[Federal Register Volume 63, Number 21 (Monday, February 2, 1998)]
[Rules and Regulations]
[Pages 5233-5254]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-2407]
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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: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is issuing regulations
requiring the sponsor of any drug, including a biological product, or
device marketing application (applicant), to submit certain information
concerning the compensation to, and financial interests of, any
clinical investigator conducting certain clinical studies. This
requirement will apply to any covered clinical study of a drug or
device submitted in a marketing application that the applicant or FDA
relies on to establish that the product is effective, including studies
that show equivalence to an effective product, or that make a
significant contribution to the demonstration of safety. This final
rule requires applicants to certify to the absence of certain financial
interests of clinical investigators and/or disclose those financial
interests, as required, when covered clinical studies are submitted to
FDA in support of product marketing. This regulation is intended to
ensure that financial interests and arrangements of clinical
investigators that could affect reliability of data submitted to FDA in
support of product marketing are identified and disclosed by the
sponsor of any drug, biological product, or device marketing
application. If the applicant does not include certification or
disclosure, or both, if required, or does not certify that it was not
possible to obtain the information, the agency may refuse to file the
application. FDA intends to propose to extend these requirements to
submissions for marketing approval related to human foods, animal
foods, and animal drugs in a subsequent issue of the Federal Register.
DATES: This regulation becomes effective on February 2, 1999. Submit
written comments on the information collection requirements by April 3,
1998.
ADDRESSES: Submit written comments on the information collection
requirements to the Dockets Management Branch (HFA-305), Food and Drug
Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: Mary C. Gross, Office of External
Affairs, Food and Drug Administration (HF-60), 5600 Fishers Lane,
Rockville, MD 20857, 301-827-3440, FAX 301-594-0113.
SUPPLEMENTARY INFORMATION:
I. Background
In the Federal Register of September 22, 1994 (59 FR 48708), FDA
published a proposed regulation to help ensure that financial interests
and arrangements of clinical investigators that could affect
reliability of data submitted to FDA in support of product marketing
are identified and disclosed by the sponsor of any drug, biological
product or device marketing application (applicant). In this document,
FDA proposed to require disclosure by applicants of the following types
of financial interests and arrangements: Compensation made to the
clinical investigator in which the value of the compensation could be
affected by the
[[Page 5234]]
study outcome; a proprietary interest by the investigator in the tested
product, such as a patent; a significant equity interest in the sponsor
of the covered study; or significant payments by the sponsor of the
covered study of other sorts, such as a grant to fund ongoing research,
compensation in the form of equipment, or retainers for ongoing
consultation or honoraria. If, to the best of the applicant's
knowledge, a clinical investigator did not have any of these financial
interests or arrangements, FDA proposed that an applicant might provide
a statement of certification to FDA.
In the course of developing this rule, FDA met with many outside
groups with an interest in the issues involved, including regulated
industry, consumer groups, health professionals and clinical
investigators. These issues were also discussed at a meeting with FDA's
Science Board in September 1993, and, at that meeting, there was
general support for the concept of disclosure of potentially biasing
financial interests and arrangements of clinical investigators to FDA,
not only from Science Board members but also from the pharmaceutical,
device and biotechnology industries.
FDA received 58 written comments on the proposed rule. Many of
these comments supported the proposed rule, some raised substantive
concerns and challenges to the rule, and one comment, from the
Pharmaceutical Research and Manufacturer's Association urged FDA to
hold a public hearing on the provisions of the proposed rule. In
response, FDA convened a public meeting on July 20, 1995, to provide
interested parties with an opportunity to present further public
comment to FDA on the proposed rule. Representatives of seven
organizations presented testimony to FDA during the public meeting;
copies of the testimony and related comments have been filed with the
Dockets Management Branch (address above) and are available for public
review. FDA also convened a second meeting on March 29, 1996, with the
agency's Science Board. At this meeting, issues relating to the
proposed rule were discussed by a panel that included representatives
from the: Pharmaceutical Research and Manufacturers Association, Health
Industry Manufacturer's Association, Public Citizen Health Research
Group, American Medical Association, Association of American Medical
Colleges, and the Biotechnology Industry Organization. According to
representatives of drug and device manufacturers, the financial
arrangements in the proposed rule required to be disclosed are
uncommon, and the proposed rule as written would not impose an extreme
burden on industry. The groups represented and the Science Board
members agreed unanimously that applicants should disclose to FDA any
financial arrangement with a clinical investigator and any clinical
investigator interest, whereby the compensation to the clinical
investigator or interest could be affected by study outcome (e.g.,
payments in the form of stock options or royalties, possession of a
patent, etc.), and Science Board members recommended that FDA finalize
the proposed rule with only slight modifications. Transcripts, meeting
minutes, and executive summaries from these open meetings may be
examined at FDA's Dockets Management Branch (address above).
