center for Drug Evaluation and Research, 301– 796–3400, e-mail:
p.000089: druginfo@fda.hhs.gov. After normal working hours (8 a.m. to 4:30 p.m.), the request should be di-
p.000089: rected to the FDA Emergency Call Cen- ter, 866–300–4374, e-mail: emer-
p.000089: gency.operations@fda.hhs.gov.
p.000089: (2) The licensed physician or sponsor must explain how the expanded access use will meet the
p.000089: requirements of
p.000089: §§ 312.305 and 312.310 and must agree to submit an expanded access submission within 15 working days of
p.000089: FDA’s au- thorization of the use.
p.000089: [74 FR 40942, Aug. 13, 2009, as amended at 75
p.000089: FR 32659, June 9, 2010]
p.000089:
p.000090: 90
p.000090: 21 CFR Ch. I (4–1–12 Edition)
p.000090:
p.000090: § 312.315 Intermediate-size patient populations.
p.000090: Under this section, FDA may permit an investigational drug to be used for the treatment of a patient
p.000090: population smaller than that typical of a treat- ment IND or treatment protocol. FDA may ask a sponsor
p.000090: to consolidate ex- panded access under this section when the agency has received a significant number of
p.000090: requests for individual pa- tient expanded access to an investiga- tional drug for the same use.
p.000090: (a) Need for expanded access. Expanded
p.000090: access under this section may be need- ed in the following situations:
...
General/Other / Relationship to Authority
Searching for indicator authority:
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p.000050: 312.84 Risk-benefit analysis in review of marketing applications for drugs to treat life-threatening and
p.000050: severely-debilitating illnesses.
p.000050: 312.85 Phase 4 studies.
p.000050: 312.86 Focused FDA regulatory research.
p.000050: 312.87 Active monitoring of conduct and evaluation of clinical trials.
p.000050: 312.88 Safeguards for patient safety.
p.000050: Subpart F—Miscellaneous
p.000050: 312.110 Import and export requirements.
p.000050: 312.120 Foreign clinical studies not con- ducted under an IND.
p.000050: 312.130 Availability for public disclosure of data and information in an IND.
p.000050: 312.140 Address for correspondence.
p.000050: 312.145 Guidance documents.
p.000050:
p.000050: Subpart G—Drugs for Investigational Use in Laboratory Research Animals or in Vitro Tests
p.000050: 312.160 Drugs for investigational use in lab- oratory research animals or in vitro tests.
p.000050: Subpart H [Reserved]
p.000050:
p.000050:
p.000050:
p.000050:
p.000050:
p.000050:
p.000050:
p.000050: Food and Drug Administration, HHS § 312.2
p.000050:
p.000050: Subpart I—Expanded Access to Investigational Drugs for Treatment Use
p.000050: 312.300 General.
p.000050: 312.305 Requirements for all expanded ac- cess uses.
p.000050: 312.310 Individual patients, including for emergency use.
p.000050: 312.315 Intermediate-size patient popu- lations.
p.000050: 312.320 Treatment IND or treatment pro- tocol.
p.000050: AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353,
p.000050: 355, 360bbb, 371; 42 U.S.C. 262.
p.000050: SOURCE: 52 FR 8831, Mar. 19, 1987, unless
p.000050: otherwise noted.
p.000050: EDITORIAL NOTE: Nomenclature changes to part 312 can be found at 69 FR 13717, Mar. 24,
p.000050: 2004.
p.000050:
p.000050: Subpart A—General Provisions
p.000050: § 312.1 Scope.
p.000050: (a) This part contains procedures and requirements governing the use of in- vestigational new drugs, including
p.000050: pro- cedures and requirements for the sub- mission to, and review by, the Food and Drug Administration of
p.000050: investiga- tional new drug applications (IND’s). An investigational new drug for which an IND is in
p.000050: effect in accordance with this part is exempt from the premar- keting approval requirements that are
p.000050: otherwise applicable and may be shipped lawfully for the purpose of con- ducting clinical
p.000050: investigations of that drug.
p.000050: (b) References in this part to regula-
p.000050: tions in the Code of Federal Regula- tions are to chapter I of title 21, unless otherwise noted.
p.000050: § 312.2 Applicability.
p.000050: (a) Applicability. Except as provided in this section, this part applies to all clinical investigations of
p.000050: products that are subject to section 505 of the Federal Food, Drug, and Cosmetic Act or to the licensing provisions
p.000050: of the Public Health Service Act (58 Stat. 632, as amended (42 U.S.C. 201 et seq.)).
