94-23414. Financial Disclosure by Clinical Investigators; Proposed Rule DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 59, Number 183 (Thursday, September 22, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-23414]

[[Page Unknown]]

[Federal Register: September 22, 1994]

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Part IV

Department of Health and Human Services

_______________________________________________________________________

Food and Drug Administration

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21 CFR Part 54, et al.

Financial Disclosure by Clinical Investigators; Proposed Rule
DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 54, 312, 314, 320, 330, 601, 807, 812, 814, and 860

[Docket No. 93N-0445]

Financial Disclosure by Clinical Investigators

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to require
that the sponsor of any drug, biological product, or device submit
certain information concerning the compensation to, and financial
interests of, any clinical investigator conducting clinical studies to
determine whether that product meets the marketing requirements
specified by the agency. This requirement will apply to most clinical
studies involving human subjects, as well as any study to establish
bioavailability or bioequivalence. The agency is proposing to require
that sponsors certify to the absence of certain financial interests of
clinical investigators or disclose those financial interests when
clinical studies are submitted to FDA in support of product marketing.
If the agency adopts this proposal, and the sponsor does not include
one of the required submissions with the application for marketing a
covered product that contains clinical data, the agency will refuse to
file the application. FDA will propose to extend these requirements to
submissions for marketing approval related to human foods, animal
foods, and animal drugs in a notice to be published in a subsequent
issue of the Federal Register. FDA is seeking public comment on these
proposed requirements.

DATES: Written comments on or before December 21, 1994. The agency is
proposing that any final rule that may issue based on this proposed
rule become effective 6 months after the date of its publication.

ADDRESSEES: Submit written comments and responses to questions to the
Dockets Management Branch (HFA-305), Food and Drug Administration, rm.
1-23, 12420 Parklawn Dr., Rockville, MD 20857. Comments should be
identified with the docket number found in brackets in the heading of
this document.

FOR FURTHER INFORMATION CONTACT: John S. Ensign, Office of Health
Affairs (HFY-22), Food and Drug Administration, 5600 Fishers Lane,
Rockville, MD 20852, 301-443-1382.

SUPPLEMENTARY INFORMATION:

I. Background

There is a growing recognition in the academic and scientific
communities that certain financial arrangements between clinical
investigators and product sponsors, or the personal financial interests
of clinical investigators, can potentially bias the outcome of clinical
trials. Although FDA and other government agencies, in parallel with
these communities, are increasingly concerned about the potential for
such interests to bias data generated by these studies, the agency
currently has no mechanism to collect information concerning specific
financial interests of clinical investigators who conduct studies in
support of product marketing. The creation of a system to collect and
analyze this information will strengthen the product review process.
In the Federal Register of June 28, 1994, the Public Health Service
published a notice of proposed rulemaking on objectivity in research
(59 FR 33242-33251); and the National Science Foundation published a
statement of policy on financial disclosure by scientific investigators
(59 FR 33308-33312).
The fact that these other government agencies have developed such
policies and regulations reinforces FDA's concerns and its decision to
seek an appropriate approach to the issue. Of necessity, such an
approach differs in some respects among different agencies, based on
differences in their responsibilities and the nature of their
relationships with external communities (i.e., the role of a regulatory
agency versus a grant-making agency).
For example, the PHS and NSF documents are broader in scope than
the FDA proposed rule and respond to principles that govern federally
funded grants and contracts. The concerns of PHS and NSF include the
stewardship of public research funds and the assurance of objectivity
in the research supported by these funds. Receipt of Federal funds for
research is a privilege, and, just as such funds are granted for all
types of research, PHS and NSF are interested in guarding against bias
in all research.
In contrast, drug and device manufacturers are required under
statutory authority to submit clinical trial data in order to gain FDA
approval to market a product. FDA's concerns are more narrowly focused
on evaluating the reliability of clinical data submissions in support
of marketing approval because FDA must rely on submitted clinical data
in making decisions on the safety and effectiveness of regulated
products. FDA's primary interest is in the potential of certain
financial interests to bias the outcome of clinical studies.
Because of the agency's special regulatory responsibilities, FDA's
proposed rule differs from the NIH regulation and the NSF policy in
terms of the research conducted by potentially affected investigators
and in two other respects as well. FDA's proposed rule does not include
a financial interest of a clinical investigator in a firm that owns a
product that would compete with the tested product for market share,
and FDA is not proposing to require disclosure of financial interests
and arrangements in or with the sponsor by full-time employees of the
sponsor. In addition, FDA's proposed rule does not identify a specific
threshold dollar which would trigger disclosure of financial interests.
Instead, FDA is requesting public comment on whether setting a
threshold amount is appropriate, and if so, what the dollar amount
should be. These additional differences, and FDA's interest in
obtaining comment on them, are discussed further in section II.D. of
this document.
FDA is concerned about financial interests that are unknown or
undisclosed to the agency and potentially unmanaged by product sponsors
to guard against purposeful or inadvertent bias. In particular, FDA is
concerned about those types of financial interests whose value is
heavily influenced by the outcome of the research.
Clinical research data provide the basis for FDA's assessment of
the safety and effectiveness of new human drugs, devices, and
biologics, the assessment of the bioequivalence of generic drugs and
sometimes the substantial equivalence of devices. It is essential that
these data be reliable and that steps be taken to minimize possible
effects on the data resulting from potential bias on the part of an
investigator. FDA acknowledges that there are many factors that could
give investigators a preference for a particular outcome, but a
significant financial interest in the outcome of the study is of
particular concern. Bias, as used here, means a purposeful or
inadvertent preference of the clinical investigator for a particular
study outcome that interferes with the clinical investigator's
impartiality in conducting a clinical study. Bias could, for example,
interfere with a clinical investigator's impartiality in assessing the
outcome of therapy; in assigning patients to treatment (so that
patients who receive the test product are those with a better
prognosis); in interpreting an adverse event: in assessing the outcome
of the therapy; or in deciding upon use of concomitant therapy.
In any discussion of potential sources of bias, it is important to
distinguish between the actual conduct of studies and collection of
data by clinical investigators, on the one hand, and the use of those
studies, i.e., the analysis, interpretation, and presentation of the
data from those studies by the sponsor, on the other. In the analysis,
interpretation, and presentation of data, a commercial sponsor would be
expected to have a clear preference for a particular result, and FDA's
review of the sponsor's submissions proceeds with awareness of the
sponsor's interests and potential biases. The agency regularly
examines, and in some cases repeats, the statistical analysis carried
out by sponsors for scientific adequacy and for accuracy, basing these
examinations on the raw data collected by clinical investigators. When
there is a choice of analysis or study endpoints, the agency can
usually determine whether they were specified prospectively or chosen
without knowledge of the study outcome, and whether the choice appears
scientifically credible. Where more than one analysis is possible, FDA
can independently weigh the arguments for and against a given approach.
FDA can, thus, deal with potential sponsor biases in the analyses and
interpretation of submitted data because the agency has complete access
to the raw data and a complete description of the analyses the sponsor
chose.
In contrast, there is no way to assess completely the accuracy of
the raw data themselves, although the agency can, and does, take steps
to help assure their validity. FDA provides guidance to sponsors of
drugs, biologics and devices on how to develop monitoring systems that
their study monitors can use to ensure that data generated in clinical
trials are accurate and complete. As further protection against
isolated unreliable data, the agency generally requires findings to be
replicated before they can serve as the basis for marketing decisions;
and clinical data may also be subjected to field inspections through
the agency's bioresearch monitoring program. In many cases, clinical
trial results arise from the combined efforts of many investigators, so
that a regulatory conclusion does not depend on a single investigator's
efforts.
There are, however, limits to the protection these steps provide
against potential bias. Even if the primary responsibility of the study
monitor to the sponsor is discounted, monitors cannot verify many of
the observations made independently by investigators. Moreover, while
the bioresearch monitoring program is immensely valuable in detecting
certain kinds of data problems, including errors or bias leading to an
inconsistency between what is reported to FDA and information in
independently generated records (for example, nurses's notes,
laboratory slips, office records, hospital records) and can often
detect sloppiness or deliberate fraud, it has limited ability to detect
faulty assessment of study endpoints, or failure to record adverse
effects. Thus, although the agency tries to ensure that data are
reliable, FDA relies considerably on independent clinical investigators
to provide valid and reliable data.
Assessing the reliability of data is a fundamental aspect of FDA's
evaluation. It is just as critical as assessing the adequacy of study
design, the completeness of the studies carried out, and the meaning of
the results. Therefore, financial arrangements and interests that could
affect reliability of data need to be identified and considered. Such
interests are already considered to exist and are taken into account
when a clinical investigator is a full-time employee of a sponsor. When
the investigator is not a full-time employee, the interests and
arrangements that need to be identified and considered include
financial arrangements in which the value of financial compensation
received by the clinical investigator could be affected by the study
outcome; significant payments of other sorts, such as grants for
ongoing research, compensations in the form of equipment, retainers or
honoraria; a proprietary interest of the investigator in the tested
product, such as a patent; or a significant equity interest in the
sponsoring company. Such arrangements and interests, especially if
combined with such clinical trial features as open (unblinded) study
designs, studies with subjective endpoints, and single-investigator
studies, may increase the risk that purposeful or inadvertent bias
could influence the outcome of the study. FDA needs to be aware of
influences that could affect data reliability.

