§ 810.18 shall include a copy of the most cur- rent status report submitted to the agency under § 810.16. A request for ter- mination of a recall order shall include a description of the disposition of the recalled device. (b) FDA may terminate a cease dis- tribution and notification order issued under § 810.10 or a mandatory recall order issued under § 810.13 when the agency determines that the person named in the order: (1) Has taken all reasonable efforts to ensure and to verify that all health professionals, device user facilities, consignees, and, where appropriate, in- dividuals have been notified of the cease distribution and notification order, and to verify that they have been instructed to cease use of the de- vice and to take other appropriate ac- tion; or (2) Has removed the device from the market or has corrected the device so that use of the device would not cause serious, adverse health consequences or death. (c) FDA will provide written notifica- tion to the person named in the order when a request for termination of a cease distribution and notification order or a mandatory recall order has been granted or denied. FDA will re- spond to a written request for termi- nation of a cease distribution and noti- fication or recall order within 30 work- ing days of its receipt. § 810.18 Public notice. The agency will make available to the public in the weekly FDA Enforce- ment Report a descriptive listing of each new mandatory recall issued under § 810.13. The agency will delay public notification of orders when the agency determines that such notifica- tion may cause unnecessary and harm- ful anxiety in individuals and that ini- tial consultation between individuals and their health professionals is essen- tial. PART 812—INVESTIGATIONAL DEVICE EXEMPTIONS Subpart A—General Provisions Sec. 812.1 Scope. 21 CFR Ch. I (4–1–11 Edition) 812.2 Applicability. 812.3 Definitions. 812.5 Labeling of investigational devices. 812.7 Prohibition of promotion and other practices. 812.10 Waivers. 812.18 Import and export requirements. 812.19 Address for IDE correspondence. Subpart B—Application and Administrative Action 812.20 Application. 812.25 Investigational plan. 812.27 Report of prior investigations. 812.30 FDA action on applications. 812.35 Supplemental applications. 812.36 Treatment use of an investigational device. 812.38 Confidentiality of data and informa- tion. Subpart C—Responsibilities of Sponsors 812.40 General responsibilities of sponsors. 812.42 FDA and IRB approval. 812.43 Selecting investigators and monitors. 812.45 Informing investigators. 812.46 Monitoring investigations. 812.47 Emergency research under § 50.24 of this chapter. Subpart D—IRB Review and Approval 812.60 IRB composition, duties, and func- tions. 812.62 IRB approval. 812.64 IRB’s continuing review. 812.65 [Reserved] 812.66 Significant risk device determina- tions. Subpart E—Responsibilities of Investigators 812.100 General responsibilities of investiga- tors. 812.110 Specific responsibilities of investiga- tors. 812.119 Disqualification of a clinical investi- gator. Subpart F [Reserved] Subpart G—Records and Reports 812.140 Records. 812.145 Inspections. 812.150 Reports. AUTHORITY: 21 U.S.C. 331, 351, 352, 353, 355, 360, 360c–360f, 360h–360j, 371, 372, 374, 379e, 381, 382, 383; 42 U.S.C. 216, 241, 262, 263b–263n. SOURCE: 45 FR 3751, Jan. 18, 1980, unless otherwise noted. 102 Food and Drug Administration, HHS § 812.2 Subpart A—General Provisions § 812.1 Scope. (a) The purpose of this part is to en- courage, to the extent consistent with the protection of public health and safety and with ethical standards, the discovery and development of useful devices intended for human use, and to that end to maintain optimum freedom for scientific investigators in their pur- suit of this purpose. This part provides procedures for the conduct of clinical investigations of devices. An approved investigational device exemption (IDE) permits a device that otherwise would be required to comply with a perform- ance standard or to have premarket ap- proval to be shipped lawfully for the purpose of conducting investigations of that device. An IDE approved under § 812.30 or considered approved under § 812.2(b) exempts a device from the re- quirements of the following sections of the Federal Food, Drug, and Cosmetic Act (the act) and regulations issued thereunder: Misbranding under section 502 of the act, registration, listing, and premarket notification under section 510, performance standards under sec- tion 514, premarket approval under sec- tion 515, a banned device regulation under section 516, records and reports under section 519, restricted device re- quirements under section 520(e), good manufacturing practice requirements under section 520(f) except for the re- quirements found in § 820.30, if applica- ble (unless the sponsor states an inten- tion to comply with these require- ments under § 812.20(b)(3) or § 812.140(b)(4)(v)) and color additive re- quirements under section 721. (b) References in this part to regu- latory sections of the Code of Federal Regulations are to chapter I of title 21, unless otherwise noted. [45 FR 3751, Jan. 18, 1980, as amended at 59 FR 14366, Mar. 28, 1994; 61 FR 52654, Oct. 7, 1996] § 812.2 Applicability. (a) General. This part applies to all clinical investigations of devices to de- termine safety and effectiveness, ex- cept as provided in paragraph (c) of this section. (b) Abbreviated requirements. The fol- lowing categories of investigations are considered to have approved applica- tions for IDE’s, unless FDA has noti- fied a sponsor under § 812.20(a) that ap- proval of an application is required: (1) An investigation of a device other than a significant risk device, if the de- vice is not a banned device and the sponsor: (i) Labels the device in accordance with § 812.5; (ii) Obtains IRB approval of the in- vestigation after presenting the re- viewing IRB with a brief explanation of why the device is not a significant risk device, and maintains such approval; (iii) Ensures that each investigator participating in an investigation of the device obtains from each subject under the investigator’s care, informed con- sent under part 50 and documents it, unless documentation is waived by an IRB under § 56.109(c). (iv) Complies with the requirements of § 812.46 with respect to monitoring investigations; (v) Maintains the records required under § 812.140(b) (4) and (5) and makes the reports required under § 812.150(b) (1) through (3) and (5) through (10); (vi) Ensures that participating inves- tigators maintain the records required by § 812.140(a)(3)(i) and make the re- ports required under § 812.150(a) (1), (2), (5), and (7); and (vii) Complies with the prohibitions in § 812.7 against promotion and other practices. (2) An investigation of a device other than one subject to paragraph (e) of this section, if the investigation was begun on or before July 16, 1980, and to be completed, and is completed, on or before January 19, 1981. (c) Exempted investigations. This part, with the exception of § 812.119, does not apply to investigations of the following categories of devices: (1) A device, other than a transi- tional device, in commercial distribu- tion immediately before May 28, 1976, when used or investigated in accord- ance with the indications in labeling in effect at that time. (2) A device, other than a transi- tional device, introduced into commer- cial distribution on or after May 28, 1976, that FDA has determined to be substantially equivalent to a device in commercial distribution immediately 103 § 812.3 before May 28, 1976, and that is used or investigated in accordance with the in- dications in the labeling FDA reviewed under subpart E of part 807 in deter- mining substantial equivalence. (3) A diagnostic device, if the sponsor complies with applicable requirements in § 809.10(c) and if the testing: (i) Is noninvasive, (ii) Does not require an invasive sam- pling procedure that presents signifi- cant risk, (iii) Does not by design or intention introduce energy into a subject, and (iv) Is not used as a diagnostic proce- dure without confirmation of the diag- nosis by another, medically established diagnostic product or procedure. (4) A device undergoing consumer preference testing, testing of a modi- fication, or testing of a combination of two or more devices in commercial dis- tribution, if the testing is not for the purpose of determining safety or effec- tiveness and does not put subjects at risk. (5) A device intended solely for vet- erinary use. (6) A device shipped solely for re- search on or with laboratory animals and labeled in accordance with § 812.5(c). (7) A custom device as defined in § 812.3(b), unless the device is being used to determine safety or effective- ness for commercial distribution. (d) Limit on certain exemptions. In the case of class II or class III device de- scribed in paragraph (c)(1) or (2) of this section, this part applies beginning on the date stipulated in an FDA regula- tion or order that calls for the submis- sion of premarket approval applica- tions for an unapproved class III de- vice, or establishes a performance standard for a class II device. (e) Investigations subject to IND’s. A sponsor that, on July 16, 1980, has an effective investigational new drug ap- plication (IND) for an investigation of a device shall continue to comply with the requirements of part 312 until 90 days after that date. To continue the investigation after that date, a sponsor shall comply with paragraph (b)(1) of this section, if the device is not a sig- nificant risk device, or