...
p.000078: an opportunity for a regulatory hear- ing under part 16. If a danger to the public health exists, however,
p.000078: the Com- missioner shall terminate the IND im- mediately and notify the sponsor of the determination. In such
p.000078: case, the spon- sor shall have an opportunity for a reg- ulatory hearing before FDA under part 16 on the question
p.000078: of whether the IND should be reinstated.
p.000078: (e) If the Commissioner determines,
p.000078: after the unreliable data submitted by the investigator are eliminated from consideration, that the
p.000078: continued ap- proval of the drug product for which the data were submitted cannot be jus- tified, the
p.000078: Commissioner will proceed to withdraw approval of the drug prod- uct in accordance with the applicable
p.000078: provisions of the act.
p.000078: (f) An investigator who has been de- termined to be ineligible to receive in- vestigational drugs may be
p.000078: reinstated as eligible when the Commissioner de- termines that the investigator has pre-
p.000079: 79
p.000079:
p.000079: sented adequate assurances that the in- vestigator will employ investigational drugs solely in compliance
p.000079: with the provisions of this part and of parts 50 and 56.
p.000079: [52 FR 8831, Mar. 19, 1987, as amended at 52
p.000079: FR 23031, June 17, 1987; 55 FR 11580, Mar. 29,
p.000079: 1990; 62 FR 46876, Sept. 5, 1997; 67 FR 9586,
p.000079: Mar. 4, 2002]
p.000079:
p.000079: Subpart E—Drugs Intended to Treat Life-threatening and Se- verely-debilitating Illnesses
p.000079:
p.000079: AUTHORITY: 21 U.S.C. 351, 352, 353, 355, 371;
p.000079: 42 U.S.C. 262.
p.000079: SOURCE: 53 FR 41523, Oct. 21, 1988, unless
p.000079: otherwise noted.
p.000079:
p.000079: § 312.80 Purpose.
p.000079: The purpose of this section is to es- tablish procedures designed to expedite the development, evaluation,
p.000079: and mar- keting of new therapies intended to treat persons with life-threatening and
p.000079: severely-debilitating illnesses, espe- cially where no satisfactory alter- native therapy
p.000079: exists. As stated
p.000079: § 314.105(c) of this chapter, while the statutory standards of safety and effec- tiveness apply to all
p.000079: drugs, the many kinds of drugs that are subject to them, and the wide range of uses for those
p.000079: drugs, demand flexibility in ap- plying the standards. The Food and Drug Administration (FDA) has
p.000079: deter- mined that it is appropriate to exercise the broadest flexibility in applying the statutory standards, while
p.000079: preserving appropriate guarantees for safety and effectiveness. These procedures reflect the recognition that
p.000079: physicians and pa- tients are generally willing to accept greater risks or side effects from prod- ucts that
p.000079: treat life-threatening and se- verely-debilitating illnesses, than they would accept from products that treat
p.000079: less serious illnesses. These procedures also reflect the recognition that the benefits of the drug
p.000079: need to be evalu- ated in light of the severity of the dis- ease being treated. The procedure out-
...