II. Proposed Action

A. The Proposal

In developing this proposal, the agency has considered three broad
areas: (1) Identification of financial information that should be
reported by sponsors to FDA; (2) procedures for reporting this
information; and (3) steps the agency should take to deal with
potential bias in data from studies by clinical investigators found to
have potentially problematic financial interests. FDA has also
considered the proper balance between the agency's desire to detect and
help to minimize bias in clinical data and the need to avoid intrusion
into the privacy of clinical investigators and unreasonable
administrative burdens on sponsors and on agency staff.
In considering procedures for reporting such information, the
agency has sought to identify the method that would be least burdensome
for sponsors and for agency staff. FDA has determined that a simple,
direct and effective method of minimizing reporting requirements would
be to give every sponsor the option of either certifying to FDA as to
the absence of certain financial interests and arrangements of the
investigators conducting clinical studies of the sponsor's product or
alternatively, disclosing those interests and describing the steps
taken to minimize the impact of possible bias. Accordingly, FDA is
proposing to require that the sponsor of any product submitted to the
agency for marketing approval submit a list of clinical investigators
and make one of two alternative submissions for each clinical
investigator who is not identified by the sponsor as a full-time
employee of the sponsor at the time reports of clinical studies and
their accompanying data are submitted in support of product marketing.
The alternative submissions are:
(1) The sponsor may certify that for any clinical study relied upon
by the sponsor to establish that the product meets the regulatory
requirements for approval: (a) The sponsor has not entered into any
financial arrangement with any clinical investigator in which the value
of financial compensation received by the clinical investigator for
conducting the studies could be affected by the outcome of the
research; (b) the investigator has not received significant payments of
other sorts from the sponsor, such as a grant to fund ongoing research,
compensation in the form of equipment, a retainer for ongoing
consultation, or honoraria; (c) the clinical investigator has no
proprietary interest, such as a patent or other direct financial
interest in the clinically tested product; and (d) the clinical
investigator holds no significant equity interest in the sponsor's
company.
(2) If the sponsor does not provide certification, the sponsor must
disclose the specific financial arrangements made with the clinical
investigator, the investigator's proprietary and equity interests in
the tested product and the sponsor's company, and describe steps taken
to minimize the potential for bias in data submitted in support of
product applications.
If a statement of certification or disclosure does not accompany an
application containing clinical data, the agency will refuse to file
the application. The agency believes that clinical investigators are
responsible for providing the sponsor with sufficient accurate
financial information to allow preparation of complete and accurate
statements and is proposing to require that investigators make such
information available to sponsors. Disclosure and certification
requirements will extend not only to the clinical investigator, but
also to the investigator's immediate family (i.e., spouse and dependent
children).
Although this proposed regulation applies only to submissions for
human drugs, biological products, and devices, sponsors also submit
data from independent clinical investigators--i.e., clinical
investigators who are not the sponsor's employees--in support of
submissions such as food and color additives, infant formulas, health
claims, and animal drug applications (i.e., studies involving animals
that are equivalent to clinical studies). The agency will also propose
to apply these requirements to submissions for marketing approval
related to human foods, animal foods, and animal drugs in a notice to
be published in a subsequent issue of the Federal Register.

B. The Certification Statement

The agency is proposing in Sec. 54.4(a)(1) the following language
for use by sponsors as a certification statement:

With respect to all covered clinical studies [or to specific
clinical studies listed below] submitted in support of this
application, I certify that (name of applicant) has not entered into
any financial arrangement with any clinical investigator, whereby
the value of compensation to the investigator to conduct the study
could be affected by the outcome of the study. I also certify that
each clinical investigator was required to disclose to (name of
applicant) whether the investigator had a proprietary interest in
this product, or a significant equity interest in (name of
applicant), and that no such interests were disclosed. I further
certify that the investigator was not the recipient of significant
payments of other kinds as defined in 21 CFR 54.2(f).
For purposes of this statement, a clinical investigator includes
the spouse, and each dependent child of the investigator as defined
in 21 CFR 54.2(d). This certification is made in compliance with 21
CFR part 54.

C. Rationale for the Proposal

In developing this policy, FDA met with representatives of numerous
scientific and health care organizations, as well as industry,
consumers and other Government agencies. On September 9, 1993, FDA's
Science Board convened a public meeting to discuss financial disclosure
by clinical investigators. There was general support for development of
this policy expressed at the meeting by board members and most public
speakers. The following Government groups were represented at the
meeting: PHS, the National Institutes of Health, NSF, and the National
Academy of Sciences. The discussion included updates by representatives
of these government agencies on the development of their policies and
rules pertaining to conflict of interest and financial disclosure.
Presentations were also made by the American Medical Association,
the Society for Clinical Trials, the American Federation for Clinical
Research, the Association of American Medical Colleges, the Health
Research Group, the National Coalition of Hispanic Health and Human
Service Organizations, the Women's Health Network, the Pharmaceutical
Manufacturers Association, and the Health Industry Manufacturers
Association. The Biotechnology Industry Organization submitted a
written statement to the Board.
In addition, FDA met informally with organizations representing
major segments of the regulated industry, consumer organizations,
professional societies, and investigators. During the meetings, the
following issues were discussed: (1) The identification of financial
arrangements that have the potential for generating bias; (2) the
extent of disclosure by clinical investigators to sponsors; (3) the
impact of public disclosure of clinical investigators' financial
interests; and (4) to whom a requirement for disclosure of financial
interests might apply (e.g., the investigator's immediate family,
significant business partners). Financial arrangements discussed
included payments in the form of equity, such as stock and stock
options, and compensation tied to the sales of the product, such as
royalty interests. From these informal discussions, it appears that in
most cases clinical investigators are not asked by sponsors to divulge
any financial interest held by the investigators in the sponsoring firm
prior to performing a clinical study. (Minutes and other disclosable
statements are available at the Dockets Management Branch (address
above)).
Requiring sponsors to obtain information on and either certify or
disclose their clinical investigators' relevant financial interests and
arrangements is intended to help ensure that sponsors consider these
matters in the early stages of product development and, if necessary,
consider how best to minimize potential sources of bias. FDA believes
that in most cases, sponsors would be able to provide certification for
clinical investigators and would not need to submit any further
information.
FDA recognizes that therapeutically beneficial products have been
developed through investigations in which clinical investigators were
compensated in ways that may have influenced the outcome of the study
and is therefore not intending to prohibit such arrangements, or rule
out reliance on affected studies as a basis for product approval, but
intends to give such studies particularly close scrutiny and
evaluation.
Requiring certification or disclosure at the time of submission of
marketing applications does not preclude a sponsor from seeking the
agency's advice at the early stages of product development with respect
to a potentially problematic financial arrangement with a clinical
investigator. Indeed, FDA strongly encourages early consultation in
cases where the sponsor may be entering into problematic financial
arrangements with a clinical investigator. The agency will work with
sponsors in planning careful management of such situations.
FDA is proposing to require certification or disclosure only with
respect to the clinical data submissions in support of marketing
applications because if this information were submitted prior to
beginning clinical studies, agency staff would be unduly burdened with
evaluating financial information for every clinical study undertaken,
many of which never lead to marketing applications.
FDA has tentatively chosen not to seek information on investigators
carrying out preclinical or manufacturing and controls operations for a
number of reasons. Employees of the sponsor develop most of these data,
and FDA already considers the financial interests of these employees.
Also, these data are often verified independently and are relatively
insensitive to inadvertent bias. In contrast, clinical data are more
susceptible to inadvertent, unrecognized bias on the part of
investigators. FDA recognizes that, despite these reasons, biased
preclinical or chemistry work could also affect product approvals and
welcomes comments on possible approaches the agency could take to
ensure the reliability of such work.
FDA believes that these requirements for certification or
disclosure should apply not only to the clinical investigator's
interests, but to the interests of the investigator's immediate family
as well. The financial interests of a clinical investigator's immediate
family are effectively shared by the investigator and thus would be as
potentially biasing as if they were under the investigator's name.
The agency envisions that the financial arrangements and steps
taken to minimize bias will vary with different product applications
and will review these applications on a case-by-case basis. For
example, if a study design is sufficiently robust as a result of
factors such as independent data monitoring, multiple investigators,
blinding, and independent endpoint assessment, FDA could determine that
a problematic financial interest would not likely introduce bias. In
other situations, there might be sufficient replication of critical
results to render the questionable data less important, or it might be
possible to carry out further analyses or observations (reexamination
of hospital records or patients) that would provide assurance as to the
reliability of the data. In still others, intensified scrutiny by FDA's
bioresearch monitoring staff might be sufficient to permit FDA to
accept the data in support of product marketing applications. In some
cases, however, FDA might not be able to conclude that the data were
reliable and might require sponsors to conduct further studies. The
agency seeks comment as to other appropriate steps that FDA might take
to respond to applications that may be considered problematic with
respect to potential bias.