shall have ob- tained FDA approval under § 812.30 of 21 CFR Ch. I (4–1–11 Edition) an IDE application for the investiga- tion of the device. [45 FR 3751, Jan. 18, 1980, as amended at 46 FR 8956, Jan. 27, 1981; 46 FR 14340, Feb. 27, 1981; 53 FR 11252, Apr. 6, 1988; 62 FR 4165, Jan, 29, 1997; 62 FR 12096, Mar. 14, 1997] § 812.3 Definitions. (a) Act means the Federal Food, Drug, and Cosmetic Act (sections 201– 901, 52 Stat. 1040 et seq., as amended (21 U.S.C. 301–392)). (b) Custom device means a device that: (1) Necessarily deviates from devices generally available or from an applica- ble performance standard or premarket approval requirement in order to com- ply with the order of an individual phy- sician or dentist; (2) Is not generally available to, or generally used by, other physicians or dentists; (3) Is not generally available in fin- ished form for purchase or for dis- pensing upon prescription; (4) Is not offered for commercial dis- tribution through labeling or adver- tising; and (5) Is intended for use by an indi- vidual patient named in the order of a physician or dentist, and is to be made in a specific form for that patient, or is intended to meet the special needs of the physician or dentist in the course of professional practice. (c) FDA means the Food and Drug Administration. (d) Implant means a device that is placed into a surgically or naturally formed cavity of the human body if it is intended to remain there for a period of 30 days or more. FDA may, in order to protect public health, determine that devices placed in subjects for shorter periods are also ‘‘implants’’ for purposes of this part. (e) Institution means a person, other than an individual, who engages in the conduct of research on subjects or in the delivery of medical services to indi- viduals as a primary activity or as an adjunct to providing residential or cus- todial care to humans. The term in- cludes, for example, a hospital, retire- ment home, confinement facility, aca- demic establishment, and device manu- facturer. The term has the same mean- ing as ‘‘facility’’ in section 520(g) of the act. 104 Food and Drug Administration, HHS § 812.3 (f) Institutional revie board (IRB) means any board, committee, or other group formally designated by an insti- tution to review biomedical research involving subjects and established, op- erated, and functioning in conformance with part 56. The term has the same meaning as ‘‘institutional review com- mittee’’ in section 520(g) of the act. (g) Investigational device means a de- vice, including a transitional device, that is the object of an investigation. (h) Investigation means a clinical in- vestigation or research involving one or more subjects to determine the safe- ty or effectiveness of a device. (i) Investigator means an individual who actually conducts a clinical inves- tigation, i.e., under whose immediate direction the test article is adminis- tered or dispensed to, or used involv- ing, a subject, or, in the event of an in- vestigation conducted by a team of in- dividuals, is the responsible leader of that team. (j) Monitor, when used as a noun, means an individual designated by a sponsor or contract research organiza- tion to oversee the progress of an in- vestigation. The monitor may be an employee of a sponsor or a consultant to the sponsor, or an employee of or consultant to a contract research orga- nization. Monitor, when used as a verb, means to oversee an investigation. (k) Noninvasive, when applied to a di- agnostic device or procedure, means one that does not by design or inten- tion: (1) Penetrate or pierce the skin or mucous membranes of the body, the oc- ular cavity, or the urethra, or (2) enter the ear beyond the external auditory canal, the nose beyond the nares, the mouth beyond the pharynx, the anal canal beyond the rectum, or the vagina beyond the cervical os. For purposes of this part, blood sampling that involves simple venipuncture is considered noninvasive, and the use of surplus samples of body fluids or tissues that are left over from samples taken for noninvestigational purposes is also considered noninvasive. (l) Person includes any individual, partnership, corporation, association, scientific or academic establishment, Government agency or organizational unit of a Government agency, and any other legal entity. (m) Significant risk device means an investigational device that: (1) Is intended as an implant and pre- sents a potential for serious risk to the health, safety, or welfare of a subject; (2) Is purported or represented to be for a use in supporting or sustaining human life and presents a potential for serious risk to the health, safety, or welfare of a subject; (3) Is for a use of substantial impor- tance in diagnosing, curing, miti- gating, or treating disease, or other- wise preventing impairment of human health and presents a potential for se- rious risk to the health, safety, or wel- fare of a subject; or (4) Otherwise presents a potential for serious risk to the health, safety, or welfare of a subject. (n) Sponsor means a person who initi- ates, but who does not actually con- duct, the investigation, that is, the in- vestigational device is administered, dispensed, or used under the immediate direction of another individual. A per- son other than an individual that uses one or more of its own employees to conduct an investigation that it has initiated is a sponsor, not a sponsor-in- vestigator, and the employees are in- vestigators. (o) Sponsor-investigator means an indi- vidual who both initiates and actually conducts, alone or with others, an in- vestigation, that is, under whose im- mediate direction the investigational device is administered, dispensed, or used. The term does not include any person other than an individual. The obligations of a sponsor-investigator under this part include those of an in- vestigator and those of a sponsor. (p) Subject means a human who par- ticipates in an investigation, either as an individual on whom or on whose specimen an investigational device is used or as a control. A subject may be in normal health or may have a med- ical condition or disease. (q) Termination means a discontinu- ance, by sponsor or by withdrawal of IRB or FDA approval, of an investiga- tion before completion. (r) Transitional device means a device subject to section 520(l) of the act, that is, a device that FDA considered to be a new drug or an antibiotic drug before May 28, 1976. 105 § 812.5 (s) Unanticipated adverse device effect means any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associ- ated with, a device, if that effect, prob- lem, or death was not previously iden- tified in nature, severity, or degree of incidence in the investigational plan or application (including a supplementary plan or application), or any other un- anticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects. [45 FR 3751, Jan. 18, 1980, as amended at 46 FR 8956, Jan. 27, 1981; 48 FR 15622, Apr. 12, 1983] § 812.5 Labeling of investigational de- vices. (a) Contents. An investigational de- vice or its immediate package shall bear a label with the following infor- mation: the name and place of business of the manufacturer, packer, or dis- tributor (in accordance with § 801.1), the quantity of contents, if appro- priate, and the following statement: ‘‘CAUTION—Investigational device. Limited by Federal (or United States) law to investigational use.’’ The label or other labeling shall describe all rel- evant contraindications, hazards, ad- verse effects, interfering substances or devices, warnings, and precautions. (b) Prohibitions. The labeling of an in- vestigational device shall not bear any statement that is false or misleading in any particular and shall not represent that the device is safe or effective for the purposes for which it is being in- vestigated. (c) Animal research. An investiga- tional device shipped solely for re- search on or with laboratory animals shall bear on its label the following statement: ‘‘CAUTION—Device for in- vestigational use in laboratory animals or other tests that do not involve human subjects.’’ (d) The appropriate FDA Center Di- rector, according to the procedures set forth in § 801.128 or § 809.11 of this chap- ter, may grant an exception or alter- native to the provisions in paragraphs (a) and (c) of this section, to the extent that these provisions are not explicitly required by statute, for specified lots, batches, or other units of a device that 21 CFR Ch. I (4–1–11 Edition) are or will be included in the Strategic National Stockpile. [45 FR 3751, Jan. 18, 1980, as amended at 45 FR 58842, Sept. 5, 1980; 72 FR 73602, Dec. 28, 2007] § 812.7 Prohibition of promotion and other practices. A sponsor, investigator, or any per- son acting for or on behalf of a sponsor or investigator shall not: (a) Promote or test market an inves- tigational device, until after FDA has approved the device for commercial distribution. (b) Commercialize an investigational device by charging the subjects or in- vestigators for a device a price larger than that necessary to recover costs of manufacture, research, development, and handling. (c) Unduly prolong an investigation. If data developed by the investigation indicate in the case of a class III device that premarket approval cannot be jus- tified or in the case of a class II device that it will not comply with an appli- cable performance standard or an amendment to that standard, the spon- sor shall promptly terminate the inves- tigation. (d) Represent that an investigational device is safe or effective for the pur- poses for which it is being