General/Other / participants in a control group
Searching for indicator control group:
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p.000057: be reported to FDA only in the annual report.
p.000057: (ii) In Phases 2 and 3, detailed proto-
p.000057: cols describing all aspects of the study should be submitted. A protocol for a Phase 2 or 3 investigation
p.000057: should be de- signed in such a way that, if the spon- sor anticipates that some deviation from the
p.000057: study design may become nec- essary as the investigation progresses, alternatives or contingencies to pro-
p.000057: vide for such deviation are built into the protocols at the outset. For exam- ple, a protocol for a
p.000057: controlled short- term study might include a plan for an early crossover of nonresponders to an alternative
p.000057: therapy.
p.000057: (iii) A protocol is required to contain
p.000057: the following, with the specific ele- ments and detail of the protocol re- flecting the above
p.000057: distinctions depend- ing on the phase of study:
p.000057: (a) A statement of the objectives and purpose of the study.
p.000057: (b) The name and address and a state- ment of the qualifications (curriculum vitae or other statement of
p.000057: qualifica- tions) of each investigator, and the name of each subinvestigator (e.g., re- search fellow,
p.000057: resident) working under the supervision of the investigator; the name and address of the research fa- cilities
p.000057: to be used; and the name and address of each reviewing Institutional Review Board.
p.000057: (c) The criteria for patient selection and for exclusion of patients and an es-
p.000057:
p.000058: 58
p.000058: 21 CFR Ch. I (4–1–12 Edition)
p.000058: timate of the number of patients to be studied.
p.000058: (d) A description of the design of the study, including the kind of control group to be used, if any,
p.000058: and a descrip- tion of methods to be used to minimize bias on the part of subjects, investiga- tors, and
p.000058: analysts.
p.000058: (e) The method for determining the dose(s) to be administered, the planned maximum dosage, and the duration
p.000058: of individual patient exposure to the drug.
p.000058: (f) A description of the observations and measurements to be made to fulfill the objectives of the study.
p.000058: (g) A description of clinical proce- dures, laboratory tests, or other meas- ures to be taken to monitor
p.000058: the effects of the drug in human subjects and to minimize risk.
p.000058: (7) Chemistry, manufacturing, and con- trol information. (i) As appropriate for the particular
p.000058: investigations covered by the IND, a section describing the composition, manufacture, and control of the
p.000058: drug substance and the drug product. Although in each phase of the investigation sufficient information is
p.000058: required to be submitted to assure the proper identification, quality, purity, and strength of the
p.000058: investigational drug, the amount of information need- ed to make that assurance will vary with the phase of
p.000058: the investigation, the proposed duration of the investigation, the dosage form, and the amount of in- formation
...
p.000060: a separate IND for such investigation.
p.000061: 61
p.000061:
p.000061: (a) Ne protocol. Whenever a sponsor intends to conduct a study that is not covered by a protocol
p.000061: already con- tained in the IND, the sponsor shall submit to FDA a protocol amendment containing the
p.000061: protocol for the study. Such study may begin provided two conditions are met: (1) The sponsor has
p.000061: submitted the protocol to FDA for its review; and (2) the protocol has been approved by the
p.000061: Institutional Review Board (IRB) with responsibility for re- view and approval of the study in ac-
p.000061: cordance with the requirements of part
p.000061: 56. The sponsor may comply with these
p.000061: two conditions in either order.
p.000061: (b) Changes in a protocol. (1) A sponsor shall submit a protocol amendment de- scribing any change in a Phase 1
p.000061: pro- tocol that significantly affects the safety of subjects or any change in a Phase 2 or 3
p.000061: protocol that significantly affects the safety of subjects, the scope of the investigation, or the scientific
p.000061: quality of the study. Examples of changes requiring an amendment under this paragraph include:
p.000061: (i) Any increase in drug dosage or du- ration of exposure of individual sub- jects to the drug beyond
p.000061: that in the current protocol, or any significant in- crease in the number of subjects under study.
p.000061: (ii) Any significant change in the de- sign of a protocol (such as the addition or dropping of a control group).
p.000061: (iii) The addition of a new test or procedure that is intended to improve monitoring for, or reduce the
p.000061: risk of, a side effect or adverse event; or the dropping of a test intended to monitor safety.
