§ 50.56 IRB must take into account the ages, maturity, and psychological state of the children involved. This judgment may be made for all children to be in- volved in clinical investigations under a particular protocol, or for each child, as the IRB deems appropriate. (c) The assent of the children is not a necessary condition for proceeding with the clinical investigation if the IRB determines: (1) That the capability of some or all of the children is so limited that they cannot reasonably be consulted, or (2) That the intervention or proce- dure involved in the clinical investiga- tion holds out a prospect of direct ben- efit that is important to the health or well-being of the children and is avail- able only in the context of the clinical investigation. (d) Even where the IRB determines that the subjects are capable of assent- ing, the IRB may still waive the assent requirement if it finds and documents that: (1) The clinical investigation in- volves no more than minimal risk to the subjects; (2) The waiver will not adversely af- fect the rights and welfare of the sub- jects; (3) The clinical investigation could not practicably be carried out without the waiver; and (4) Whenever appropriate, the sub- jects will be provided with additional pertinent information after participa- tion. (e) In addition to the determinations required under other applicable sec- tions of this subpart D, the IRB must determine, in accordance with and to the extent that consent is required under part 50, that the permission of each child’s parents or guardian is granted. (1) Where parental permission is to be obtained, the IRB may find that the permission of one parent is sufficient for clinical investigations to be con- ducted under § 50.51 or § 50.52. (2) Where clinical investigations are covered by § 50.53 or § 50.54 and permis- sion is to be obtained from parents, both parents must give their permis- sion unless one parent is deceased, un- known, incompetent, or not reasonably available, or when only one parent has 21 CFR Ch. I (4–1–16 Edition) legal responsibility for the care and custody of the child. (f) Permission by parents or guard- ians must be documented in accordance with and to the extent required by § 50.27. (g) When the IRB determines that as- sent is required, it must also determine whether and how assent must be docu- mented. [66 FR 20598, Apr. 24, 2001, as amended at 78 FR 12951, Feb. 26, 2013] § 50.56 Wards. (a) Children who are wards of the State or any other agency, institution, or entity can be included in clinical in- vestigations approved under § 50.53 or § 50.54 only if such clinical investiga- tions are: (1) Related to their status as wards; or (2) Conducted in schools, camps, hos- pitals, institutions, or similar settings in which the majority of children in- volved as subjects are not wards. (b) If the clinical investigation is ap- proved under paragraph (a) of this sec- tion, the IRB must require appoint- ment of an advocate for each child who is a ward. (1) The advocate will serve in addi- tion to any other individual acting on behalf of the child as guardian or in loco parentis. (2) One individual may serve as advo- cate for more than one child. (3) The advocate must be an indi- vidual who has the background and ex- perience to act in, and agrees to act in, the best interest of the child for the duration of the child’s participation in the clinical investigation. (4) The advocate must not be associ- ated in any way (except in the role as advocate or member of the IRB) with the clinical investigation, the investi- gator(s), or the guardian organization. PART 54—FINANCIAL DISCLOSURE BY CLINICAL INVESTIGATORS Sec. 54.1 Purpose. 54.2 Definitions. 54.3 Scope. 54.4 Certification and disclosure require- ments. 352 Food and Drug Administration, HHS § 54.2 54.5 Agency evaluation of financial inter- ests. 54.6 Recordkeeping and record retention. AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360c–360j, 371, 372, 373, 374, 375, 376, 379; 42 U.S.C. 262. SOURCE: 63 FR 5250, Feb. 2, 1998, unless oth- erwise noted. § 54.1 Purpose. (a) The Food and Drug Administra- tion (FDA) evaluates clinical studies submitted in marketing applications, required by law, for new human drugs and biological products and marketing applications and reclassification peti- tions for medical devices. (b) The agency reviews data gen- erated in these clinical studies to de- termine whether the applications are approvable under the statutory re- quirements. FDA may consider clinical studies inadequate and the data inad- equate if, among other things, appro- priate steps have not been taken in the design, conduct, reporting, and anal- ysis of the studies to minimize bias. One potential source of bias in clinical studies is a financial interest of the clinical investigator in the outcome of the study because of the way payment is arranged (e.g., a royalty) or because the investigator has a proprietary in- terest in the product (e.g., a patent) or because the