D. Related Issues for Comment

1. Public Disclosure
The agency also seeks comment on whether publicly disclosing a
clinical investigator's financial interests would serve a useful
purpose. FDA also requests comment on what might constitute an
appropriate forum for such release--for example, whether it would be
useful to disclose such information to an outside advisory committee
considering the tested product. Public disclosure of such information
is subject to any limitations on disclosure imposed by the Privacy Act,
the Freedom of Information Act and other applicable Federal statutes.
FDA requests comment on whether the value of public release is
outweighed by the right to privacy of clinical investigators with
respect to their financial affairs.
2. Definition of a Clinical Investigator
For the purposes of this proposed rule, FDA defines a clinical
investigator as including the spouse and each dependent child of the
investigator. FDA is aware of instances in which problematic financial
interests or arrangements have been listed under the name of a business
partner or business associate of a clinical investigator with whom the
investigator shared the interests or arrangements, so that the
potentially biasing factor is not readily traceable to the clinical
investigator. The agency seeks comment on whether the definition of a
clinical investigator should include business partners of the
investigator as well and, if so, how ``business partner'' should be
defined.
3. Scope and Amount of Financial Interests that Should Be Disclosed
In proposing to require disclosure of any significant equity
interest held by a clinical investigator in the sponsor, the agency has
defined a significant equity interest as ``any ownership interest,
stock options, or other financial interest whose value cannot be
readily determined through reference to public prices, or any equity
interest in a publicly traded corporation that exceeds 5 percent of
total equity (see proposed Sec. 54.2(b)). FDA seeks public comment on
this definition.
FDA also seeks comment on whether to require information on other
investigator interests or payments to investigators that are not
directly related to the conduct of a study. These types of arrangements
might give the investigator an ``interest'' in the company, such as
financial ties with a firm or other entity that supplies, or is likely
to supply equipment, materials, or services for work performed by the
investigator; financial ties with parties whose financial interests
would be, or would seem to be, directly and significantly affected by
the investigator's work; financial ties with, or financial support
from, any firm that markets, produces, or has in premarket testing a
product that is, or will likely be, affected by the investigator's
research. FDA also requests comment on whether there should be a
``threshold of concern'' with respect to such payments, (i.e., whether
the agency should be concerned only when these forms of compensation to
investigators exceed a certain threshold amount). Several academic
institutions have instituted de minimis levels for disclosure, such as
$5,000 cash and $20,000 equity interest in a publicly held and widely
traded company. FDA has not identified a threshold amount and seeks
public comment on whether a threshold dollar amount should be set, and
if so, what that amount should be. The agency also seeks comments on
any other financial relationships or arrangements that should raise
concern.
4. Ownership by a Clinical Investigator of Stock in a Competing Product
The approach taken by FDA in this proposed rule differs from that
of PHS and NSF in that the agency has not included ownership by a
clinical investigator of stock in a product that would compete with the
tested product for market share. This issue, FDA believes, is
appropriately of concern to sponsors. The agency seeks comment on
whether such ownership substantially threatens an individual clinical
investigator's objectivity and whether there is a manageable basis for
reporting this kind of interest.
5. Disclosure of Financial Interests by Full-Time Employees of the
Sponsor
FDA's approach also differs from that of PHS and NSF in that FDA is
not proposing to require disclosure of financial interests and
arrangements in or with the sponsor by full-time employees of the
sponsor. FDA assumes the clinical investigator who is a full-time
employee of the sponsor has a clear interest in the outcome of research
and accounts for this potential bias in the level of scrutiny with
which the agency reviews the submitted data. FDA seeks comment as to
what disclosure, if any, by a clinical investigator, who is a full-time
employee of the sponsor, of interests in the sponsor other than salary
might contribute to minimizing bias.
6. Disclosure by Clinical Investigators to Both PHS and FDA
The PHS notice of proposed rulemaking on objectivity in research
(59 FR 33242) would require that an institution receiving a PHS grant
for research must solicit and review financial disclosure statements
from each investigator who is planning to participate in PHS-funded
research. The Institution would make available to the Department of
Health and Human Services, upon request, information regarding all
significant financial interests identified by the institution and how
those interests have been managed, reduced, or eliminated to protect
the research from bias. In this proposed regulation, FDA would require
that the sponsor of a marketing application for a regulated product
either certify as to the absence of certain financial interests and
arrangements of the investigators conducting clinical studies of the
sponsor's product, or disclose those interests and describe the steps
taken to minimize the impact of possible bias.
As noted in Section I. of this document, these two proposed
regulations respond to different principles and are based on different
relationships with external communities. Nevertheless, there is
potential for the two regulations to overlap in a small number of
instances involving PHS-funded clinical research on FDA-regulated
products. Public comment is sought on whether, in such instances,
clinical investigators should be required to disclose financial
interests both to the institution receiving PHS funds and to the
sponsor submitting a marketing application to FDA, and whether meeting
the PHS requirement for disclosure to the institution should be
considered to satisfy FDA's requirement for disclosure to the sponsor
of a marketing application.