II. Summary of Comments
1. Several comments stated that section 704 of the Federal Food,
Drug, and Cosmetic Act (21 U.S.C. 374) (the act) expressly prohibits
FDA from inspecting financial data of companies and that FDA cannot
obtain access to this information by having the request come from a
reviewing division at headquarters rather than a field investigator.
One comment said that there is nothing in section 505(d) of the act (21
U.S.C. 355(d)) that might be construed as authorizing FDA to require
submission of financial data in order to evaluate the approvability of
a new drug application (NDA). The same comment said that section 505(b)
of the act specifically lists the information that must be submitted
with an NDA, and it does not include submission of financial data.
In the preamble to the proposal (59 FR 48708 at 48712 to 48713),
FDA discussed in detail the legal authority for this regulation. The
agency cited sections 505, 510(k), 513, 515, 519, 520(g), 522, and
701(a) of the act (21 U.S.C. 360(k), 360c, 360e, 360i, 360j(g), 360l,
371(a) and section 351 of the Public Health Service Act (PHS Act) (42
U.S.C. 262)) as authority for the regulation and noted that the Supreme
Court has upheld FDA's authority 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).) After reviewing the comments, FDA continues to
believe, for the reasons stated in the preamble to the proposal that it
has authority to require applicants to submit information concerning
certain financial interests of clinical investigators conducting
clinical studies. To conclude otherwise would unduly restrict FDA's
ability to perform the role assigned to it by Congress to assess data
submitted in product marketing applications and to determine whether
the products meet the criteria for approval set for in the act.
Although the authority provided in section 704 of the act does not
extend to financial data, other provisions of the act provide the
agency with the authority to obtain the information it needs to
adequately assess the safety and effectiveness of drugs and devices.
For example, section 505(d) of the act includes the requirement that
efficacy of drugs be demonstrated by adequate and well controlled
investigations. The language in section 505(d) of the act is intended
to help ensure that consumers are not exposed to products for which
efficacy has not been demonstrated. A critical factor in determining
whether a study is well controlled is the extent to which potential
bias on the part of the investigator has been minimized (see 21 CFR
314.126(b)(5)). FDA believes that a clinical investigator's financial
interests could introduce bias into a study and affect the reliability
of data submitted to FDA in support of a marketing application.
Information about such interests is critical to the agency's role of
determining efficacy of products based on valid, reliable, and unbiased
data.
Section 505(k) of the act also provides authority for the issuance
of these regulations. Under section 505(k) of the act, the agency may
issue regulations requiring the applicant to make and keep records and
reports of data relating to clinical study experience and other data
and information that are necessary to determine whether grounds exist
to withdraw approval of an NDA or an abbreviated new drug application
(ANDA). Section 505(k) of the act also provides the agency with the
authority to access such records and to copy and verify them. The
additional authorities relied on by FDA to issue these regulations are
discussed in the preamble to the proposal.
FDA believes this rule is consistent with the agency's general
rulemaking authority set forth in section 701(a) of the act, which
authorizes the agency to issue regulations for the efficient
enforcement of the act. The agency continues to rely on the statutory
authorities discussed here and in the preamble to the proposal as
authority for this regulation.
2. Some comments said that FDA has not demonstrated an adequate
need for the rule, that there is no factual justification for the rule
and that FDA
[[Page 5235]]
has never shown that if FDA does not receive financial disclosure
information, public health or safety would be threatened. One comment
said that there is no evidence to demonstrate that studies by clinical
investigators with particular financial interests are more likely to be
biased than studies performed by other clinical investigators, and that
there are many other potential sources of bias that FDA does not take
into account.