investigated. § 812.10 Waivers. (a) Request. A sponsor may request FDA to waive any requirement of this part. A waiver request, with supporting documentation, may be submitted sep- arately or as part of an application to the address in § 812.19. (b) FDA action. FDA may by letter grant a waiver of any requirement that FDA finds is not required by the act and is unnecessary to protect the rights, safety, or welfare of human sub- jects. (c) Effect of request. Any requirement shall continue to apply unless and until FDA waives it. § 812.18 Import and export require- ments. (a) Imports. In addition to complying with other requirements of this part, a person who imports or offers for impor- tation an investigational device sub- ject to this part shall be the agent of 106 Food and Drug Administration, HHS § 812.20 the foreign exporter with respect to in- vestigations of the device and shall act as the sponsor of the clinical investiga- tion, or ensure that another person acts as the agent of the foreign ex- porter and the sponsor of the investiga- tion. (b) Exports. A person exporting an in- vestigational device subject to this part shall obtain FDA’s prior approval, as required by section 801(e) of the act or comply with section 802 of the act. [45 FR 3751, Jan. 18, 1980, as amended at 62 FR 26229, May 13, 1997] § 812.19 Address for IDE correspond- ence. (a) If you are sending an application, supplemental application, report, re- quest for waiver, request for import or export approval, or other correspond- ence relating to matters covered by this part, you must send the submis- sion to the appropriate address as fol- lows: (1) For devices regulated by the Cen- ter for Devices and Radiological Health, send it to Food and Drug Ad- ministration, Center for Devices and Radiological Health, Document Mail Center, 10903 New Hampshire Ave., Bldg. 66, rm. G609, Silver Spring, MD 20993–0002. (2) For devices regulated by the Cen- ter for Biologics Evaluation and Re- search, send it to the Document Con- trol Center (HFM–99), Center for Bio- logics Evaluation and Research, Food and Drug Administration, 1401 Rock- ville Pike, suite 200N, Rockville, MD 20852–1448. (3) For devices regulated by the Cen- ter for Drug Evaluation and Research, send it to Central Document Control Room, Center for Drug Evaluation and Research, Food and Drug Administra- tion, 5901–B Ammendale Rd., Beltsville, MD 20705–1266. (b) You must state on the outside wrapper of each submission what the submission is, for example, an ‘‘IDE ap- plication,’’ a ‘‘supplemental IDE appli- cation,’’ or a ‘‘correspondence con- cerning an IDE (or an IDE applica- tion).’’ [71 FR 42048, July 25, 2006, as amended at 75 FR 20915, Apr. 22, 2010] Subpart B—Application and Administrative Action § 812.20 Application. (a) Submission. (1) A sponsor shall submit an application to FDA if the sponsor intends to use a significant risk device in an investigation, intends to conduct an investigation that in- volves an exception from informed con- sent under § 50.24 of this chapter, or if FDA notifies the sponsor that an appli- cation is required for an investigation. (2) A sponsor shall not begin an in- vestigation for which FDA’s approval of an application is required until FDA has approved the application. (3) A sponsor shall submit three cop- ies of a signed ‘‘Application for an In- vestigational Device Exemption’’ (IDE application), together with accom- panying materials, by registered mail or by hand to the address in § 812.19. Subsequent correspondence concerning an application or a supplemental appli- cation shall be submitted by registered mail or by hand. (4)(i) A sponsor shall submit a sepa- rate IDE for any clinical investigation involving an exception from informed consent under § 50.24 of this chapter. Such a clinical investigation is not permitted to proceed without the prior written authorization of FDA. FDA shall provide a written determination 30 days after FDA receives the IDE or earlier. (ii) If the investigation involves an exception from informed consent under § 50.24 of this chapter, the sponsor shall prominently identify on the cover sheet that the investigation is subject to the requirements in § 50.24 of this chapter. (b) Contents. An IDE application shall include, in the following order: (1) The name and address of the spon- sor. (2) A complete report of prior inves- tigations of the device and an accurate summary of those sections of the inves- tigational plan described in § 812.25(a) through (e) or, in lieu of the summary, the complete plan. The sponsor shall submit to FDA a complete investiga- tional plan and a complete report of prior investigations of the device if no IRB has reviewed them, if FDA has 107 § 812.25 found an IRB’s review inadequate, or if FDA requests them. (3) A description of the methods, fa- cilities, and controls used for the man- ufacture, processing, packing, storage, and, where appropriate, installation of the device, in sufficient detail so that a person generally familiar with good manufacturing practices can make a knowledgeable judgment about the quality control used in the manufac- ture of the device. (4) An example of the agreements to be entered into by all investigators to comply with investigator obligations under this part, and a list of the names and addresses of all investigators who have signed the agreement. (5) A certification that all investiga- tors who will participate in the inves- tigation have signed the agreement, that the list of investigators includes all the investigators participating in the investigation, and that no inves- tigators will be added to the investiga- tion until they have signed the agree- ment. (6) A list of the name, address, and chairperson of each IRB that has been or will be asked to review the inves- tigation and a certification of the ac- tion concerning the investigation taken by each such IRB. (7) The name and address of any in- stitution at which a part of the inves- tigation may be conducted that has not been identified in accordance with paragraph (b)(6) of this section. (8) If the device is to be sold, the amount to be charged and an expla- nation of why sale does not constitute commercialization of the device. (9) A claim for categorical exclusion under § 25.30 or § 25.34 or an environ- mental assessment under § 25.40. (10) Copies of all labeling for the de- vice. (11) Copies of all forms and informa- tional materials to be provided to sub- jects to obtain informed consent. (12) Any other relevant information FDA requests for review of the applica- tion. (c) Additional information. FDA may request additional information con- cerning an investigation or revision in the investigational plan. The sponsor may treat such a request as a dis- approval of the application for pur- 21 CFR Ch. I (4–1–11 Edition) poses of requesting a hearing under part 16. (d) Information previously submitted. Information previously submitted to the Center for Devices and Radio- logical Health, the Center for Biologics Evaluation and Research, or the Center for Drug Evaluation and Research, as applicable, in accordance with this chapter ordinarily need not be resub- mitted, but may be incorporated by reference. [45 FR 3751, Jan. 18, 1980, as amended at 46 FR 8956, Jan. 27, 1981; 50 FR 16669, Apr. 26, 1985; 53 FR 11252, Apr. 6, 1988; 61 FR 51530, Oct. 2, 1996; 62 FR 40600, July 29, 1997; 64 FR 10942, Mar. 8, 1999; 73 FR 49942, Aug. 25, 2008] § 812.25 Investigational plan. The investigational plan shall in- clude, in the following order: (a) Purpose. The name and intended use of the device and the objectives and duration of the investigation. (b) Protocol. A written protocol de- scribing the methodology to be used and an analysis of the protocol dem- onstrating that the investigation is scientifically sound. (c) Risk analysis. A description and analysis of all increased risks to which subjects will be exposed by the inves- tigation; the manner in which these risks will be minimized; a justification for the investigation; and a description of the patient population, including the number, age, sex, and condition. (d) Description of device. A description of each important component, ingre- dient, property, and principle of oper- ation of the device and of each antici- pated change in the device during the course of the investigation. (e) Monitoring procedures. The spon- sor’s written procedures for monitoring the investigation and the name and ad- dress of any monitor. (f) Labeling. Copies of all labeling for the device. (g) Consent materials. Copies of all forms and informational materials to be provided to subjects to obtain in- formed consent. (h) IRB information. A list of the names, locations, and chairpersons of all IRB’s that have been or will be asked to review the investigation, and a certification of any action taken by 108 Food and Drug Administration, HHS § 812.30 any of those IRB’s with respect to the investigation. (i) Other institutions. The name and address of each institution at which a part of the investigation may be con- ducted that has not been identified in paragraph (h) of this section. (j) Additional records and reports. A de- scription of records and reports that will be maintained on the investigation in addition to those prescribed in sub- part G. § 812.27 Report of prior investigations. (a) General. The report of prior inves- tigations shall include reports of all prior clinical, animal, and laboratory testing of the device and shall be com- prehensive and adequate to justify the proposed investigation. (b) Specific contents. The report also shall include: (1) A