III. Legal Authority

The agency is generally authorized by the Federal Food, Drug, and
Cosmetic Act (the act) and the Public Health Service Act to approve
drugs, devices, and biological products for marketing if the products
are demonstrated to be safe and effective for their intended uses and
are properly labeled. More specifically, new drugs are approved for
marketing if they meet the safety and effectiveness criteria set forth
in section 505(d) of the act (21 U.S.C. 355(d)) and the implementing
regulations (21 CFR part 314). To demonstrate effectiveness, the law
requires evidence from adequate and well-controlled clinical studies on
the basis of which qualified experts could fairly and responsibly
conclude that the drug has the effect it is purported to have. Section
505(j)(3)(F) of the act authorizes the approval of an abbreviated new
drug application if, among other things, there is sufficient
information to show that the drug is ``bioequivalent to the listed drug
referred to in the application.'' Under section 505(e) of the act,
approval of a new drug application is to be withdrawn if new
information shows that the drug has not been demonstrated to be either
safe or effective. Approval may also be withdrawn if new information
shows that the drug's labeling is false or misleading. Under section
505(d)(4) of the act, in determining whether a drug is ``safe for use''
under the conditions proposed, the agency may consider not only
information such as data from clinical studies, but also ``any other
information'' before the agency relevant to the determination. In
deciding whether the drug's proposed labeling would be ``false or
misleading'' under section 505(d)(7) of the act, the agency is also to
evaluate ``all material facts.''
Section 505(k) of the act authorizes the agency to promulgate
regulations requiring applicants to make records and reports of data or
other information that are necessary to enable the agency to determine
whether there is reason to withdraw approval of a new drug application
or an abbreviated new drug application.
There is similar authority under section 351(d) of the Public
Health Service Act (42 U.S.C. 262) to approve biological products if
their ``safety, purity, and potency'' are demonstrated; section 351
also authorizes the promulgation of regulations designed to ensure the
continued safety, purity, and potency of the products.
FDA's authority to regulate medical devices arises from the Federal
Food, Drug, and Cosmetic Act of 1938, as amended by the Medical Device
Amendments of 1976 (the 1976 amendments), the Safe Medical Device
Amendments of 1990, and the Medical Device Amendments of 1992.
Under the 1976 amendments, devices are divided into preamendments
devices, i.e., those devices in commercial distribution prior to May
28, 1976, the date of the enactment of the 1976 amendments, and
postamendments devices, i.e., those devices first in commercial
distribution on or after the enactment of the 1976 amendments. All
devices are then further classified into class I, II, or III, depending
on the degree of regulatory control necessary to ensure safety and
effectiveness. Class III devices are the most highly regulated category
of devices and, unless exempted, are subject to premarket approval by
FDA. A device may be classified into class III: (1) By operation of law
if the device is a ``new'' device, i.e., it was not on the market
before the date of the enactment of the 1976 amendments; (2) if FDA
classifies or reclassifies the device into class III; or (3) by
operation of law under 21 U.S.C. 360j(l) because it is a transitional
device that was previously regarded as a new drug.
An unapproved class III device may be investigated for purposes of
obtaining FDA approval under an investigational device exemption (IDE)
(21 U.S.C. 360j(g)). Under three IDE regulatory provisions, FDA can
require any information ``relevant'' to the review of the application
(21 CFR 812.20(b)(12), 812.20(c), and 813.20(b)(18)).
Clinical data generated under an IDE and other data and information
are used by FDA as a basis to grant marketing approval for class III
devices and as a basis to reclassify a device. The law requires that a
premarket approval application (PMA) contain ``full reports of all
information,'' known to, or which should reasonably be known to, the
applicant concerning investigations concerning the safety and
effectiveness of the device (21 U.S.C. 360e(c)(1)(A)). In approving a
PMA, FDA must make the determination, inter alia, that there is a
showing of reasonable assurance that the device is safe and effective
under the conditions of use prescribed, recommended, or suggested in
the proposed labeling, and that based on a fair evaluation of all
material facts the proposed labeling is not false or misleading (21
U.S.C. 360e(b)). In deciding whether to grant or deny approval of a
PMA, FDA relies upon ``valid scientific evidence'' which includes
evidence from well-controlled investigations, partially controlled
studies, studies and objective trials without matched controls, well-
documented case histories conducted by qualified experts, and reports
of significant human experience with a marketed device * * *.'' (21 CFR
860.7(c)(2)). FDA evaluates the data submitted and determines whether
it constitutes ``valid scientific evidence'' for the purpose of
determining the safety and effectiveness of a particular device ``and
whether the available evidence, when taken as a whole is adequate to
support a determination that there is a reasonable assurance that the
device is safe and effective for its conditions of use.'' (21 CFR
860.7(c)(1)). In determining whether a device should be reclassified,
FDA relies upon the same regulatory definition of ``valid scientific
evidence.'' Section 515(e)(1) of the act (21 U.S.C 360(e)(1))
authorizes the agency to withdraw approval of an application if, on the
basis of ``new information,'' there is a lack of a showing of
reasonable assurance that the device is safe and effective under the
conditions of use, or the labeling of the device is false or misleading
in any particular.
FDA may also use clinical data to determine whether a ``new
device,'' i.e. a device marketed after the date of the enactment of the
1976 amendments, may be removed from its automatic statutory class III
status and thereby be exempt from premarket approval requirements (21
U.S.C. 360c(f)(1)). Such devices may be marketed without premarket
approval if FDA issues an order finding them ``substantially
equivalent'' to a predicate device that does not require premarket
approval (21 U.S.C. 360c(i)(1)). In determining whether a device is
``substantially equivalent'' to a predicate device, FDA must determine,
on the basis of a premarket application submission (510(k)
submission)(21 U.S.C. 360(k)), that the device has the same intended
use as the predicate device, and that the device ``has the same
technological characteristics as the predicate device, or * * * has
different technological characteristics and the [submission] * * *
contains information, including clinical data if deemed necessary by
the Secretary, that demonstrates that the device is as safe and
effective'' as the predicate device and does not raise different
questions of safety and efficacy than the predicate device. (Id.)
Pursuant to sections 519 and 701 of the act, (21 U.S.C. 360i and
371) FDA has broad authority to promulgate regulations governing the
approval of devices. Section 519(a) of the act requires manufacturers
of devices to ``establish and maintain such records, make such reports,
and provide such information, as the Secretary may, by regulation,
reasonably require to assure that such device is not adulterated or
misbranded and to otherwise assure its safety and effectiveness.''
Thus, a critical part of the agency's function is examining
clinical data to determine if the safety and effectiveness requirements
of the act and the Public Health Service Act have been met. FDA is
authorized by sections 505(i) and 701(a) of the act to promulgate
regulations governing the conduct of studies of investigational drugs,
including unlicensed biological products. There is similar authority
relating to studies of devices under sections 510(k), 513, 515, 520(g),
and 522 of the act (21 U.S.C. 360(k), 360c, 360e, 360j(g), and 360l).
Pursuant to this authority, FDA has previously promulgated regulations
whose purpose is to ensure the reliability of data submitted to FDA in
support of marketing applications. FDA's investigational new drug
application regulations (21 CFR part 312), promulgated under section
505(i) of the act, and its investigational device exemptions
regulations (21 CFR parts 812 and 813), promulgated under section
520(g) of the act, are intended, among other things, to help ensure the
validity and reliability of clinical study results submitted to FDA in
support of new drug applications (NDA's) and supplements; premarket
approval applications, and premarket notification submissions (510(k)
submissions) for devices; and license applications and supplements for
biological products. The Supreme Court has upheld the authority of the
Commissioner of Food and Drugs to issue regulations to ensure the
reliability of clinical study results, including requirements to
minimize bias. (See Weinberger v. Hynson, Westcott & Dunning, Inc., 412
U.S. 606 (1973)).
In recent years, the academic and scientific communities have
turned their attention to the general issue of conflict of interest on
research. One issue that has received particular attention has been the
potential for the financial interests of investigators to bias the
results of studies. There has been much discussion of the importance of
protecting study outcomes from potential bias resulting from
investigator interests in the area of applied research, such as
research that supports the marketing applications for human medical
products. This concern is shared by the PHS and NSF, both of which are
currently developing regulations and policies regarding financial
disclosure by clinical investigators and by FDA. FDA believes that it
is important to the public health to ensure that the data submitted to
the agency in support of marketing applications are free of the effects
of such bias as much as possible. The agency has concluded that this
regulation requiring certification and disclosure of certain financial
information of clinical investigators is necessary to enable FDA to
approve human medical products on the basis of valid, reliable, and
unbiased data. FDA believes that the regulation is fully authorized
under sections 505, 510(k), 513, 515, 519, 520(g), 522, and 701(a) of
the act, and by section 351 of the Public Health Service Act.
FDA is proposing these reporting requirements because the
information received will enable the agency to determine the
reliability of data submitted in marketing applications more
effectively. More effective review of products proposed for marketing
provides greater protection to the public health, and therefore results
in improved implementation of the act. FDA believes that it is
essential to be able to inspect the underlying documents forming the
basis of a sponsor's certification or disclosure statement. Access to
these records is consistent with the agency's overall statutory
authority to ensure the safety and effectiveness of drugs, biological
product, and devices. FDA's authority to require maintenance of records
and to provide for agency access to these records was upheld in
National Confectioners Association v. Califano, 569 F.2d 690 (D.C. Cir.
1978).

