[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