bibliography of all publications, whether adverse or supportive, that are relevant to an evaluation of the safety or effectiveness of the device, copies of all published and unpublished adverse information, and, if requested by an IRB or FDA, copies of other significant publications. (2) A summary of all other unpub- lished information (whether adverse or supportive) in the possession of, or rea- sonably obtainable by, the sponsor that is relevant to an evaluation of the safe- ty or effectiveness of the device. (3) If information on nonclinical lab- oratory studies is provided, a state- ment that all such studies have been conducted in compliance with applica- ble requirements in the good labora- tory practice regulations in part 58, or if any such study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance. Failure or inability to comply with this requirement does not justify failure to provide information on a relevant nonclinical test study. [45 FR 3751, Jan. 18, 1980, as amended at 50 FR 7518, Feb. 22, 1985] § 812.30 FDA action on applications. (a) Approval or disapproval. FDA will notify the sponsor in writing of the date it receives an application. FDA may approve an investigation as pro- posed, approve it with modifications, or disapprove it. An investigation may not begin until: (1) Thirty days after FDA receives the application at the address in § 812.19 for the investigation of a device other than a banned device, unless FDA noti- fies the sponsor that the investigation may not begin; or (2) FDA approves, by order, an IDE for the investigation. (b) Grounds for disapproval or ith- dra al. FDA may disapprove or with- draw approval of an application if FDA finds that: (1) There has been a failure to comply with any requirement of this part or the act, any other applicable regula- tion or statute, or any condition of ap- proval imposed by an IRB or FDA. (2) The application or a report con- tains an untrue statement of a mate- rial fact, or omits material informa- tion required by this part. (3) The sponsor fails to respond to a request for additional information within the time prescribed by FDA. (4) There is reason to believe that the risks to the subjects are not out- weighed by the anticipated benefits to the subjects and the importance of the knowledge to be gained, or informed consent is inadquate, or the investiga- tion is scientifically unsound, or there is reason to believe that the device as used is ineffective. (5) It is otherwise unreasonable to begin or to continue the investigation owing to the way in which the device is used or the inadequacy of: (i) The report of prior investigations or the investigational plan; (ii) The methods, facilities, and con- trols used for the manufacturing, proc- essing, packaging, storage, and, where appropriate, installation of the device; or (iii) Monitoring and review of the in- vestigation. (c) Notice of disapproval or ithdra al. If FDA disapproves an application or proposes to withdraw approval of an application, FDA will notify the spon- sor in writing. (1) A disapproval order will contain a complete statement of the reasons for disapproval and a statement that the sponsor has an opportunity to request a hearing under part 16. 109 § 812.35 (2) A notice of a proposed withdrawal of approval will contain a complete statement of the reasons for with- drawal and a statement that the spon- sor has an opportunity to request a hearing under part 16. FDA will provide the opportunity for hearing before withdrawal of approval, unless FDA de- termines in the notice that continu- ation of testing under the exemption will result in an unreasonble risk to the public health and orders with- drawal of approval before any hearing. [45 FR 3751, Jan. 18, 1980, as amended at 45 FR 58842, Sept. 5, 1980] § 812.35 Supplemental applications. (a) Changes in investigational plan—(1) Changes requiring prior approval. Except as described in paragraphs (a)(2) through (a)(4) of this section, a sponsor must obtain approval of a supple- mental application under § 812.30(a), and IRB approval when appropriate (see §§ 56.110 and 56.111 of this chapter), prior to implementing a change to an investigational plan. If a sponsor in- tends to conduct an investigation that involves an exception to informed con- sent under § 50.24 of this chapter, the sponsor shall submit a separate inves- tigational device exemption (IDE) ap- plication in accordance with § 812.20(a). (2) Changes effected for emergency use. The requirements of paragraph (a)(1) of this section regarding FDA approval of a supplement do not apply in the case of a deviation from the investigational plan to protect the life or physical well-being of a subject in an emer- gency. Such deviation shall be reported to FDA within 5-working days after the sponsor learns of it (see § 812.150(a)(4)). (3) Changes effected ith notice to FDA ithin 5 days. A sponsor may make cer- tain changes without prior approval of a supplemental application under para- graph (a)(1) of this section if the spon- sor determines that these changes meet the criteria described in para- graphs (a)(3)(i) and (a)(3)(ii) of this sec- tion, on the basis of credible informa- tion defined in paragraph (a)(3)(iii) of this section, and the sponsor provides notice to FDA within 5-working days of making these changes. (i) Developmental changes. The re- quirements in paragraph (a)(1) of this section regarding FDA approval of a 21 CFR Ch. I (4–1–11 Edition) supplement do not apply to develop- mental changes in the device (includ- ing manufacturing changes) that do not constitute a significant change in design or basic principles of operation and that are made in response to infor- mation gathered during the course of an investigation. (ii) Changes to clinical protocol. The requirements in paragraph (a)(1) of this section regarding FDA approval of a supplement do not apply to changes to clinical protocols that do not affect: (A) The validity of the data or infor- mation resulting from the completion of the approved protocol, or the rela- tionship of likely patient risk to ben- efit relied upon to approve the pro- tocol; (B) The scientific soundness of the in- vestigational plan; or (C) The rights, safety, or welfare of the human subjects involved in the in- vestigation. (iii) Definition of credible information. (A) Credible information to support de- velopmental changes in the device (in- cluding manufacturing changes) in- cludes data generated under the design control procedures of § 820.30, pre- clinical/animal testing, peer reviewed published literature, or other reliable information such as clinical informa- tion gathered during a trial or mar- keting. (B) Credible information to support changes to clinical protocols is defined as the sponsor’s documentation sup- porting the conclusion that a change does not have a significant impact on the study design or planned statistical analysis, and that the change does not affect the rights, safety, or welfare of the subjects. Documentation shall in- clude information such as peer re- viewed published literature, the rec- ommendation of the clinical investi- gator(s), and/or the data gathered dur- ing the clinical trial or marketing. (iv) Notice of IDE change. Changes meeting the criteria in paragraphs (a)(3)(i) and (a)(3)(ii) of this section that are supported by credible informa- tion as defined in paragraph (a)(3)(iii) of this section may be made without prior FDA approval if the sponsor sub- mits a notice of the change to the IDE not later than 5-working days after making the change. Changes to devices 110 Food and Drug Administration, HHS § 812.36 are deemed to occur on the date the de- vice, manufactured incorporating the design or manufacturing change, is dis- tributed to the investigator(s). Changes to a clinical protocol are deemed to occur when a clinical investigator is notified by the sponsor that the change should be implemented in the protocol or, for sponsor-investigator studies, when a sponsor-investigator incor- porates the change in the protocol. Such notices shall be identified as a ‘‘notice of IDE change.’’ (A) For a developmental or manufac- turing change to the device, the notice shall include a summary of the rel- evant information gathered during the course of the investigation upon which the change was based; a description of the change to the device or manufac- turing process (cross-referenced to the appropriate sections of the original de- vice description or manufacturing process); and, if design controls were used to assess the change, a statement that no new risks were identified by appropriate risk analysis and that the verification and validation testing, as appropriate, demonstrated that the de- sign outputs met the design input re- quirements. If another method of as- sessment was used, the notice shall in- clude a summary of the information which served as the credible informa- tion supporting the change. (B) For a protocol change, the notice shall include a description of the change (cross-referenced to the appro- priate sections of the original pro- tocol); an assessment supporting the conclusion that the change does not have a significant impact on the study design or planned statistical analysis; and a summary of the information that served as the credible information sup- porting the sponsor’s determination that the change does not affect the rights, safety, or welfare of the sub- jects. (4) Changes submitted in annual report. The requirements of paragraph (a)(1) of this section do not apply to minor changes to the purpose of the study, risk analysis, monitoring