IV. Alternatives Considered

FDA considered several approaches to handling the issue of
potential bias of research data resulting from the financial interests
of clinical investigators before deciding to adopt the certification
and disclosure procedures described in this document. Two other obvious
possibilities would be the prohibition of certain financial interests
by the agency, e.g., compensation in the form of equity in the firm,
and divestiture by the investigator of a prohibited interest. FDA
believes that prohibition and divestiture of financial interests might
have a disproportionate and unduly severe effect on certain industries
in which an individual who has the closest financial ties, e.g., the
inventor of a device being tested, is often involved as an
investigator.
In other situations, such as small start up biotechnology firms,
payments to clinical investigators are sometimes made in the form of
equity interests, such as stock options, because these firms have
limited capital. These industries rely heavily on such arrangements
because they are young and not well capitalized and yet are highly
creative and produce many novel products. In addition, the agency
believes that the proposed approach is more appropriate in light of the
fact that a number of Federal programs have been created in recent
years specifically to encourage partnerships between industry,
academia, and Government in the belief that such relationships result
in important innovation. Examples of such programs include the
Stevenson-Wydler Technology Innovation Act of 1980 (Pub. L. 96-480),
which encourages technological transfer, particularly through
collaboration between industry and the academic community. The Patent
and Trademark Act Amendments of 1980 (Pub. L. 96-517) allow
universities and other funding recipients to apply for patents
developed with Federal funding (rather than awarding such rights to the
Government), and expressly promote collaboration between commercial
concerns and nonprofit organizations. The Economic Recovery Tax Act of
1981 (Pub. L. 97-34) is aimed at fostering research and development by
small companies and associated university partners. The Federal
Technology Transfer Act of 1986 (Pub. L. 99-502), which amended Pub. L.
96-480, and Executive Order 12592, provide similar patent and licensing
authority to Federal laboratories and encourage them to participate in
cooperative research and development agreements with the private sector
and nonprofit organizations.

V. Paperwork Reduction Act of 1980

This proposed rule contains information collections which are
subject to review by the Office of Management and Budget (OMB) under
the Paperwork Reduction Act of 1980. The title, description, and
respondents of the information collections are shown below with an
estimate of the annual recordkeeping and periodic reporting burden.
Title: Financial Disclosure by Clinical Investigators: 21 CFR Part
54.
Description: FDA is proposing to require that the sponsor of any
product submitted to the agency for marketing approval for new drugs,
biological products, and devices make one of two alternative
submissions at the time data from clinical studies are submitted in
support of product marketing. The sponsor may either certify as to the
financial arrangements and interests of clinical investigators or
disclose certain financial arrangements between the sponsor and its
clinical investigators and certain interests of the clinical
investigators in the tested product or in the sponsor.
Description of Respondents: Sponsors of FDA regulated products that
are the subject of clinical data submitted in support of marketing
applications.

Estimated Annual Burden for Reporting
----------------------------------------------------------------------------------------------------------------
No. of
No. of responses Total Hours per
Section Center respondents per annual response Total hours
respondent responses
----------------------------------------------------------------------------------------------------------------
54.4................... Biologics............. 20 11 220 .5 110
Drugs................. 246 120 29,520 .5 14,760
Devices............... 125 10 1,250 .5 625
----------------------------------------------------------------------------------------
Total............ reporting burden\1\... ........... ........... ........... ........... 15,495
----------------------------------------------------------------------------------------------------------------
\1\In calculating this burden respondents are assumed to be sponsors of marketing applications. On average, 20
sponsors submit marketing applications for biologics each year, 246 submit applications for drugs, and 125
submit applications for devices. Responses are broken down into the number of investigators certifying and
disclosing for each sponsor's application. The average number of clinical investigators conducting studies
related to a marketing application for a biologic is 11; for a drug, 120; and for a device, 10. It is
estimated that the sponsor for a marketing application for a biologic will submit certification statements for
10 investigators and a disclosure statement for 1. It is estimated that a drug sponsor will submit
certification statements for 115 and disclosure statements for 5. It is estimated that a device sponsor will
submit certification statements for 8 investigators and disclosure statements for 2. Finally, it is estimated
that .5 hours (30 minutes) will be required per submission. In the absence of a firm basis for estimating the
frequency of either certification or disclosure, the agency is using the conservative estimate of .5 hours per
response, although it is estimated that .25 hours (15 minutes) will be required for the preparation and
submission of a certification statement and .5 hours (30 minutes) will be required for the preparation and
submission of a disclosure statement.

Estimated Annual Burden for Recordkeeping
----------------------------------------------------------------------------------------------------------------
Total
Section Center No. of Hours per recordkeeping
recordkeepers recordkeeper hours
----------------------------------------------------------------------------------------------------------------
54.6............................. Biologics....................... 20 5.5 110
Drugs........................... 246 60 14,760
Devices......................... 125 5 625
------------------------------------------------------------------------------
Total...................... recordkeeping burden\1\......... ............. ............ 15,945
----------------------------------------------------------------------------------------------------------------
\1\In calculating this burden, recordkeepers are assumed to be sponsors. It is assumed that each sponsor will
submit one application. The hours per recordkeeper are arrived at by multiplying the average number of
clinical investigators involved in each sponsor's submitted application (11 for biologics, 120 for drugs, and
10 for devices) by the time estimated for filing the financial information received from each investigator,
which is .5 hours. This is considered to be a one-time burden and one that would not be repeated on an annual
basis.

As required by section 3504(h) of the Paperwork Reduction Act of
1980, FDA is submitting a copy of this proposed rule to OMB for its
review of these information collection requirements. Other
organizations and individuals desiring to submit comments regarding
this burden estimate or any aspect of these information collection
requirements, including suggestions for reducing the burden, should
direct them to FDA's Dockets Management Branch (address above) and to
the Office of Information and Regulatory Affairs, OMB, rm. 3208, New
Executive Office Bldg., Washington, DC 20503, Attn: Desk Officer for
FDA.

VI. Environmental Impact

The agency has determined under 21 CFR 25.24(a)(8) that this action
is of a type that does not individually or cumulatively have a
significant effect on the human environment. Therefore, neither an
environmental assessment nor an environmental impact statement is
required.

VII. Economic Impact

FDA has examined the impacts of the proposed rule under Executive
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354).
Executive Order 12866 directs agencies to assess all costs and benefits
of available regulatory alternatives and, when regulation is necessary,
to select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The agency believes that
this proposed rule is consistent with the regulatory philosophy and
principles identified in the Executive Order. In addition, the proposed
rule is consistent on essential points with actions proposed by other
agencies of which FDA is aware.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. This rule will create costs in three areas:
reporting, recordkeeping, and research. The reporting and recordkeeping
burdens, which are fully described in section V. of this document, are
the minimum necessary to achieve the goals of this proposed regulation.
Research costs will amount to costs incurred by sponsors in validating
data that is potentially compromised and are difficult to estimate
because these situations can be expected to vary and will be dealt with
on a case-by-case basis. FDA will encourage sponsors to consult with
agency staff on management of potentially problematic situations early
on so that verifying the reliability of the data will be less
burdensome. FDA has not proposed to prohibit certain financial
interests, such as compensation to investigators in the form of equity
in the sponsor's firm, nor is the agency proposing to require
divestiture by the investigator of any financial interest, because such
provisions could impact significantly on certain small entities and
hinder their ability to bring innovative products to market. For these
reasons, the agency certifies that the proposed rule will not have a
significant economic impact on a substantial number of small entities.
Therefore, under the Regulatory Flexibility Act, no further analysis is
required.