investigator has an equity interest in the sponsor of the covered study. This section and conforming regulations require an applicant whose submission relies in part on clinical data to disclose certain financial ar- rangements between sponsor(s) of the covered studies and the clinical inves- tigators and certain interests of the clinical investigators in the product under study or in the sponsor of the covered studies. FDA will use this in- formation, in conjunction with infor- mation about the design and purpose of the study, as well as information ob- tained through on-site inspections, in the agency’s assessment of the reli- ability of the data. § 54.2 Definitions. For the purposes of this part: (a) Compensation affected by the out- come of clinical studies means compensa- tion that could be higher for a favor- able outcome than for an unfavorable outcome, such as compensation that is explicitly greater for a favorable result or compensation to the investigator in the form of an equity interest in the sponsor of a covered study or in the form of compensation tied to sales of the product, such as a royalty interest. (b) Significant equity interest in the sponsor of a covered study means any ownership interest, stock options, or other financial interest whose value cannot be readily determined through reference to public prices (generally, interests in a nonpublicly traded cor- poration), or any equity interest in a publicly traded corporation that ex- ceeds $50,000 during the time the clin- ical investigator is carrying out the study and for 1 year following comple- tion of the study. (c) Proprietary interest in the tested product means property or other finan- cial interest in the product including, but not limited to, a patent, trade- mark, copyright or licensing agree- ment. (d) Clinical investigator means only a listed or identified investigator or sub- investigator who is directly involved in the treatment or evaluation of re- search subjects. The term also includes the spouse and each dependent child of the investigator. (e) Covered clinical study means any study of a drug or device in humans submitted in a marketing application or reclassification petition subject to this part that the applicant or FDA re- lies on to establish that the product is effective (including studies that show equivalence to an effective product) or any study in which a single investi- gator makes a significant contribution to the demonstration of safety. This would, in general, not include phase l tolerance studies or pharmacokinetic studies, most clinical pharmacology studies (unless they are critical to an efficacy determination), large open safety studies conducted at multiple sites, treatment protocols, and parallel track protocols. An applicant may con- sult with FDA as to which clinical studies constitute ‘‘covered clinical studies’’ for purposes of complying with financial disclosure requirements. (f) Significant payments of other sorts means payments made by the sponsor of a covered study to the investigator 353 § 54.3 or the institution to support activities of the investigator that have a mone- tary value of more than $25,000, exclu- sive of the costs of conducting the clin- ical study or other clinical studies, (e.g., a grant to fund ongoing research, compensation in the form of equipment or retainers for ongoing consultation or honoraria) during the time the clin- ical investigator is carrying out the study and for 1 year following the com- pletion of the study. (g) Applicant means the party who submits a marketing application to FDA for approval of a drug, device, or biologic product. The applicant is re- sponsible for submitting the appro- priate certification and disclosure statements required in this part. (h) Sponsor of the covered clinical study means the party supporting a par- ticular study at the time it was carried out. [63 FR 5250, Feb. 2, 1998, as amended at 63 FR 72181, Dec. 31, 1998] § 54.3 Scope. The requirements in this part apply to any applicant who submits a mar- keting application for a human drug, biological product, or device and who submits covered clinical studies. The applicant is responsible for making the appropriate certification or disclosure statement where the applicant either contracted with one or more clinical investigators to conduct the studies or submitted studies conducted by others not under contract to the applicant. § 54.4 Certification and disclosure re- quirements. For purposes of this part, an appli- cant must submit a list of all clinical investigators who conducted covered clinical studies to determine whether the applicant’s product meets FDA’s marketing requirements, identifying those clinical investigators who are full-time or part-time employees of the sponsor of each covered study. The ap- plicant must also completely and accu- rately disclose or certify information concerning the financial interests of a clinical investigator who is not a full- time or part-time employee of the sponsor