FDA disagrees with these comments and believes there is factual
justification to require collection of this information. Over the past
several years, FDA has received information on potentially problematic
payment schemes through numerous sources, including: Published
newspaper articles, congressional reports, a Government Accounting
Office report, congressional inquiries and public testimony and
comments. Although FDA learned through these sources that problematic
financial interests and arrangements do exist, FDA has had no formal
mechanism to collect this information from applicants. FDA acknowledges
that other sources of potential bias exist and could influence a
clinical investigator's judgment or behavior, such as a quest for
prestige within the scientific community, a preference for confirming a
personal hypothesis or the desire for future contracts with the sponsor
of a study. Such potential biases are difficult to assess and minimize,
but the reliability to assess and minimize all bias does not argue
against addressing some potential sources of bias. Certain kinds of
payment arrangements for clinical trials would result in a higher
payment or financial gain from a particular outcome (that is, from a
``successful'' study rather than one that did not show the therapy's
effectiveness) and gives the investigator a potential ``stake'' in that
outcome. Payments that are greater for one outcome than another or that
are in the form of stock options or royalties are examples of such
payment arrangements and clearly have the potential to bias the outcome
of clinical trials, adversely affecting the integrity of the data
submitted to FDA.
In June 1991, the Inspector General of the Department of Health and
Human Services submitted a management advisory report to FDA asserting
that FDA's failure to have a mechanism for collecting information on
``financial conflicts of interest'' among clinical investigators who
study products undergoing FDA review could constitute a ``material
weakness'' under the Federal Managers' Financial Integrity Act.
Although FDA determined that a material weakness did not exist, FDA has
concluded there is a need to address this issue through rulemaking. In
the preamble to the proposed rule, the agency explained that the
existence of unbiased clinical research and reliable data are essential
to FDA's assessment of the safety and effectiveness of new human drugs,
biological products, and medical devices. Although payment arrangements
required to be disclosed in this final rule have been described by
industry sponsors as uncommon, small businesses in certain medical
device and biologic industries appear to enter into certain
arrangements more frequently, because of a lack of readily available
capital or as a natural byproduct of the ``inventor/investigator''
relationship (see comment 3 of section I of this document). For these
reasons, FDA believes the rule is needed and justified.
3. One comment, although not opposed to the concept of disclosure,
said the requirement as proposed was not an effective way to ferret out
the corruption of studies by financial arrangements. Another comment
said that disclosure is warranted, but that disclosure alone is not
enough, that clinical investigators should be banned from owning an
equity interest that exceeds $25,000 in the sponsor of a covered study
and should be banned from receiving significant payments of other sorts
from the sponsor of a covered study that exceed $5,000 per year.
FDA's intention, by finalizing the rule, is to make the agency
aware of payments and financial arrangements by sponsors of covered
studies that could lead to the introduction of bias into the clinical
trial process, so that this can be taken into account in the review
process and to discourage such practices, not to ``ferret out
corruption of studies.'' FDA is encouraging applicants to work with FDA
and clinical investigators to minimize the occurrence of such financial
arrangements or to ensure that covered clinical studies are
sufficiently well designed and managed to eliminate the possibility
that bias due to potentially problematic financial arrangements will
influence the outcome of the study.
FDA does not agree that it should ban certain financial
arrangements. FDA recognizes that therapeutically beneficial products
have been developed through clinical investigations that were conducted
by the product-patent holder, or for which clinical investigators were
compensated with equity in the sponsor's firm, and is therefore not
prohibiting any arrangement, nor ruling out the possibility of relying
on studies conducted under these circumstances as a basis for product
approval. Rather FDA intends to give such studies particularly close
scrutiny and evaluation.
4. Several comments said the rule will affect acceptance of data
from studies conducted outside the United States by investigators who
are foreign nationals. One comment suggested that an exemption for
foreign investigators may be necessary. Some comments stated that the
disclosure requirements may be in conflict with foreign privacy
regulations, and that different cultural standards may prevent
compliance with the rule by foreign investigators. A few comments also
said the final rule should be applied prospectively to avoid penalizing
applicants and clinical investigators whose clinical investigations are
already in progress.
In response to these comments, FDA notes that the comments relating
to acceptance of data from studies conducted outside the United States
did not specifically identify information pertinent to this rule that
could not be supplied by a foreign investigator. Most of the
information sought, even for studies conducted outside the United
States, is known to the applicant and needs no clinical investigator
disclosure. Only the question of ownership of equity in the sponsor of
the covered study requires disclosure by the clinical investigator.
