[Code of Federal Regulations]
[Title 21, Volume 1, Parts 1 to 99]
[Revised as of April 1, 2000]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR54]
[Page 285-288]
TITLE 21--FOOD AND DRUGS
PART 54--FINANCIAL DISCLOSURE BY CLINICAL INVESTIGATORS
Sec.
54.1 Purpose.
54.2 Definitions.
54.3 Scope.
54.4 Certification and disclosure requirements.
54.5 Agency evaluation of financial interests.
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 otherwise noted.
Sec. 54.1 Purpose.
(a) The Food and Drug Administration (FDA) evaluates clinical
studies submitted in marketing applications, required by law, for new
human drugs and biological products and marketing applications and
reclassification petitions for medical devices.
(b) The agency reviews data generated in these clinical studies to
determine whether the applications are approvable under the statutory
requirements. FDA may consider clinical studies inadequate and the data
inadequate if, among other things, appropriate steps have not been taken
in the design, conduct, reporting, and analysis 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 interest 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 arrangements between
sponsor(s) of the covered studies and the clinical investigators and
certain interests of the clinical investigators in the product under
study or in the sponsor of the covered studies. FDA will use this
information, in conjunction with information about the design and
purpose of the study, as well as information obtained through on-site
inspections, in the agency's assessment of the reliability of the data.
Sec. 54.2 Definitions.
For the purposes of this part:
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(a) Compensation affected by the outcome of clinical studies means
compensation that could be higher for a favorable 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 corporation), or
any equity interest in a publicly traded corporation that exceeds
$50,000 during the time the clinical investigator is carrying out the
study and for 1 year following completion of the study.
(c) Proprietary interest in the tested product means property or
other financial interest in the product including, but not limited to, a
patent, trademark, copyright or licensing agreement.
(d) Clinical investigator means only a listed or identified
investigator or subinvestigator who is directly involved in the
treatment or evaluation of research 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 relies on to establish
that the product is effective (including studies that show equivalence
to an effective product) or any study in which a single investigator
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 consult 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 or the institution to
support activities of the investigator that have a monetary value of
more than $25,000, exclusive of the costs of conducting the clinical
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 clinical investigator is
carrying out the study and for 1 year following the completion 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 responsible for submitting the appropriate certification and
disclosure statements required in this part.
(h) Sponsor of the covered clinical study means the party supporting
a particular study at the time it was carried out.
[63 FR 5250, Feb. 2, 1998, as amended at 63 FR 72181, Dec. 31, 1998]
Sec. 54.3 Scope.
The requirements in this part apply to any applicant who submits a
marketing 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.
Sec. 54.4 Certification and disclosure requirements.
For purposes of this part, an applicant 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
applicant must also completely and accurately disclose or certify
information concerning the financial interests of a
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clinical investigator who is not a full-time or part-time employee of
the sponsor for each covered clinical study. Clinical investigators
subject to investigational new drug or investigational device exemption
regulations must provide the sponsor of the study with sufficient
accurate information needed to allow subsequent disclosure or
certification. The applicant is required to submit for each clinical
investigator who participates in a covered study, either a certification
that none of the financial arrangements described in Sec. 54.2 exist, or
disclose the nature of those arrangements to the agency. Where the
applicant acts with due diligence to obtain the information required in
this section but is unable to do so, the applicant shall certify that
despite the applicant's due diligence in attempting to obtain the
information, the applicant was unable to obtain the information 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 covered clinical study, either a certification
described in paragraph (a)(1) of this section or a disclosure statement
described in paragraph (a)(3) of this section.
(1) Certification: The applicant covered by this section shall
submit for all clinical investigators (as defined in Sec. 54.2(d)), to
whom the certification applies, a completed Form FDA 3454 attesting to
the absence of financial interests and arrangements described in
paragraph (a)(3) of this section. The form shall be dated and signed by
the chief financial officer or other responsible corporate official or
representative.
(2) If the certification covers less than all covered clinical data
in the application, 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
Sec. 54.2(d) for whom the applicant does not submit the certification
described in paragraph (a)(1) of this section, the applicant shall
submit a completed Form FDA 3455 disclosing completely and accurately
the following:
(i) Any financial arrangement entered into between the sponsor of
the covered study and the clinical investigator involved in the conduct
of a covered clinical trial, whereby the value of the compensation to
the clinical investigator 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
covered study, such as a grant to fund ongoing research, compensation in
the form of equipment, retainer for ongoing consultation, or honoraria;
(iii) Any proprietary interest in the tested product held by any
clinical investigator 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 information to allow the
sponsor to submit complete and accurate certification or disclosure
statements as required in paragraph (a) of this section. The
investigator shall promptly update this information if any relevant
changes occur in the course of the investigation or for 1 year following
completion of the study.
(c) Refusal to file application. FDA may refuse to file any
marketing application 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
diligence 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]
[[Page 288]]
Sec. 54.5 Agency evaluation of financial interests.
(a) Evaluation of disclosure statement. FDA will evaluate the
information disclosed under Sec. 54.4(a)(2) about each covered 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 increase in the value of the interest if the product is
approved) and steps that have been taken to minimize the potential for
bias.
(b) Effect of study design. In assessing the potential of an
investigator's financial interests to bias a study, FDA will take into
account the design and purpose of the study. Study designs that utilize
such approaches as multiple investigators (most of whom do not have a
disclosable interest), blinding, objective 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 financial interests of any clinical investigator 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
including:
(1) Initiating agency audits of the data derived from the clinical
investigator in question;
(2) Requesting that the applicant submit further analyses of data,
e.g., to evaluate the effect of the clinical investigator's data on
overall study outcome;
(3) Requesting that the applicant conduct additional independent
studies to confirm the results of the questioned study; and
(4) Refusing to treat the covered clinical study as providing data
that can be the basis for an agency action.
Sec. 54.6 Recordkeeping and record retention.
(a) Financial records of clinical investigators 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
employees of the applicant, as follows:
(1) Complete records showing any financial interest or arrangement
as described in Sec. 54.4(a)(3)(i) paid to such clinical investigators
by the sponsor of the covered study.
(2) Complete records showing significant payments of other sorts, as
described in Sec. 54.4(a)(3)(ii), made by the sponsor of the covered
clinical study to the clinical investigator.
(3) Complete records showing any financial interests held by
clinical investigators as set forth in Sec. 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 retain 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.