for each covered clinical study. Clinical investigators subject to inves- tigational new drug or investigational 21 CFR Ch. I (4–1–16 Edition) device exemption regulations must provide the sponsor of the study with sufficient accurate information needed to allow subsequent disclosure or cer- tification. The applicant is required to submit for each clinical investigator who participates in a covered study, ei- ther a certification that none of the fi- nancial arrangements described in § 54.2 exist, or disclose the nature of those arrangements to the agency. Where the applicant acts with due diligence to ob- tain the information required in this section but is unable to do so, the ap- plicant shall certify that despite the applicant’s due diligence in attempting to obtain the information, the appli- cant was unable to obtain the informa- tion and shall include the reason. (a) The applicant (of an application submitted under sections 505, 506, 510(k), 513, or 515 of the Federal Food, Drug, and Cosmetic Act, or section 351 of the Public Health Service Act) that relies in whole or in part on clinical studies shall submit, for each clinical investigator who participated in a cov- ered clinical study, either a certifi- cation described in paragraph (a)(1) of this section or a disclosure statement described in paragraph (a)(3) of this section. (1) Certification: The applicant cov- ered by this section shall submit for all clinical investigators (as defined in § 54.2(d)), to whom the certification ap- plies, a completed Form FDA 3454 at- testing to the absence of financial in- terests and arrangements described in paragraph (a)(3) of this section. The form shall be dated and signed by the chief financial officer or other respon- sible corporate official or representa- tive. (2) If the certification covers less than all covered clinical data in the ap- plication, the applicant shall include in the certification a list of the studies covered by this certification. (3) Disclosure Statement: For any clinical investigator defined in § 54.2(d) for whom the applicant does not sub- mit the certification described in para- graph (a)(1) of this section, the appli- cant shall submit a completed Form FDA 3455 disclosing completely and ac- curately the following: (i) Any financial arrangement en- tered into between the sponsor of the 354 Food and Drug Administration, HHS § 54.6 covered study and the clinical investi- gator involved in the conduct of a cov- ered clinical trial, whereby the value of the compensation to the clinical inves- tigator for conducting the study could be influenced by the outcome of the study; (ii) Any significant payments of other sorts from the sponsor of the cov- ered study, such as a grant to fund on- going research, compensation in the form of equipment, retainer for ongo- ing consultation, or honoraria; (iii) Any proprietary interest in the tested product held by any clinical in- vestigator involved in a study; (iv) Any significant equity interest in the sponsor of the covered study held by any clinical investigator involved in any clinical study; and (v) Any steps taken to minimize the potential for bias resulting from any of the disclosed arrangements, interests, or payments. (b) The clinical investigator shall provide to the sponsor of the covered study sufficient accurate financial in- formation to allow the sponsor to sub- mit complete and accurate certifi- cation or disclosure statements as re- quired in paragraph (a) of this section. The investigator shall promptly update this information if any relevant changes occur in the course of the in- vestigation or for 1 year following com- pletion of the study. (c) Refusal to file application. FDA may refuse to file any marketing appli- cation described in paragraph (a) of this section that does not contain the information required by this section or a certification by the applicant that the applicant has acted with due dili- gence to obtain the information but was unable to do so and stating the reason. [63 FR 5250, Feb. 2, 1998; 63 FR 35134, June 29, 1998, as amended at 64 FR 399, Jan. 5, 1999] § 54.5 Agency evaluation of financial interests. (a) Evaluation of disclosure statement. FDA will evaluate the information dis- closed under § 54.4(a)(2) about each cov- ered clinical study in an application to determine the impact of any disclosed financial interests on the reliability of the study. FDA may consider both the size and nature of a disclosed financial interest (including the potential in- crease in the value of the interest if the product is approved) and steps that have been taken to minimize the po- tential for bias. (b) Effect of study design. In assessing the potential of an investigator’s finan- cial interests to bias a study, FDA will take into account the design and pur- pose of the study. Study designs that utilize such approaches as multiple in- vestigators (most of whom do not have a disclosable interest), blinding, objec- tive endpoints, or measurement