With regard to comments about applying the rule retrospectively, FDA
believes it is important to know about the financial arrangements and
payments considered in this rule that are problematic in a timely
manner and does not believe implementation should be long deferred. In
order to give applicants time to comply with the final rule and to
avoid delayed submissions, however, FDA will require applicants to
comply with the rule 1 year after the publication date of the final
rule. FDA recognizes that there may be times where, despite the
applicant's diligent efforts to obtain the needed information to make
appropriate certification or disclosure, the applicant may be unable to
obtain the information. Thus, FDA is amending the final rule to permit
an applicant, who can show conclusively why this information cannot be
obtained, to certify that the applicant acted diligently to obtain the
information but was unable to do so and to include the reason why such
information could not be obtained.
5. Several comments said the proposed rule is unnecessary because
adequate controls exist to ensure data integrity. For example, the
comments
[[Page 5236]]
said that FDA has adequate mechanisms in place in its review and
inspection processes to detect and deal with investigator bias. Another
comment said that FDA already has substantial oversight to assess
whether clinical studies are well controlled and designed with
scientific rigor. Others said that the primary methods for managing
potential bias based on financial interests are quality study design
(e.g. multiple investigators, multiple investigational sites,
segregation or pooling of data for comparative analyses and objective
tests to evaluate key safety and effectiveness parameters), study
monitoring, and statistical analysis. One comment said that for double-
blinded studies, it was theoretically impossible for any type of bias
to affect the conduct of the study, irrespective of any separate
financial relationship.
FDA agrees that excellence in study designs, careful monitoring and
analysis of trials by sponsors, the ability of FDA to inspect study
sites, and FDA's detailed review of studies are critical elements in
assessing data integrity. No single component is entirely adequate to
ensure study integrity, however, and as explained in the proposed rule,
the independence and lack of bias of clinical investigators is also
critical. FDA believes that in addition to other steps, a mechanism is
needed for collecting information concerning specific financial
interests of clinical investigators that could affect data integrity.
6. Some comments objected to the lack of objective criteria for use
by FDA reviewers to evaluate financial interest disclosure statements.
These comments said that FDA reviewers should not be given unfettered
discretion in making this determination, but that FDA should develop
specific criteria based on factual need. One comment said that lack of
resources would prevent FDA from carrying out this function adequately
and that specific criteria should be developed to help alleviate this
concern. This comment also suggested that certain interests should be
prohibited to provide a more clear-cut and less labor intensive
evaluative approach. Other comments supported FDA's plan to evaluate
the information on a case-by-case basis, stating that FDA should
exercise flexibility and not state specific criteria for this purpose.
As noted in the preamble to the proposed rule, FDA believes that
the specific financial arrangements and the steps taken to minimize
bias (e.g., through study design) must be considered on a case-by-case
basis. Many factors could affect the believability of data derived from
clinical studies, such as the endpoint used, number of investigators,
the methods of blinding and the method of evaluation. For example, if a
covered study had randomized assignment of patients to treatment, an
easily determined endpoint or an endpoint assessed by a blinded
observer other than the investigator, and multiple study sites, FDA
could determine that an otherwise problematic financial interest of a
clinical investigator would not have affected the covered study. In
other cases, 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 that would provide
assurance as to the reliability of the data. If FDA were to determine
that the financial interests of any clinical investigator raised a
serious question about the integrity of the data, FDA could choose from
a range of remedial actions. Depending on the seriousness of the
questions raised, the agency could initiate agency audits of the data
derived from the clinical investigator in question; request that the
applicant submit further analyses of the data (e.g., to evaluate the
effect of investigator's data on study results); or request that the
applicant conduct additional independent studies to confirm the results
of the covered study; or refuse to treat the covered clinical study as
pivotal or primary data upon which an agency action can be taken. Any
attempt to write rigid evaluation criteria would inhibit the
flexibility needed to interpret submissions in a fair and reasonable
way.
7. Three comments suggested that applicants should know in advance
what FDA considers to be problematic arrangements so as not to delay
product review. One comment stated that FDA should include in the
regulation a timeframe for the agency to inform an applicant of a
remedial action that FDA might deem appropriate to take under new
Sec. 54.5(c). The comment added that, once FDA has received all
required financial disclosure information, the agency should be
required to inform the applicant within a reasonable period of time,
not to exceed 60 days, if the financial interests of a clinical
investigator raised a sufficiently serious question about the integrity
of the study data to warrant any of the steps included in new Sec. 54.5
(c), i.e., initiate agency audits of data derived from the clinical
investigator in question; request that the applicant submit further
analyses of data to evaluate the effect of the investigator's data;
request that the applicant conduct additional independent studies to
confirm the results of the covered study; or refuse to treat the
covered clinical study as pivotal or primary data upon which an agency
action could be based.