procedures, labeling, informed consent materials, and IRB information that do not affect: (i) The validity of the data or infor- mation resulting from the completion of the approved protocol, or the rela- tionship of likely patient risk to ben- efit relied upon to approve the pro- tocol; (ii) The scientific soundness of the investigational plan; or (iii) The rights, safety, or welfare of the human subjects involved in the in- vestigation. Such changes shall be re- ported in the annual progress report for the IDE, under § 812.150(b)(5). (b) IRB approval for ne facilities. A sponsor shall submit to FDA a certifi- cation of any IRB approval of an inves- tigation or a part of an investigation not included in the IDE application. If the investigation is otherwise un- changed, the supplemental application shall consist of an updating of the in- formation required by § 812.20(b) and (c) and a description of any modifications in the investigational plan required by the IRB as a condition of approval. A certification of IRB approval need not be included in the initial submission of the supplemental application, and such certification is not a precondition for agency consideration of the applica- tion. Nevertheless, a sponsor may not begin a part of an investigation at a fa- cility until the IRB has approved the investigation, FDA has received the certification of IRB approval, and FDA, under § 812.30(a), has approved the sup- plemental application relating to that part of the investigation (see § 56.103(a)). [50 FR 25909, June 24, 1985; 50 FR 28932, July 17, 1985, as amended at 61 FR 51531, Oct. 2, 1996; 63 FR 64625, Nov. 23, 1998] § 812.36 Treatment use of an investiga- tional device. (a) General. A device that is not ap- proved for marketing may be under clinical investigation for a serious or immediately life-threatening disease or condition in patients for whom no com- parable or satisfactory alternative de- vice or other therapy is available. Dur- ing the clinical trial or prior to final action on the marketing application, it may be appropriate to use the device in the treatment of patients not in the trial under the provisions of a treat- ment investigational device exemption (IDE). The purpose of this section is to facilitate the availability of promising new devices to desperately ill patients as early in the device development 111 § 812.36 process as possible, before general mar- keting begins, and to obtain additional data on the device’s safety and effec- tiveness. In the case of a serious dis- ease, a device ordinarily may be made available for treatment use under this section after all clinical trials have been completed. In the case of an im- mediately life-threatening disease, a device may be made available for treat- ment use under this section prior to the completion of all clinical trials. For the purpose of this section, an ‘‘immediately life-threatening’’ disease means a stage of a disease in which there is a reasonable likelihood that death will occur within a matter of months or in which premature death is likely without early treatment. For purposes of this section, ‘‘treatment use’’of a device includes the use of a de- vice for diagnostic purposes. (b) Criteria. FDA shall consider the use of an investigational device under a treatment IDE if: (1) The device is intended to treat or diagnose a serious or immediately life- threatening disease or condition; (2) There is no comparable or satis- factory alternative device or other therapy available to treat or diagnose that stage of the disease or condition in the intended patient population; (3) The device is under investigation in a controlled clinical trial for the same use under an approved IDE, or such clinical trials have been com- pleted; and (4) The sponsor of the investigation is actively pursuing marketing approval/ clearance of the investigational device with due diligence. (c) Applications for treatment use. (1) A treatment IDE application shall in- clude, in the following order: (i) The name, address, and telephone number of the sponsor of the treatment IDE; (ii) The intended use of the device, the criteria for patient selection, and a written protocol describing the treat- ment use; (iii) An explanation of the rationale for use of the device, including, as ap- propriate, either a list of the available regimens that ordinarily should be tried before using the investigational device or an explanation of why the use of the investigational device is pref- 21 CFR Ch. I (4–1–11 Edition) erable to the use of available marketed treatments; (iv) A description of clinical proce- dures, laboratory tests, or other meas- ures that will be used to evaluate the effects of the device and to minimize risk; (v) Written procedures for moni- toring the treatment use and the name and address of the monitor; (vi) Instructions for use for the de- vice and all other labeling as required under § 812.5(a) and (b); (vii) Information that is relevant to the safety and effectiveness of the de- vice for the intended treatment use. In- formation from other IDE’s may be in- corporated by reference to support the treatment use; (viii) A statement of the sponsor’s commitment to meet all applicable re- sponsibilities under this part and part 56 of this chapter and to ensure compli- ance of all participating investigators with the informed consent require- ments of part 50 of this chapter; (ix) An example of the agreement to be signed by all investigators partici- pating in the treatment IDE and cer- tification that no investigator will be added to the treatment IDE before the agreement is signed; and (x) If the device is to be sold, the price to be charged and a statement in- dicating that the price is based on manufacturing and handling costs only. (2) A licensed practitioner who re- ceives an investigational device for treatment use under a treatment IDE is an ‘‘investigator’’ under the IDE and is responsible for meeting all applica- ble investigator responsibilities under this part and parts 50 and 56 of this chapter. (d) FDA action on treatment IDE appli- cations—(1) Approval of treatment IDE’s. Treatment use may begin 30 days after FDA receives the treatment IDE sub- mission at the address specified in § 812.19, unless FDA notifies the sponsor in writing earlier than the 30 days that the treatment use may or may not begin. FDA may approve the treatment use as proposed or approve it with modifications. 112 Food and Drug Administration, HHS § 812.38 (2) Disapproval or ithdra al of ap- proval of treatment IDE’s. FDA may dis- approve or withdraw approval of a treatment IDE if: (i) The criteria specified in § 812.36(b) are not met or the treatment IDE does not contain the information required in § 812.36(c); (ii) FDA determines that any of the grounds for disapproval or withdrawal of approval listed in § 812.30(b)(1) through (b)(5) apply; (iii) The device is intended for a seri- ous disease or condition and there is insufficient evidence of safety and ef- fectiveness to support such use; (iv) The device is intended for an im- mediately life-threatening disease or condition and the available scientific evidence, taken as a whole, fails to pro- vide a reasonable basis for concluding that the device: (A) May be effective for its intended use in its intended population; or (B) Would not expose the patients to whom the device is to be administered to an unreasonable and significant ad- ditional risk of illness or injury; (v) There is reasonable evidence that the treatment use is impeding enroll- ment in, or otherwise interfering with the conduct or completion of, a con- trolled investigation of the same or an- other investigational device; (vi) The device has received mar- keting approval/clearance or a com- parable device or therapy becomes available to treat or diagnose the same indication in the same patient popu- lation for which the investigational de- vice is being used; (vii) The sponsor of the controlled clinical trial is not pursuing marketing approval/clearance with due diligence; (viii) Approval of the IDE for the con- trolled clinical investigation of the de- vice has been withdrawn; or (ix) The clinical investigator(s) named in the treatment IDE are not qualified by reason of their scientific training and/or experience to use the investigational device for the intended treatment use. (3) Notice of disapproval or ithdra al. If FDA disapproves or proposes to with- draw approval of a treatment IDE, FDA will follow the procedures set forth in § 812.30(c). (e) Safeguards. Treatment use of an investigational device is conditioned upon the sponsor and investigators complying with the safeguards of the IDE process and the regulations gov- erning informed consent (part 50 of this chapter) and institutional review boards (part 56 of this chapter). (f) Reporting requirements. The spon- sor of a treatment IDE shall submit progress reports on a semi-annual basis to all reviewing IRB’s and FDA until the filing of a marketing application. These reports shall be based on the pe- riod of time since initial approval of the treatment IDE and shall include the number of patients treated with the device under the treatment IDE, the names of the investigators partici- pating in the treatment IDE, and a brief description of the sponsor’s ef- forts to pursue marketing approval/ clearance of the device. Upon filing of a marketing application, progress re- ports shall be submitted annually in accordance with § 812.150(b)(5). The sponsor of a treatment IDE is respon- sible for submitting all other reports required under § 812.150. [62 FR 48947, Sept. 18, 1997] § 812.38 