of endpoints by someone other than the investigator may adequately protect against any bias created by a disclosable financial interest. (c) Agency actions to ensure reliability of data. If FDA determines that the fi- nancial interests of any clinical inves- tigator raise a serious question about the integrity of the data, FDA will take any action it deems necessary to ensure the reliability of the data in- cluding: (1) Initiating agency audits of the data derived from the clinical investi- gator in question; (2) Requesting that the applicant submit further analyses of data, e.g., to evaluate the effect of the clinical in- vestigator’s data on overall study out- come; (3) Requesting that the applicant conduct additional independent studies to confirm the results of the ques- tioned study; and (4) Refusing to treat the covered clin- ical study as providing data that can be the basis for an agency action. § 54.6 Recordkeeping and record re- tention. (a) Financial records of clinical inves- tigators to be retained. An applicant who has submitted a marketing application containing covered clinical studies shall keep on file certain information pertaining to the financial interests of clinical investigators who conducted studies on which the application relies and who are not full or part-time em- ployees of the applicant, as follows: (1) Complete records showing any fi- nancial interest or arrangement as de- scribed in § 54.4(a)(3)(i) paid to such clinical investigators by the sponsor of the covered study. 355 Pt. 56 (2) Complete records showing signifi- cant payments of other sorts, as de- scribed in § 54.4(a)(3)(ii), made by the sponsor of the covered clinical study to the clinical investigator. (3) Complete records showing any fi- nancial interests held by clinical inves- tigators as set forth in § 54.4(a)(3)(iii) and (a)(3)(iv). (b) Requirements for maintenance of clinical investigators’ financial records. (1) For any application submitted for a covered product, an applicant shall re- tain records as described in paragraph (a) of this section for 2 years after the date of approval of the application. (2) The person maintaining these records shall, upon request from any properly authorized officer or employee of FDA, at reasonable times, permit such officer or employee to have access to and copy and verify these records. PART 56—INSTITUTIONAL REVIEW BOARDS Subpart A—General Provisions Sec. 56.101 Scope. 56.102 Definitions. 56.103 Circumstances in which IRB review is required. 56.104 Exemptions from IRB requirement. 56.105 Waiver of IRB requirement. 56.106 Registration. Subpart B—Organization and Personnel 56.107 IRB membership. Subpart C—IRB Functions and Operations 56.108 IRB functions and operations. 56.109 IRB review of research. 56.110 Expedited review procedures for cer- tain kinds of research involving no more than minimal risk, and for minor changes in approved research. 56.111 Criteria for IRB approval of research. 56.112 Review by institution. 56.113 Suspension or termination of IRB ap- proval of research. 56.114 Cooperative research. Subpart D—Records and Reports 56.115 IRB records. Subpart E—Administrative Actions for Noncompliance 56.120 Lesser administrative actions. 21 CFR Ch. I (4–1–16 Edition) 56.121 Disqualification of an IRB or an insti- tution. 56.122 Public disclosure of information re- garding revocation. 56.123 Reinstatement of an IRB or an insti- tution. 56.124 Actions alternative or additional to disqualification. AUTHORITY: 21 U.S.C. 321, 343, 346, 346a, 348, 350a, 350b, 351, 352, 353, 355, 360, 360c–360f, 360h–360j, 371, 379e, 381; 42 U.S.C. 216, 241, 262, 263b–263n. SOURCE: 46 FR 8975, Jan. 27, 1981, unless otherwise noted. Subpart A—General Provisions § 56.101 Scope. (a) This part contains the general standards for the composition, oper- ation, and responsibility of an Institu- tional Review Board (IRB) that reviews clinical investigations regulated by the Food and Drug Administration under sections 505(i) and 520(g) of the act, as well as clinical investigations that sup- port applications for research or mar- keting permits for products regulated by the Food and Drug Administration, including foods, including dietary sup- plements, that bear a nutrient content claim or a health claim, infant for- mulas, food and color additives, drugs for human use, medical devices for human use, biological products for human use, and electronic products. Compliance with this part is intended to protect the rights and welfare of human subjects involved in such inves- tigations. (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. [46 FR 8975, Jan. 27, 1981, as amended at 64 FR 399, Jan. 5, 1999; 66 FR 20599, Apr. 24, 2001] § 56.102 Definitions. As used in this part: (a) Act means the Federal Food, Drug, and Cosmetic Act, as amended (secs. 201–902, 52 Stat. 1040 et seq., as amended (21 U.S.C. 321–392)). (b) Application for research or mar- keting permit includes: (1) A color additive petition, de- scribed in part 71. 356