FDA disagrees with the comments requesting that FDA be required to
inform the applicant about potentially problematic financial
arrangements within a specified time period because the determination
of such remedies is inseparable from the review of the application and
depends on such factors as the study design, and availability of other
data, etc. Concerns arising from financial disclosure will be treated
like any other concerns arising from the review of a marketing
application and will be communicated along similar timeframes. As was
stated in the proposed rule, however, FDA strongly encourages early
consultation with the agency in cases where the sponsor of the clinical
study is concerned that he may be entering into problematic financial
arrangements with a clinical investigator.
8. In the proposed rule, FDA asked for comment on its proposed
definition of a significant equity interest as ``any ownership
interest, stock option, 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.'' The responses covered a wide range. One comment
requested that FDA clarify whether 5 percent of total equity refers to
5 percent of the investigator's equity or 5 percent of the equity of
the corporation and said that holding 5 percent of equity of publicly
traded companies is only relevant if it represents a significant
portion of the investigator's net worth. A second comment said that a
``significant interest'' (determined by reference to a dollar amount)
in the equity or other securities of the sponsor should be of relevance
regardless of whether that interest exceeds 5 percent and that the
reference point of 5 percent is not sufficient in and of itself in
light of the wide range of capitalization of corporations in the
industry. Another comment said that FDA's rule should be made
consistent as far as setting dollar or equity thresholds with the
Public Health Service (PHS) final rule and the National Science
Foundation (NSF) statement of policy on objectivity in research
published on July 11, 1995. One comment recommended the threshold for
disclosure of an equity interest be $10,000 or 2.5 percent ownership
interest in the sponsor.
FDA has carefully considered whether equity interests should be
disclosed to
[[Page 5237]]
FDA and what threshold level should trigger disclosure. There are
varied thresholds applied within academia, such as threshold levels at
some institutions for disclosure of $5,000 cash and $20,000 equity
interest in a publicly traded company. In addition, the PHS final rule
and the NSF statement of policy have defined a significant financial
interest to be ``anything of monetary value, including but not limited
to, salary or other payments for services (e.g., consulting fees or
honoraria); equity interests (e.g., stocks, stock options or other
ownership interests); and intellectual property rights (e.g., patents
copyrights and royalties from such rights). The term does not include *
* * :
any equity interest that, when aggregated for the Investigator
and the Investigator's spouse and children, meets both the following
tests: does not exceed $10,000 in value as determined through
reference to public prices or other reasonable measures of fair
market value, and does not represent more than a 5 percent ownership
interest in any single entity; or salary, royalties or other
payments that when aggregated for the Investigator and the
Investigator's spouse and dependent children over the next 12 months
are not expected to exceed $10,000.
In response to the comments submitted to the proposed rule, as well
as the comments and recommendations made by FDA's Science Board at the
meeting held on March 29, 1996, FDA has eliminated the 5 percent equity
holding provision from the final rule. The agency recognizes that for
many corporations, this would represent an unrealistically large
threshold interest. Instead, in this final rule, FDA defines
``significant equity interest in the sponsor of the covered study'' to
mean any ownership interest, stock option, or other financial interest
whose value cannot be readily determined through reference to public
prices or any equity interest in a publicly traded company that exceeds
$50,000 that is held by the clinical investigator during the time the
clinical investigator is carrying out the study and for 1 year
following the completion of the study. FDA, thus, agrees with the
comments stating that a 5 percent equity interest in a publicly held
company could vary enormously and believes that a $50,000 disclosure
threshold strikes the appropriate balance between the agency's need to
be aware of and help minimize the potential for bias in clinical data
and the need to avoid unreasonably burdening clinical investigators and
applicants.
9. A few comments said that the definition of significant payments
of other sorts in new Sec. 54.2(f) should apply only to research
grants, retainers and honoraria that are related to the study. A few
comments said that the $5,000 threshold limit for such payments was too
low and that the applicable timeframe should be clarified. Some
comments suggested that FDA only require disclosure of payments made
directly to the clinical investigator and not to an institution, such
as a university that employs the investigator. Some comments suggested
that FDA delete the requirement for disclosure of significant payments
of other sorts entirely.