VIII. Conforming Amendments

A. Amendments to Regulations for Human Drug Products

While the proposed rule would not require sponsors to submit
certification and disclosure statements until they submit a marketing
application, FDA believes that sponsors should acquire financial
information from investigators before starting clinical investigations.
Consequently, FDA is proposing to amend Sec. 312.53(c), the regulation
governing the selection of investigators, to require sponsors to obtain
financial information from clinical investigators. The agency believes
that early acquisition of financial information by sponsors would be
prudent to enable sponsors to discover any possible bias by the
investigator that might affect the conduct of the clinical
investigation before the investigation begins. Additionally, this would
permit sponsors to consult FDA regarding potential bias before the
sponsor and the agency have devoted resources to the clinical
investigation.
The proposed amendment to Sec. 312.57 would require sponsors to
maintain records on compensation agreements and all other financial
interests of investigators and investigators' immediate families as
described in part 54. The agency notes that such information would be
required to be made available for inspection under existing
regulations. The proposed amendment to Sec. 312.64 would require
clinical investigators to provide sponsors with sufficient accurate
information to allow the sponsor to submit complete and accurate
certification or disclosure statements.
The agency is proposing to amend Secs. 314.50 and 314.60 (21 CFR
314.50 and 314.60) to require that all new drug applications,
amendments to applications, and supplements that contain new data from
a previously unreported study include a certification or disclosure
statement.
FDA is proposing to amend Sec. 314.94 to require certification or
disclosure statements in abbreviated new drug applications. While
section 505(j)(2)(A) of the act does not specifically mention
certification or disclosure statements, section 505(j)(2)(A)(iv) of the
act authorizes the agency to require ``information to show that the new
drug is bioequivalent to the listed drug.'' Thus, the proposed
requirement would allow FDA to better judge the reliability of
bioequivalence data, and is within the scope of section
505(j)(2)(A)(iv) of the act.
Under this proposal, the agency would refuse to file any
application or abbreviated antibiotic application, and refuse to
receive any abbreviated new drug application that does not contain a
certification or disclosure statement. Current regulations allow FDA to
refuse to file or receive incomplete applications. Proposed amendments
to Secs. 314.50 and 314.94 would require certification or disclosure to
accompany applications and abbreviated applications, therefore, any
application or abbreviated application not containing a certification
or disclosure statement would be incomplete and would not be filed or
received. If FDA refuses to file or receive an application or
abbreviated application, FDA will not review the application because
the agency has determined that the application is not sufficiently
complete to allow substantive review. FDA is proposing to amend
Sec. 314.60 to allow the agency to refuse to accept amendments that
contain clinical data without a certification or disclosure statement.
The agency would amend Secs. 314.200 and 314.300 to require any
person who submits clinical data as part of the hearing process for
refusals to approve and for withdrawals of approvals for NDA's,
abbreviated antibiotic drug applications (AADA's), or abbreviated new
drug applications (ANDA's) or the hearing process for issuing,
amending, and withdrawing antibiotic regulations to submit a
certification or disclosure statement.
Proposed amendments to Sec. 320.36 (21 CFR 320.36) would require
similar reporting and recordkeeping for certification and disclosure
statements accompanying bioequivalence studies as would be required
under part 312.
Proposed amendments to Sec. 330.10 (21 CFR 330.10) would require
certification or disclosure statements to accompany clinical data
submitted as a part of the over-the-counter (OTC) monograph process.
FDA believes that the clinical data submitted for OTC drug products are
no less important than data submitted as part of the NDA or ANDA
processes and should be treated similarly. In the case of OTC
monographs, because all data are publicly available, this disclosure
should also be part of the public record even if it is not made public
for NDA's and ANDA's.

B. Amendments to Regulations for Biologicals

FDA is proposing to amend the regulations at Sec. 601.2(a) (21 CFR
601.2(a)) governing the filing of applications for product licenses by
adding a sentence to require the inclusion of a financial certification
or disclosure statement as follows: ``The applicant shall also include
a financial certification or disclosure statement as required by part
54 of this chapter.''

C. Amendments to Regulations for Medical Devices

The agency realizes that not all 510(k) premarket notification
submissions contain clinical data. Because current regulations do not
authorize FDA to require certification or disclosure statements, the
agency proposes to specifically require such statements by adding a new
paragraph to Sec. 807.87 (21 CFR 807.87). After review of a 510(k), FDA
does not ``file the application'' but has other options, depending upon
the information contained in the submission. Therefore, the agency
proposes to withhold the decision on the 510(k) submission until a
certification or disclosure statement is submitted.
The agency recognizes that the historical file relating to a device
may be retained in more than one location. FDA believes however, that a
copy of the certification or disclosure statement should be accessible
pursuant to Sec. 807.31 (21 CFR 807.31) and proposes to amend the
regulation to accommodate accessibility. A proposed amendment to
Sec. 812.110 would require clinical investigators to provide to
sponsors sufficient accurate financial information to allow sponsors to
submit complete and accurate certification or disclosure statements.
Therefore, FDA is also proposing to amend Sec. 814.20 to require
sponsors to include in premarket approval applications a financial
certification or disclosure statement as required by part 54, and to
amend Sec. 814.42 (21 CFR 814.42) to allow the agency to refuse to file
an application or amendments that contain clinical data without a
certification or disclosure statement.
Because supporting data are needed in a reclassification petition
to satisfy the requirements of a determination of safety and
effectiveness of a device, FDA is proposing to amend Sec. 860.123 to
require any sponsor who submits clinical data as part of a
reclassification petition to include a certification or disclosure
statement.

IX. Request for Comments

Interested persons may on or before December 21, 1994 submit to the
Dockets Management Branch (HFA-305) (address above) written comments
regarding this proposal. Two copies of any comments are to be
submitted, except that individuals may submit one copy. Comments are to
be identified with the docket number found in brackets in the heading
of this document. Received comments may be seen in the office above
between 9 a.m. and 4 p.m., Monday through Friday.

List of Subjects

21 CFR Part 54

Clinical investigations, Financial disclosure, Reporting and
recordkeeping requirements.

21 CFR Part 312

Drugs, Exports, Imports, Investigations, Labeling, Medical
research, Reporting and recordkeeping requirements, Safety.

21 CFR Part 314

Administrative practice and procedure, Confidential business
information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 320

Drugs, Reporting and Recordkeeping requirements.

21 CFR Part 330

Over-the-counter drugs.

21 CFR Part 601

Biologics, Confidential business information.

21 CFR Part 807

Confidential business information, Medical devices, Reporting and
recordkeeping requirements.

21 CFR Part 814

Administrative practice and procedure, Confidential business
information, Medical Devices, Medical Research, Reporting and
recordkeeping requirements.

21 CFR Part 860

Administrative practice and procedure, Medical devices.

Therefore, under the Federal Food, Drug, and Cosmetic Act, it is
proposed that 21 CFR chapter I be amended as follows:
1. New part 54 is added to read as follows:

PART 54--FINANCIAL DISCLOSURE BY CLINICAL INVESTIGATORS

Sec.
54.1 Purpose.
54.2 Definitions.
54.3 Scope.
54.4 Disclosure requirements.
54.5 Agency evaluation of financial interests.
54.6 Recordkeeping and record retention.

Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 510,
513-520, 701, 702, 703, 704, 705, 706, and 708 of the Federal Food,
Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356,
357, 360, 360c-360j, 371, 372, 373, 374, 375, 376, and 379); sec.
351 of the Public Health Service Act (42 U.S.C. 262).

Sec. 54.1 Purpose.