p.000061: (2)(i) A protocol change under para- graph (b)(1) of this section may be made provided two
p.000061: conditions are met:
p.000061: (a) The sponsor has submitted the change to FDA for its review; and
p.000061: (b) The change has been approved by the IRB with responsibility for review and approval of the study. The
p.000061: sponsor may comply with these two conditions in either order.
p.000061: (ii) Notwithstanding paragraph (b)(2)(i) of this section, a protocol change intended to
p.000061: eliminate an appar- ent immediate hazard to subjects may be implemented immediately provided FDA is
p.000061: subsequently notified by pro- tocol amendment and the reviewing
p.000061:
p.000061:
p.000061:
p.000061:
p.000061:
p.000061:
p.000061:
p.000061:
p.000061: § 312.31
p.000061: IRB is notified in accordance with
p.000061: § 56.104(c).
p.000061: (c) Ne investigator. A sponsor shall submit a protocol amendment when a new investigator is added to
p.000061: carry out a previously submitted protocol, except that a protocol amendment is not re- quired when a licensed
p.000061: practitioner is added in the case of a treatment pro- tocol under § 312.315 or § 312.320. Once the
p.000061: investigator is added to the study, the investigational drug may be shipped to the investigator
...
Searching for indicator placebo:
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p.000051: the risks) associated with the use of the drug product;
p.000051: (iv) The investigation is conducted in compliance with the requirements for institutional review set forth in part
p.000051: 56 and with the requirements for informed consent set forth in part 50; and
p.000051: (v) The investigation is conducted in compliance with the requirements of
p.000051: § 312.7.
p.000051: (2)(i) A clinical investigation involv- ing an in vitro diagnostic biological product listed in
p.000051: paragraph (b)(2)(ii) of this section is exempt from the re- quirements of this part if (a) it is
p.000051: in- tended to be used in a diagnostic proce- dure that confirms the diagnosis made by another, medically
p.000051: established, di- agnostic product or procedure and (b) it is shipped in compliance with § 312.160.
p.000051: (ii) In accordance with paragraph (b)(2)(i) of this section, the following products are exempt from
p.000051: the require- ments of this part: (a) blood grouping serum; (b) reagent red blood cells; and
p.000051: (c) anti-human globulin.
p.000051: (3) A drug intended solely for tests in vitro or in laboratory research animals is exempt from the requirements
p.000051: of this part if shipped in accordance with
p.000051: § 312.160.
p.000051: (4) FDA will not accept an applica- tion for an investigation that is ex- empt under the provisions
p.000051: of paragraph (b)(1) of this section.
p.000051: (5) A clinical investigation involving use of a placebo is exempt from the re- quirements of this part if the
p.000051: inves- tigation does not otherwise require submission of an IND.
p.000051: (6) A clinical investigation involving an exception from informed consent under § 50.24 of this chapter
p.000051: is not ex- empt from the requirements of this part.
p.000051:
p.000051:
p.000051:
p.000051:
p.000051:
p.000051:
p.000051:
p.000051:
p.000051: § 312.3
p.000051: (c) Bioavailability studies. The applica- bility of this part to in vivo bio- availability studies in
p.000051: humans is sub- ject to the provisions of § 320.31.
p.000051: (d) Unlabeled indication. This part does not apply to the use in the prac- tice of medicine for
p.000051: an unlabeled indi- cation of a new drug product approved under part 314 or of a licensed biologi- cal
p.000051: product.
p.000051: (e) Guidance. FDA may, on its own initiative, issue guidance on the appli- cability of this part to
p.000051: particular in- vestigational uses of drugs. On request, FDA will advise on the applicability of this part to a
p.000051: planned clinical inves- tigation.
p.000051: [52 FR 8831, Mar. 19, 1987, as amended at 61
p.000051: FR 51529, Oct. 2, 1996; 64 FR 401, Jan. 5, 1999]
p.000051: § 312.3 Definitions and interpretations.
p.000051: (a) The definitions and interpreta- tions of terms contained in section 201 of the Act apply to
p.000051: those terms when used in this part:
p.000051: (b) The following definitions of terms also apply to this part:
...