Retention of this provision, as proposed, was discussed at the FDA
Science Board meeting on March 29, 1996. Most Science Board members and
many panelists agreed that information on ``significant payments of
other sorts'' made by the sponsor of the covered study (such as a grant
to fund ongoing research, compensation in the form of equipment, a
retainer for ongoing consultation, or honoraria), even if not directly
related to the conduct of the study, should be disclosed because these
types of financial arrangements exist and have the potential to give
the clinical investigator an ``interest'' in the company. In response
to the comments that described the $5,000 disclosure threshold for
these payments as too low and taking into account the discussion with
Science Board members, FDA has raised the threshold dollar amount that
would trigger disclosure to FDA from $5,000 to any amount exceeding
$25,000 made by the sponsor of the covered study directly to the
clinical investigator or to the institution for support of activities
of the investigator, exclusive of costs associated with the conduct of
the trial or of any other clinical trial. FDA believes this approach
strikes a reasonable balance between the agency's need to be aware of
and help minimize the potential for bias in clinical data and the need
to avoid unreasonably burdening applicants. FDA is also clarifying that
the period for which this disclosure must be made includes the period
during the conduct of the study and for 1 year following completion of
the study.
10. One comment said that applicants should not be responsible for
veracity of the investigators' disclosure statements to the companies.
FDA recognizes that clinical investigators could provide incorrect
financial information to applicants. FDA does not expect to prosecute
any applicant who takes appropriate steps to obtain accurate
information and through no fault of its own unknowingly submits to FDA
erroneous financial information that was provided to the applicant by
the clinical investigator.
11. In the proposed rule, FDA requested comment on whether
certification and disclosure statements should be generally disclosable
to the public. FDA received many comments on this issue, the majority
opposing the public release of this information. Those who argued in
favor of releasing this information said that public disclosure of
financial information in some useful form is critical because shrinking
Government resources make it impossible for FDA to monitor these
arrangements properly, and the public should be able to play some
effective oversight role in this area. These comments said that public
disclosure of this information is necessary in order to discourage the
occurrence of substantive financial abuses at the outset of the
clinical trial process. Comments opposing this view argued that the
public would not be in a position to interpret this information
properly, that public release of this information is an unwarranted
intrusion into the private affairs of clinical investigators, and that
disclosure of this information could discourage highly qualified
investigators from participating in research. One comment said that
there may be some instances where public disclosure should be required,
and that disclosure to an advisory committee should be kept
confidential and limited to the circumstances where the investigator's
interests surpass a specific threshold.
FDA agrees with those comments that stated that certain types of
financial information requested under the rule, notably equity
interests, should be surrounded by a reasonable expectation of privacy.
Therefore, such information would be protected from public disclosure
unless circumstances clearly outweigh the identified privacy interest.
FDA does believe, however, that there may be legitimate public
interest in the information that warrants its disclosure. Certain
requested information such as a patent ownership, already may be public
information and would, therefore, be releasable. In other cases, a
financial arrangement may so affect the reliability of the study that
it may become necessary for the information to be disclosed publicly
during the evaluation of the study (e.g., during an advisory committee
meeting).
Because the full range and impact of such arrangements cannot be
predicted, and because of the variability of both clinical trials and
their financing mechanisms, it is impossible to establish a
comprehensive rule regarding public disclosure of reported information.
FDA, intends, therefore, to proceed on a case-by-case basis in
determining whether the circumstances
[[Page 5238]]
outweigh the privacy interest of the clinical investigator(s). FDA will
determine for each instance of disclosure when to make the information
public and by what means.
In any consideration of disclosure issues, it is useful to keep in
mind FDA's expectation that these issues will not affect the great
majority of clinical investigators who participate in studies of FDA-
regulated products. FDA expects that only a small minority of clinical
investigators will have financial interests of any kind that are
disclosable to FDA; and of that number, FDA expects that only a small
subset would be involved in situations in which the investigator's
privacy interest would be outweighed by the public interest. FDA
strongly encourages any firm that is required to disclose interests and
arrangements of one or more clinical investigators to meet with FDA
early on for guidance on management of the affected clinical study to
help ensure that the potential impact of the disclosed financial
situation on the integrity of the study does not rise to this level of
concern.
12. Some comments said that compliance with PHS disclosure
requirements should be deemed sufficient to satisfy FDA's requirements.