Confidentiality of data and in- formation. (a) Existence of IDE. FDA will not dis- close the existence of an IDE unless its existence has previously been publicly disclosed or acknowledged, until FDA approves an application for premarket approval of the device subject to the IDE; or a notice of completion of a product development protocol for the device has become effective. (b) Availability of summaries or data. (1) FDA will make publicly available, upon request, a detailed summary of information concerning the safety and effectiveness of the device that was the basis for an order approving, dis- approving, or withdrawing approval of an application for an IDE for a banned device. The summary shall include in- formation on any adverse effect on health caused by the device. (2) If a device is a banned device or if the existence of an IDE has been pub- licly disclosed or acknowledged, data or information contained in the file is 113 § 812.40 not available for public disclosure be- fore approval of an application for pre- market approval or the effective date of a notice of completion of a product development protocol except as pro- vided in this section. FDA may, in its discretion, disclose a summary of se- lected portions of the safety and effec- tiveness data, that is, clinical, animal, or laboratory studies and tests of the device, for public consideration of a specific pending issue. (3) If the existence of an IDE file has not been publicly disclosed or acknowl- edged, no data or information in the file are available for public disclosure except as provided in paragraphs (b)(1) and (c) of this section. (4) Notwithstanding paragraph (b)(2) of this section, FDA will make avail- able to the public, upon request, the in- formation in the IDE that was required to be filed in Docket Number 95S–0158 in the Division of Dockets Management (HFA–305), Food and Drug Administra- tion, 5630 Fishers Lane, rm. 1061, Rock- ville, MD 20852, for investigations in- volving an exception from informed consent under § 50.24 of this chapter. Persons wishing to request this infor- mation shall submit a request under the Freedom of Information Act. (c) Reports of adverse effects. Upon re- quest or on its own initiative, FDA shall disclose to an individual on whom an investigational device has been used a copy of a report of adverse device ef- fects relating to that use. (d) Other rules. Except as otherwise provided in this section, the avail- ability for public disclosure of data and information in an IDE file shall be han- dled in accordance with § 814.9. [45 FR 3751, Jan. 18, 1980, as amended at 53 FR 11253, Apr. 6, 1988; 61 FR 51531, Oct. 2, 1996] Subpart C—Responsibilities of Sponsors § 812.40 General responsibilities of sponsors. Sponsors are responsible for selecting qualified investigators and providing them with the information they need to conduct the investigation properly, ensuring proper monitoring of the in- vestigation, ensuring that IRB review and approval are obtained, submitting 21 CFR Ch. I (4–1–11 Edition) an IDE application to FDA, and ensur- ing that any reviewing IRB and FDA are promptly informed of significant new information about an investiga- tion. Additional responsibilities of sponsors are described in subparts B and G. § 812.42 FDA and IRB approval. A sponsor shall not begin an inves- tigation or part of an investigation until an IRB and FDA have both ap- proved the application or supplemental application relating to the investiga- tion or part of an investigation. [46 FR 8957, Jan. 27, 1981] § 812.43 Selecting investigators and monitors. (a) Selecting investigators. A sponsor shall select investigators qualified by training and experience to investigate the device. (b) Control of device. A sponsor shall ship investigational devices only to qualified investigators participating in the investigation. (c) Obtaining agreements. A sponsor shall obtain from each participating investigator a signed agreement that includes: (1) The investigator’s curriculum vitae. (2) Where applicable, a statement of the investigator’s relevant experience, including the dates, location, extent, and type of experience. (3) If the investigator was involved in an investigation or other research that was terminated, an explanation of the circumstances that led to termination. (4) A statement of the investigator’s commitment to: (i) Conduct the investigation in ac- cordance with the agreement, the in- vestigational plan, this part and other applicable FDA regulations, and condi- tions of approval imposed by the re- viewing IRB or FDA; (ii) Supervise all testing of the device involving human subjects; and (iii) Ensure that the requirements for obtaining informed consent are met. (5) Sufficient accurate financial dis- closure information to allow the spon- sor to submit a complete and accurate certification or disclosure statement as required under part 54 of this chapter. 114 Food and Drug Administration, HHS § 812.60 The sponsor shall obtain a commit- ment from the clinical investigator to promptly update this information if any relevant changes occur during the course of the investigation and for 1 year following completion of the study. This information shall not be sub- mitted in an investigational device ex- emption application, but shall be sub- mitted in any marketing application involving the device. (d) Selecting monitors. A sponsor shall select monitors qualified by training and experience to monitor the inves- tigational study in accordance with this part and other applicable FDA reg- ulations. [45 FR 3751, Jan. 18, 1980, as amended at 63 FR 5253, Feb. 2, 1998] § 812.45 Informing investigators. A sponsor shall supply all investiga- tors participating in the investigation with copies of the investigational plan and the report of prior investigations of the device. § 812.46 Monitoring investigations. (a) Securing compliance. A sponsor who discovers that an investigator is not complying with the signed agree- ment, the investigational plan, the re- quirements of this part or other appli- cable FDA regulations, or any condi- tions of approval imposed by the re- viewing IRB or FDA shall promptly ei- ther secure compliance, or discontinue shipments of the device to the investi- gator and terminate the investigator’s participation in the investigation. A sponsor shall also require such an in- vestigator to dispose of or return the device, unless this action would jeop- ardize the rights, safety, or welfare of a subject. (b) Unanticipated adverse device effects. (1) A sponsor shall immediately con- duct an evaluation of any unantici- pated adverse device effect. (2) A sponsor who determines that an unanticipated adverse device effect presents an unreasonable risk to sub- jects shall terminate all investigations or parts of investigations presenting that risk as soon as possible. Termi- nation shall occur not later than 5 working days after the sponsor makes this determination and not later than 15 working days after the sponsor first received notice of the effect. (c) Resumption of terminated studies. If the device is a significant risk device, a sponsor may not resume a termi- nated investigation without IRB and FDA approval. If the device is not a significant risk device, a sponsor may not resume a terminated investigation without IRB approval and, if the inves- tigation was terminated under para- graph (b)(2) of this section, FDA ap- proval. § 812.47 Emergency research under § 50.24 of this chapter. (a) The sponsor shall monitor the progress of all investigations involving an exception from informed consent under § 50.24 of this chapter. When the sponsor receives from the IRB informa- tion concerning the public disclosures under § 50.24(a)(7)(ii) and (a)(7)(iii) of this chapter, the sponsor shall prompt- ly submit to the IDE file and to Docket Number 95S–0158 in the Division of Dockets Management (HFA–305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852, copies of the information that was dis- closed, identified by the IDE number. (b) The sponsor also shall monitor such investigations to determine when an IRB determines that it cannot ap- prove the research because it does not meet the criteria in the exception in § 50.24(a) of this chapter or because of other relevant ethical concerns. The sponsor promptly shall provide this in- formation in writing to FDA, inves- tigators who are asked to participate in this or a substantially equivalent clinical investigation, and other IRB’s that are asked to review this or a sub- stantially equivalent investigation. [61 FR 51531, Oct. 2, 1996, as amended at 64 FR 10943, Mar. 8, 1999] Subpart D—IRB Review and Approval § 812.60 IRB composition, duties, and functions. An IRB reviewing and approving in- vestigations under this part shall com- ply with the requirements of part 56 in 115 § 812.62 all respects, including its composition, duties, and functions. [46 FR 8957, Jan. 27, 1981] § 812.62 IRB approval. (a) An IRB shall review and have au- thority to approve, require modifica- tions in (to secure approval), or dis- approve all investigations covered by this part. (b) If no IRB exists or if FDA finds that an IRB’s review is inadequate, a sponsor may submit an application to FDA. [46 FR 8957, Jan. 27, 1981] § 812.64 IRB’s continuing review. The IRB shall conduct its continuing review of an investigation in accord- ance with part 56. [46 FR 8957, Jan. 27, 1981] § 812.65 [Reserved] § 812.66 Significant risk device deter- minations. If an IRB determines that an inves- tigation, presented for approval under § 812.2(b)(1)(ii), involves a significant risk device, it