p.000058: paragraph.
p.000058: (b) Drug product. A list of all compo-
p.000058: nents, which may include reasonable alternatives for inactive compounds, used in the manufacture of
p.000058: the inves- tigational drug product, including both those components intended to appear in the drug product and
p.000058: those which may not appear but which are used in the manufacturing process, and, where applicable, the
p.000058: quantitative composi- tion of the investigational drug prod- uct, including any reasonable vari- ations
p.000058: that may be expected during the investigational stage; the name and ad- dress of the drug product manufac-
p.000058: turer; a brief general description of the manufacturing and packaging proce- dure as appropriate for the product;
p.000058: the acceptable limits and analytical meth-
p.000059: 59
p.000059:
p.000059: ods used to assure the identity, strength, quality, and purity of the drug product; and
p.000059: information suffi- cient to assure the product’s stability during the planned clinical studies.
p.000059: Reference to the current edition of the United States Pharmacopeia—National Formulary may satisfy certain require-
p.000059: ments in this paragraph.
p.000059: (c) A brief general description of the composition, manufacture, and control of any placebo used in
p.000059: a controlled clinical trial.
p.000059: (d) Labeling. A copy of all labels and labeling to be provided to each investi- gator.
p.000059: (e) Environmental analysis require- ments. A claim for categorical exclu- sion under § 25.30 or 25.31
p.000059: or an environ- mental assessment under § 25.40.
p.000059: (8) Pharmacology and toxicology infor- mation. Adequate information about pharmacological and
p.000059: toxicological studies of the drug involving labora- tory animals or in vitro, on the basis of which the sponsor
p.000059: has concluded that it is reasonably safe to conduct the proposed clinical investigations. The kind,
p.000059: duration, and scope of animal and other tests required varies with the du- ration and nature of the proposed
p.000059: clin- ical investigations. Guidance docu- ments are available from FDA that de- scribe ways in which
p.000059: these require- ments may be met. Such information is required to include the identification and qualifications
p.000059: of the individuals who evaluated the results of such stud- ies and concluded that it is reasonably safe to
p.000059: begin the proposed investiga- tions and a statement of where the in- vestigations were conducted and
p.000059: where the records are available for inspec- tion. As drug development proceeds, the sponsor is
p.000059: required to submit infor- mational amendments, as appropriate, with additional information pertinent to safety.
p.000059: (i) Pharmacology and drug disposition.
...
Orphaned Trigger Words
Appendix
Indicator List
| Indicator | Vulnerability |
|---|
| abuse | Victim of Abuse |
| access | Access to Social Goods |
| age | Age |
| authority | Relationship to Authority |
| control group | participants in a control group |
| dependence | Drug Dependence |
| dependency | Drug Dependence |
| drug | Drug Usage |
| education | education |
| emergency | Public Emergency |
| employees | employees |
| fetus | Fetus/Neonate |
| foreign country | Other Country |
| gender | gender |
| hazard | Natural Hazards |
| home | Property Ownership |
| ill | ill |
| illegal | Illegal Activity |
| illness | Physically Disabled |
| language | Linguistic Proficiency |
| nation | stateless persons |
| native | Indigenous |
| officer | Police Officer |
| opinion | philosophical differences/differences of opinion |
| placebo | participants in a control group |
| pregnant | Pregnant |
| race | Racial Minority |
| single | Marital Status |
| substance | Drug Usage |
| threat | Threat of Stigma |
| union | Trade Union Membership |
| women | Women |
Indicator Peers (Indicators in Same Vulnerability)
| Indicator | Peers |
|---|
| control group | ['placebo'] |
| dependence | ['dependency'] |
| dependency | ['dependence'] |
| drug | ['substance'] |
| placebo | ['controlXgroup'] |
| substance | ['drug'] |
Trigger Words
consent
developing
ethics
justice
protect
protection
risk
volunteer
welfare
Applicable Type / Vulnerability / Indicator Overlay for this Input