(a) The Food and Drug Administration (FDA) evaluates clinical
studies submitted in marketing applications as 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, either because the amount of compensation the investigator
receives may be influenced by the outcome of the study, or because the
investigator has a financial interest in the product under study or in
the sponsor of the marketing application. This section and conforming
regulations require the sponsor of a marketing application that relies
in part on clinical data to disclose certain financial arrangements
between the sponsor and its clinical investigators and certain
interests of the clinical investigators in the product or in the
sponsor. 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:
(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 explicitly greater in the
event of a favorable result, or compensation to the investigator in the
form of an equity interest in the sponsor's company or in the form of
compensation tied to sales of the product, such as a royalty interest.
(b) Significant equity interest in the applicant means any
ownership interest, stock options, or other financial interest whose
value cannot be readily determined through reference to public prices,
or any equity interest in a publicly traded corporation that exceeds 5
percent of total equity.
(c) Proprietary interest in the tested product means a property or
other financial interest in the product including, but not limited to,
patent, trademark, copyright or licensing agreement.
(d) Clinical investigator means any investigator who is:
(i) Directly involved in the treatment or evaluation of research
subjects, or
(ii) Could otherwise influence the outcome of the research; for the
purposes of the requirements of this part relating to financial
interests, ``investigator'' includes the spouse and each dependent
child of the investigator.
(e) Clinical study means any study involving human subjects,
including a study to establish bioavailability or bioequivalence,
submitted in a marketing application subject to this part, that either:
(1) The sponsor identifies as one that the sponsor relies on to
establish that the product meets the regulatory requirements for
marketing, or
(2) FDA identifies as one that it intends to rely on to support its
decision to permit the marketing of the product. Studies submitted as
publications or in brief summary form will generally not be considered
``covered clinical studies'' unless FDA informs the sponsor otherwise.
A sponsor 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 that exceed
$5,000 (e.g., grants to fund ongoing research, compensation in the form
of equipment or retainers for ongoing consultation or honoraria) or
that exceed 5 percent of the total equity in a publicly held and widely
traded company.

Sec. 54.3 Scope.

The requirements in this part apply to any sponsor of human drugs,
biological products, or devices who has contracted with one or more
clinical investigators to conduct studies to determine whether the
sponsor's product meets FDA marketing requirements and who submits data
from the clinical studies for agency review.

Sec. 54.4 Disclosure requirements.

For purposes of this part, a sponsor must submit a list of all
clinical investigators who conducted studies to determine whether the
sponsor's product meets FDA marketing requirements, identifying those
clinical investigators who are full-time employees of the sponsor. The
sponsor must also completely and accurately disclose or certify
information concerning the financial interests of a clinical
investigator who is not a full-time employee of the sponsor, and the
investigator's spouse and dependent children for each covered clinical
study. The clinical investigator must provide the sponsor with
sufficient accurate information to make the required disclosure or
certification.
(a) The sponsor of an application submitted under sections 505,
506, 507, 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
part on clinical studies shall submit, for each covered clinical study,
either a certification described in paragraph (a)(1) of this section or
a disclosure statement described in paragraph (a)(2) of this section.
(1) Certification. The sponsor of an application covered by this
section may submit the following certification dated and signed by the
chief financial officer or other responsible corporate official:

With respect to all covered clinical studies [or to specific
clinical studies listed below] submitted in support of this
application, I certify that (name of applicant) has not entered into
any financial arrangement with any clinical investigator, whereby
the value of compensation to the investigator to conduct the study
could be affected by the outcome of the study. I also certify that
each clinical investigator was required to disclose to (name of
applicant) whether the investigator had a proprietary interest in
this product, or a significant equity interest in (name of
applicant), and that no such interests were disclosed. I further
certify that the investigator was not the recipient of significant
payments of other kinds as defined in 21 CFR 54.2(f). For purposes
of this statement, a clinical investigator includes the spouse and
each dependent child of the investigator as defined in 21 CFR
54.2(d). This certification is made in compliance with 21 CFR part
54.

(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 application containing a covered
clinical study for which the sponsor does not submit the certification
described in Sec. 54.4(a)(1), the application shall contain a statement
disclosing, completely and accurately, the following information:
(i) Any financial arrangement entered into between the applicant
and any clinical investigator involved in the conduct of a covered
clinical trial, whereby the value of the compensation to the clinical
investigator to conduct the study could be influenced by the outcome of
the study;
(ii) Any significant payments of other sorts, 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; and
(iv) Any significant equity interest in the applicant held by any
clinical investigator involved in a covered study relied on in the
application and the steps taken to minimize the potential for bias.
(b) The clinical investigator shall provide to the sponsor
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.
(c) Refusal to file application. FDA will refuse to file any
marketing application described in paragraph (a) of this section that
does not contain the information required by this section.

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
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 assure 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 assure the reliability of the data
including:
(1) Initiate agency audits of the data derived from the
investigator in question;
(2) Request that the sponsor submit further analyses of data, e.g.,
to evaluate the effect of the investigator's data on study outcome;
(3) Request that the sponsor conduct additional independent studies
to confirm the results of the covered study;
(4) Refuse to treat the covered clinical study as pivotal or
primary data upon which an agency action could be taken.

Sec. 54.6 Recordkeeping and record retention.

(a) Financial records of clinical investigators to be retained. A
sponsor 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-time employees of
the sponsor as follows:
(1) Complete records showing all compensation paid to clinical
investigators by the sponsor and all compensation agreements between
the sponsor and clinical investigators;
(2) Complete records showing any significant payments of other
sorts, as described in Sec. 54.4(a)(3)(ii), made by the sponsor to the
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, a sponsor shall retain records as described in paragraph (a)
of this section for 2 years after the date of approval of the
application, or, if the application is not approved, for 2 years after
the product, for which the application was submitted, was shipped and
delivered to clinical investigators for testing.
(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 312--INVESTIGATIONAL NEW DRUG APPLICATION

The authority citation for 21 CFR part 312 continues to read as
follows:
2. The authority citation for 21 CFR part 312 continues to read as
follows:

Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701 of
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351,
352, 353, 355, 356, 357, 371); sec. 351 of the Public Health Service
Act (42 U.S.C. 262).

3. Section 312.53 is amended by adding new paragraph (c)(4) as
follows:

Sec. 312.53 Selecting investigators and monitors.

* * * * *
(c) * * *
(4) Financial disclosure information. Sufficient accurate financial
information to allow the sponsor to submit complete and accurate
certification or disclosure statements required under part 54 of this
chapter. The investigator shall promptly update this information if any
relevant changes occur during the course of the investigation.
* * * * *
4. Section 312.57 is amended by redesignating paragraphs (b) and
(c) as paragraphs (c) and (d), and by adding new paragraph (b) to read
as follows:

Sec. 312.57 Recordkeeping and record retention.

* * * * *
(b) A sponsor shall maintain complete and accurate records showing
all compensation paid to investigators and all compensation agreements
between the sponsor and investigators. A sponsor shall also maintain
complete and accurate records concerning all other financial interests
of investigators subject to part 54 of this chapter.
* * * * *
5. Section 312.64 is amended by adding new paragraph (d) to read as
follows:

Sec. 312.64 Investigator reports.

* * * * *
(d) Financial disclosure reports. The investigator shall provide
the sponsor with sufficient accurate financial information to allow the
sponsor to submit complete and accurate certification or disclosure
statements required under part 54 of this chapter. The investigator
shall promptly update this information if any relevant changes occur
during the course of the investigation.

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG OR AN
ANTIBIOTIC DRUG

6. The authority citation for 21 CFR part 314 is revised to read as
follows:

Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701,
721 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331,
351, 352, 353, 355, 356, 357, 371, 379e).

7. Section 314.50 is amended by redesignating paragraphs (a)(4) and
(a)(5) as paragraphs (a)(5) and (a)(6), and by adding new paragraph
(a)(4) to read as follows:

Sec. 314.50 Content and format of an application.

* * * * *
(a) * * *
(4) A financial certification or disclosure statement as required
by part 54 of this chapter.
* * * * *
8. Section 314.60 is amended in paragraph (a) by adding a new
sentence at the end of the paragraph to read as follows:

Sec. 314.60 Amendments to an unapproved application.

(a) * * * An amendment that contains new clinical data from a
previously unreported study shall contain a financial certification or
disclosure statement as required by part 54 of this chapter, or FDA
will not accept any such amendment.
* * * * *

Sec. 314.94 [Amended]

9. Section 314.94 Content and format of an abbreviated application
is amended in paragraph (a)(1) by removing ``and (a)(5)'' and replacing
it with ``(a)(5), and (a)(6)''; and in paragraph (c) by removing ``and
(a)(5)'' and replacing it with ``(a)(5), and (a)(6)''.
10. Section 314.200 is amended in paragraph (d)(3) by adding a new
sentence after the first sentence to read as follows:

Sec. 314.200 Notice of opportunity for hearing; notice of
participation and request for hearing; grant or denial of hearing.