shall so notify the inves- tigator and, where appropriate, the sponsor. A sponsor may not begin the investigation except as provided in § 812.30(a). [46 FR 8957, Jan. 27, 1981] Subpart E—Responsibilities of Investigators § 812.100 General responsibilities of in- vestigators. An investigator is responsible for en- suring that an investigation is con- ducted according to the signed agree- ment, the investigational plan and ap- plicable FDA regulations, for pro- tecting the rights, safety, and welfare of subjects under the investigator’s care, and for the control of devices under investigation. An investigator also is responsible for ensuring that in- formed consent is obtained in accord- ance with part 50 of this chapter. Addi- tional responsibilities of investigators are described in subpart G. [45 FR 3751, Jan. 18, 1980, as amended at 46 FR 8957, Jan. 27, 1981] 21 CFR Ch. I (4–1–11 Edition) § 812.110 Specific responsibilities of in- vestigators. (a) A aiting approval. An investigator may determine whether potential sub- jects would be interested in partici- pating in an investigation, but shall not request the written informed con- sent of any subject to participate, and shall not allow any subject to partici- pate before obtaining IRB and FDA ap- proval. (b) Compliance. An investigator shall conduct an investigation in accordance with the signed agreement with the sponsor, the investigational plan, this part and other applicable FDA regula- tions, and any conditions of approval imposed by an IRB or FDA. (c) Supervising device use. An investi- gator shall permit an investigational device to be used only with subjects under the investigator’s supervision. An investigator shall not supply an in- vestigational device to any person not authorized under this part to receive it. (d) Financial disclosure. A clinical in- vestigator shall disclose to the sponsor sufficient accurate financial informa- tion to allow the applicant to submit complete and accurate certification or disclosure statements required under part 54 of this chapter. The investi- gator shall promptly update this infor- mation if any relevant changes occur during the course of the investigation and for 1 year following completion of the study. (e) Disposing of device. Upon comple- tion or termination of a clinical inves- tigation or the investigator’s part of an investigation, or at the sponsor’s re- quest, an investigator shall return to the sponsor any remaining supply of the device or otherwise dispose of the device as the sponsor directs. [45 FR 3751, Jan. 18, 1980, as amended at 63 FR 5253, Feb. 2, 1998] § 812.119 Disqualification of a clinical investigator. (a) If FDA has information indicating that an investigator has repeatedly or deliberately failed to comply with the requirements of this part, part 50, or part 56 of this chapter, or has repeat- edly or deliberately submitted false in- formation either to the sponsor of the investigation or in any required report, 116 Food and Drug Administration, HHS § 812.140 the Center for Devices and Radio- logical Health, the Center for Biologics Evaluation and Research, or the Center for Drug Evaluation and Research will furnish the investigator written notice of the matter under complaint and offer the investigator an opportunity to explain the matter in writing, or, at the option of the investigator, in an in- formal conference. If an explanation is offered and accepted by the applicable Center, the disqualification process will be terminated. If an explanation is offered but not accepted by the Center, the investigator will be given an oppor- tunity for a regulatory hearing under part 16 of this chapter on the question of whether the investigator is entitled to receive investigational devices. (b) After evaluating all available in- formation, including any explanation presented by the investigator, if the Commissioner determines that the in- vestigator has repeatedly or delib- erately failed to comply with the re- quirements of this part, part 50, or part 56 of this chapter, or has deliberately or repeatedly submitted false informa- tion either to the sponsor of the inves- tigation or in any required report, the Commissioner will notify the investi- gator, the sponsor of any investigation in which the investigator has been named as a participant, and the review- ing IRB that the investigator is not en- titled to receive investigational de- vices. The notification will provide a statement of basis for such determina- tion. (c) Each investigational device ex- emption (IDE) and each cleared or ap- proved application submitted under this part, subpart E of part 807 of this chapter, or part 814 of this chapter con- taining data reported by an investi- gator who has been determined to be ineligible to receive investigational de- vices will be examined to determine whether the investigator has submitted unreliable data that are essential to the continuation of the investigation or essential to the approval or clear- ance of any marketing application. (d) If the Commissioner determines, after the unreliable data submitted by the investigator are eliminated from consideration, that the data remaining are inadequate to support a conclusion that it is reasonably safe to continue the investigation, the Commissioner will notify the sponsor who shall have an opportunity for a regulatory hear- ing under part 16 of this chapter. If a danger to the public health exists, how- ever, the Commissioner shall termi- nate the IDE immediately and notify the sponsor and the reviewing IRB of the determination. In such case, the sponsor shall have an opportunity for a regulatory hearing before FDA under part 16 of this chapter on the question of whether the IDE should be rein- stated. (e) If the Commissioner determines, after the unreliable data submitted by the investigator are eliminated from consideration, that the continued clearance or approval of the marketing application for which the data were submitted cannot be justified, the Commissioner will proceed to withdraw approval or rescind clearance of the medical device in accordance with the applicable provisions of the act. (f) An investigator who has been de- termined to be ineligible to receive in- vestigational devices may be rein- stated as eligible when the Commis- sioner determines that the investigator has presented adequate assurances that the investigator will employ investiga- tional devices solely in compliance with the provisions of this part and of parts 50 and 56 of this chapter. [62 FR 12096, Mar. 14, 1997, as amended at 71 FR 76902, Dec. 22, 2006] Subpart F [Reserved] Subpart G—Records and Reports § 812.140 Records. (a) Investigator records. A partici- pating investigator shall maintain the following accurate, complete, and cur- rent records relating to the investiga- tor’s participation in an investigation: (1) All correspondence with another investigator, an IRB, the sponsor, a monitor, or FDA, including required reports. (2) Records of receipt, use or disposi- tion of a device that relate to: (i) The type and quantity of the de- vice, the dates of its receipt, and the batch number or code mark. 117 § 812.140 (ii) The names of all persons who re- ceived, used, or disposed of each device. (iii) Why and how many units of the device have been returned to the spon- sor, repaired, or otherwise disposed of. (3) Records of each subject’s case his- tory and exposure to the device. Case histories include the case report forms and supporting data including, for ex- ample, signed and dated consent forms and medical records including, for ex- ample, progress notes of the physician, the individual’s hospital chart(s), and the nurses’ notes. Such records shall include: (i) Documents evidencing informed consent and, for any use of a device by the investigator without informed con- sent, any written concurrence of a li- censed physician and a brief descrip- tion of the circumstances justifying the failure to obtain informed consent. The case history for each individual shall document that informed consent was obtained prior to participation in the study. (ii) All relevant observations, includ- ing records concerning adverse device effects (whether anticipated or unan- ticipated), information and data on the condition of each subject upon enter- ing, and during the course of, the in- vestigation, including information about relevant previous medical his- tory and the results of all diagnostic tests. (iii) A record of the exposure of each subject to the investigational device, including the date and time of each use, and any other therapy. (4) The protocol, with documents showing the dates of and reasons for each deviation from the protocol. (5) Any other records that FDA re- quires to be maintained by regulation or by specific requirement for a cat- egory of investigations or a particular investigation. (b) Sponsor records. A sponsor shall maintain the following accurate, com- plete, and current records relating to an investigation: (1) All correspondence with another sponsor, a monitor, an investigator, an IRB, or FDA, including required re- ports. (2) Records of shipment and disposi- tion. Records of shipment shall include the name and address of the consignee, 21 CFR Ch. I (4–1–11 Edition) type and quantity of device, date of shipment, and batch number or code mark. Records of disposition shall de- scribe the batch number or code marks of any devices returned to the sponsor, repaired, or disposed of in other ways by the investigator or another person, and the reasons for and method of dis- posal. (3) Signed investigator agreements including