* * * * *
(d) * * *
(3) * * * A financial certification or disclosure statement as
required by part 54 of this chapter must accompany all clinical data
submitted. * * *
* * * * *
11. Section 314.300 is amended in paragraph (b)(6) by adding a new
sentence after the first sentence to read as follows:

Sec. 314.300 Procedure for the issuance, amendment, or repeal of
regulations.

* * * * *
(b) * * *
(6) * * * A financial certification or disclosure statement as
required by part 54 of this chapter must accompany all clinical data
submitted with the request for hearing. * * *
* * * * *

PART 320--BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS

12. The authority citation for 21 CFR part 320 continues to read as
follows:

Authority: Secs. 201, 501, 502, 505, 507, 701 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 355, 357,
371).

13. Section 320.36 is amended by designating the existing text as
paragraph (a) and by adding new paragraph (b) to read as follows:

Sec. 320.36 Requirements for maintenance of records of bioequivalence
testing.

* * * * *
(b) Any person who contracts with another party to conduct a
bioequivalence study, the data of which are intended to be submitted to
FDA as part of an application submitted under part 314 of this chapter,
shall obtain from the person conducting the study sufficient accurate
financial information to allow the submission of complete and accurate
financial certifications or disclosure statements required under part
54 of this chapter and maintain that information and all records
relating to the compensation given for that study and all other
financial interest information required under part 54 of this chapter
for 2 years after the date of approval for the application or, if the
application is not approved, for 2 years after shipment and delivery of
the drug which was the subject of the bioequivalence study. The person
maintaining these records shall, upon request from any properly
authorized officer or employee of the Food and Drug Administration, at
reasonable times, permit such officer or employee to have access to and
copy and verify these records.

PART 330--OVER-THE-COUNTER (OTC) HUMAN DRUGS WHICH ARE GENERALLY
RECOGNIZED AS SAFE AND EFFECTIVE AND NOT MISBRANDED

14. The authority citation for 21 CFR part 330 continues to read as
follows:

Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353,
355, 360, 371).

15. Section 330.10 is amended by adding new paragraph (f) to read
as follows:

Sec. 330.10 Procedures for classifying OTC drugs as generally
recognized as safe and effective and not misbranded, and for
establishing monographs.

* * * * *
(f) Financial certification or disclosure statement. Any clinical
data submitted under this section must be accompanied by financial
certifications or disclosure statements required by part 54 of this
chapter.

PART 601--LICENSING

16. The authority citation for 21 CFR part 601 continues to read as
follows:

Authority: Secs. 201, 501, 502, 503, 505, 510, 513-516, 518-520,
701, 704, 706, 801 of the Federal Food, Drug, and Cosmetic Act (21
U.S.C. 321, 351, 352, 353, 355, 360, 360c-360f, 360h-360j, 371, 374,
376, 381); secs. 215, 301, 351, 352 of the Public Health Service Act
(42 U.S.C. 216, 241, 262, 263); secs. 2-12 of the Fair Packaging and
Labeling Act (15 U.S.C. 1451-1461).

17. Section 601.2 is amended in paragraph (a) by adding a sentence
after the first sentence to read as follows:

Sec. 601.2 Applications for establishment and product licenses;
procedures for filing.

(a) * * * The applicant shall also include a financial
certification or disclosure statement as required by part 54 of this
chapter.
* * * * *

PART 807--ESTABLISHMENT REGISTRATION AND DEVICE LISTING FOR
MANUFACTURERS AND DISTRIBUTORS OF DEVICES

18. The authority citation for 21 CFR part 807 continues to read as
follows:

Authority: Secs. 301, 501, 502, 510, 513, 515, 519, 520, 701,
704 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 331, 351,
352, 360, 360c, 360e, 360i, 360j, 371, 374).

19. Section 807.31 is amended by adding new paragraph (d)(3) to
read as follows:

Sec. 807.31 Additional listing information.

* * * * *
(d) * * *
(3) A copy of the certification or disclosure statement as required
by part 54 of this chapter shall be retained and physically located at
the establishment maintaining the historical file.
* * * * *
20. Section 807.87 is amended by adding new paragraph (k) to read
as follows:

Sec. 807.87 Information required in a premarket notification
submission.

* * * * *
(k) A financial certification or disclosure statement as required
by part 54 of this chapter.
21. Section 807.100 is amended by redesignating paragraph (a)(4) as
(a)(5) and adding new paragraph (a)(4) to read as follows:

Sec. 807.100 FDA action on a premarket notification.

(a) * * *
(4) Withhold the decision until a certification or disclosure
statement is submitted to FDA pursuant to part 54 of this chapter.
* * * * *

PART 812--INVESTIGATIONAL DEVICE EXEMPTIONS

22. The authority citation for 21 CFR part 812 continues to read as
follows:

Authority: Secs. 301, 501, 502, 503, 505, 506, 507, 510, 513-
516, 518-520, 701, 702, 704, 706, 801 of the Federal Food, Drug and
Cosmetic Act (21 U.S.C. 331, 351, 352, 353, 355, 356, 357, 360,
360c-360f, 360h-360j, 371, 372, 374, 376, 381); secs. 215, 301, 351,
354-360F of the Public Health Service Act (42 U.S.C. 216, 241, 262,
263b-263n).
* * * * *
23. Section 812.110 is amended by redesignating paragraph (d) as
(e) and adding new paragraph (d) to read as follows:

Sec. 812.110 Specific responsibilities of investigators.

* * * * *
(d) Financial disclosure. An investigator shall disclose to the
sponsor sufficient accurate financial information to allow the sponsor
to submit complete and accurate certification or disclosure statements
required under part 54 of this chapter. The investigator shall promptly
update this information if any relevant changes occur during the course
of the investigation.
* * * * *

PART 814--PREMARKET APPROVAL OF MEDICAL DEVICES

24. The authority citation for 21 CFR part 814 continues to read as
follows:

Authority: Secs. 501, 502, 503, 510, 513-520, 701, 702, 703,
704, 705, 706, 708, 801 of the Federal Food, Drug, and Cosmetic Act
(21 U.S.C. 351, 352, 353, 360, 360c-360j, 371, 372, 373, 374, 375,
376, 379, 381).

25. Section 814.20 is amended by redesignating paragraph (b)(12) as
(b)(13) and adding new paragraph (b)(12) to read as follows:

Sec. 814.20 Application.

(b) * * *
(12) A financial certification or disclosure statement as required
by part 54 of this chapter.
* * * * *
26. Section 814.42 is amended by adding new paragraph (e)(5)
follows:

Sec. 814.42 Filing of PMA.

* * * * *
(e) * * *
(5) The PMA is not accompanied by a statement of either
certification or disclosure pursuant to part 54 of this chapter.

PART 860--MEDICAL DEVICE CLASSIFICATION PROCEDURES

27. The authority citation for 21 CFR part 860 continues to read as
follows:

Authority: Secs. 513, 514, 515, 519, 520, 701, 704 of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360c, 360d, 360e,
360i, 360j, 371, 374).

28. Section 860.123 is amended by adding new paragraph (a)(10) to
read as follows:

Sec. 860.123 Reclassification section: Content and form.

(a) * * *
(10) A financial certification or disclosure statement as required
by part 54 of this chapter.
* * * * *
Dated: September 13, 1994.
David A. Kessler,
Commissioner of Food and Drugs.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 94-23414 Filed 9-21-94; 8:45 am]
BILLING CODE 4160-01-P

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Document Information

Published:: 09/22/1994
Entry Type:: Uncategorized Document
Action:: Proposed rule.
Document Number:: 94-23414
Dates:: Written comments on or before December 21, 1994. The agency is proposing that any final rule that may issue based on this proposed rule become effective 6 months after the date of its publication.
Pages:: 0-0 (1 pages)
Docket Numbers:: Federal Register: September 22, 1994
CFR: (25): 21 CFR 54.2(d); 21 CFR 54.1; 21 CFR 54.2; 21 CFR 54.3; 21 CFR 54.4; More ...