the financial disclosure in- formation required to be collected under § 812.43(c)(5) in accordance with part 54 of this chapter. (4) For each investigation subject to § 812.2(b)(1) of a device other than a sig- nificant risk device, the records de- scribed in paragraph (b)(5) of this sec- tion and the following records, consoli- dated in one location and available for FDA inspection and copying: (i) The name and intended use of the device and the objectives of the inves- tigation; (ii) A brief explanation of why the de- vice is not a significant risk device: (iii) The name and address of each in- vestigator: (iv) The name and address of each IRB that has reviewed the investiga- tion: (v) A statement of the extent to which the good manufacturing practice regulation in part 820 will be followed in manufacturing the device; and (vi) Any other information required by FDA. (5) Records concerning adverse device effects (whether anticipated or unan- ticipated) and complaints and (6) Any other records that FDA re- quires to be maintained by regulation or by specific requirement for a cat- egory of investigation or a particular investigation. (c) IRB records. An IRB shall main- tain records in accordance with part 56 of this chapter. (d) Retention period. An investigator or sponsor shall maintain the records required by this subpart during the in- vestigation and for a period of 2 years after the latter of the following two dates: The date on which the investiga- tion is terminated or completed, or the 118 Food and Drug Administration, HHS § 812.150 date that the records are no longer re- quired for purposes of supporting a pre- market approval application or a no- tice of completion of a product devel- opment protocol. (e) Records custody. An investigator or sponsor may withdraw from the re- sponsibility to maintain records for the period required in paragraph (d) of this section and transfer custody of the records to any other person who will accept responsibility for them under this part, including the requirements of § 812.145. Notice of a transfer shall be given to FDA not later than 10 working days after transfer occurs. [45 FR 3751, Jan. 18, 1980, as amended at 45 FR 58843, Sept. 5, 1980; 46 FR 8957, Jan. 27, 1981; 61 FR 57280, Nov. 5, 1996; 63 FR 5253, Feb. 2, 1998] § 812.145 Inspections. (a) Entry and inspection. A sponsor or an investigator who has authority to grant access shall permit authorized FDA employees, at reasonable times and in a reasonable manner, to enter and inspect any establishment where devices are held (including any estab- lishment where devices are manufac- tured, processed, packed, installed, used, or implanted or where records of results from use of devices are kept). (b) Records inspection. A sponsor, IRB, or investigator, or any other person acting on behalf of such a person with respect to an investigation, shall per- mit authorized FDA employees, at rea- sonable times and in a reasonable man- ner, to inspect and copy all records re- lating to an investigation. (c) Records identifying subjects. An in- vestigator shall permit authorized FDA employees to inspect and copy records that identify subjects, upon notice that FDA has reason to suspect that ade- quate informed consent was not ob- tained, or that reports required to be submitted by the investigator to the sponsor or IRB have not been sub- mitted or are incomplete, inaccurate, false, or misleading. § 812.150 Reports. (a) Investigator reports. An investi- gator shall prepare and submit the fol- lowing complete, accurate, and timely reports: (1) Unanticipated adverse device effects. An investigator shall submit to the sponsor and to the reviewing IRB a re- port of any unanticipated adverse de- vice effect occurring during an inves- tigation as soon as possible, but in no event later than 10 working days after the investigator first learns of the ef- fect. (2) Withdra al of IRB approval. An in- vestigator shall report to the sponsor, within 5 working days, a withdrawal of approval by the reviewing IRB of the investigator’s part of an investigation. (3) Progress. An investigator shall submit progress reports on the inves- tigation to the sponsor, the monitor, and the reviewing IRB at regular inter- vals, but in no event less often than yearly. (4) Deviations from the investigational plan. An investigator shall notify the sponsor and the reviewing IRB (see § 56.108(a) (3) and (4)) of any deviation from the investigational plan to pro- tect the life or physical well-being of a subject in an emergency. Such notice shall be given as soon as possible, but in no event later than 5 working days after the emergency occurred. Except in such an emergency, prior approval by the sponsor is required for changes in or deviations from a plan, and if these changes or deviations may affect the scientific soundness of the plan or the rights, safety, or welfare of human subjects, FDA and IRB in accordance with § 812.35(a) also is required. (5) Informed consent. If an investi- gator uses a device without obtaining informed consent, the investigator shall report such use to the sponsor and the reviewing IRB within 5 work- ing days after the use occurs. (6) Final report. An investigator shall, within 3 months after termination or completion of the investigation or the investigator’s part of the investigation, submit a final report to the sponsor and the reviewing IRB. (7) Other. An investigator shall, upon request by a reviewing IRB or FDA, provide accurate, complete, and cur- rent information about any aspect of the investigation. (b) Sponsor reports. A sponsor shall prepare and submit the following com- plete, accurate, and timely reports: 119 Pt. 814 (1) Unanticipated adverse device effects. A sponsor who conducts an evaluation of an unanticipated adverse device ef- fect under § 812.46(b) shall report the re- sults of such evaluation to FDA and to all reviewing IRB’s and participating investigators within 10 working days after the sponsor first receives notice of the effect. Thereafter the sponsor shall submit such additional reports concerning the effect as FDA requests. (2) Withdra al of IRB approval. A sponsor shall notify FDA and all re- viewing IRB’s and participating inves- tigators of any withdrawal of approval of an investigation or a part of an in- vestigation by a reviewing IRB within 5 working days after receipt of the withdrawal of approval. (3) Withdra al of FDA approval. A sponsor shall notify all reviewing IRB’s and participating investigators of any withdrawal of FDA approval of the in- vestigation, and shall do so within 5 working days after receipt of notice of the withdrawal of approval. (4) Current investigator list. A sponsor shall submit to FDA, at 6-month inter- vals, a current list of the names and addresses of all investigators partici- pating in the investigation. The spon- sor shall submit the first such list 6 months after FDA approval. (5) Progress reports. At regular inter- vals, and at least yearly, a sponsor shall submit progress reports to all re- viewing IRB’s. In the case of a signifi- cant risk device, a sponsor shall also submit progress reports to FDA. A sponsor of a treatment IDE shall sub- mit semi-annual progress reports to all reviewing IRB’s and FDA in accordance with § 812.36(f) and annual reports in ac- cordance with this section. (6) Recall and device disposition. A sponsor shall notify FDA and all re- viewing IRB’s of any request that an investigator return, repair, or other- wise dispose of any units of a device. Such notice shall occur within 30 work- ing days after the request is made and shall state why the request was made. (7) Final report. In the case of a sig- nificant risk device, the sponsor shall notify FDA within 30 working days of the completion or termination of the investigation and shall submit a final report to FDA and all reviewing the IRB’s and participating investigators 21 CFR Ch. I (4–1–11 Edition) within 6 months after completion or termination. In the case of a device that is not a significant risk device, the sponsor shall submit a final report to all reviewing IRB’s within 6 months after termination or completion. (8) Informed consent. A sponsor shall submit to FDA a copy of any report by an investigator under paragraph (a)(5) of this section of use of a device with- out obtaining informed consent, within 5 working days of receipt of notice of such use. (9) Significant risk device determina- tions. If an IRB determines that a de- vice is a significant risk device, and the sponsor had proposed that the IRB consider the device not to be a signifi- cant risk device, the sponsor shall sub- mit to FDA a report of the IRB’s deter- mination within 5 working days after the sponsor first learns of the IRB’s de- termination. (10) Other. A sponsor shall, upon re- quest by a reviewing IRB or FDA, pro- vide accurate, complete, and current information about any aspect of the in- vestigation. [45 FR 3751, Jan. 18, 1980, as amended at 45 FR 58843, Sept. 5, 1980; 48 FR 15622, Apr. 12, 1983; 62 FR 48948, Sept. 18, 1997] PART 813 [RESERVED] PART 814—PREMARKET APPROVAL OF MEDICAL DEVICES Subpart A—General Sec. 814.1 Scope. 814.2 Purpose. 814.3 Definitions. 814.9 Confidentiality of data and informa- tion in a premarket approval application (PMA) file. 814.15 Research conducted outside the United States. 814.17 Service of orders. 814.19 Product development protocol (PDP). Subpart B—Premarket Approval Application (PMA) 814.20 Application. 814.37 PMA amendments and resubmitted PMA’s. 814.39 PMA supplements. Subpart C—FDA Action on a PMA 814.40 Time frames for reviewing a PMA. 120