One comment said that an investigator who receives PHS funds should be
required only to provide the company with a copy of his PHS disclosure
statement. A third comment said that FDA should reexamine timing of the
disclosure to be consistent with the PHS rule. Another comment said
that FDA should not rely on PHS disclosure because the two agencies are
separate and that research institutions should not have to rely on
disclosures submitted directly to institutions as substitutes for
compliance procedures imposed on companies.
This issue was raised for comment in the September 1994 proposed
rule. After considering the comments, FDA concludes PHS and FDA
disclosures should not be interchangeable. Although the PHS rule and
the comparable NSF policy have some objectives similar to those of
FDA's rule, the PHS rule and the NSF policy have a different focus.
They deal with policies of Federal grant making agencies and the
credibility of the scientific enterprise, including such issues as:
Potential personal profit from federally funded research, undue secrecy
or refusal to share scientific data from publicly funded research, and
the potential detrimental effect upon academic programs by
inappropriate use of graduate students or ``conflicts of commitment.''
Although FDA acknowledges the validity of such concerns, FDA's
responsibilities are directed at helping to ensure data integrity for
the purposes of product review. Thus, this rule is focused on payment
arrangements and other financial interests of clinical investigators
that have the potential for introducing bias into studies intended to
support marketing applications. It is important that FDA be aware of
such interests and arrangements as part of its evaluation of marketing
applications. Because much of the information reported under the PHS
rule is not related to the product review process, but is more relevant
to issues of basic research, FDA has determined that it is appropriate
for FDA to have different reporting requirements.
13. Several comments argued that FDA underestimated the paperwork
burden on applicants and clinical investigators of the procedures for
financial disclosure specified in the proposed rule. One comment from a
pharmaceutical firm maintained that, while not overly onerous for
investigators, the accumulated paperwork would probably cost
pharmaceutical companies in excess of $1 to 1.5 million annually.
Another firm said that the rule would increase study costs by 5
percent. A trade association described the disclosure procedures as
amounting to a ``severe paperwork burden,'' and another comment alleged
that FDA conducted a cursory examination of the additional number of
hours required to comply with these procedures.
The agency took a careful and thorough approach in assessing the
number of hours that would be spent by applicants because of a
continuing concern that the rulemaking should not impose undue burdens
on industry. FDA believes that the comments have overestimated the
costs and difficulties of complying with this regulation. In an effort
to provide a clearer understanding of the paperwork burden involved,
FDA has reassessed the potential paperwork costs for applicants, using
current data and more conservative assumptions than those used at the
time the proposed rule was drafted. To facilitate reporting, the agency
has developed forms for certification and disclosure and has added
language to the final rule to allow an applicant to attach to one
certification statement a list of all investigators for whom the
applicant is certifying. In this way, preparation and submission of
multiple statements is avoided, and the process is streamlined for
applicants.
FDA believes that the collection of information required by this
regulation and the preparation and submission of a certification
statement would not be onerous. Firms who contracted for covered
studies would already have on hand all information pertaining to
financial arrangements with clinical investigators and significant
payments of other sorts; proprietary interests (e.g., patents) of
clinical investigators; and equity interests of investigators in
nonpublicly traded enterprises. Applicants who were the sponsors of
covered studies would need only to obtain from investigators
information on the clinical investigators' equity interests in the
applicant, a step that would be necessary only if the applicant is
publicly traded. Applicants who did not contract for covered studies
must obtain the required information from the sponsor of the covered
studies and the investigators or demonstrate conclusively that it was
not possible to do so. In either case, a large amount of time would not
be required. Clinical investigators, for their part, can reasonably be
expected to have easily accessible records on their personal equity
interests for tax purposes. They should not have difficulty providing
this information to sponsors of the covered studies.
As noted, FDA believes that preparation and submission of the
certification statement and the list of investigators to whom the
statement applies represents a modest effort. In the estimate presented
in section V of this document, the agency has used the figure of 1 hour
of preparation time for these materials, which it believes to be more
than adequate to cover the actual work involved. FDA believes that
preparation of a disclosure statement and the accompanying explanation
of steps taken to minimize the potential for bias of the covered study
is appreciably more time-consuming and has assigned 4 hours to this
activity.
The agency assumes that every applicant will submit a certification
statement for at least one clinical investigator. The agency further
assumes, based on current data, that 1,000 sponsors will submit
marketing applications for drugs, biologics, or devices each year, with
this number broken down for different types of applications as follows:
[[Page 5239]]
Table 1.--Annual Estimated Number of Marketing Applications for Drugs,
Biologics, and Devices
------------------------------------------------------------------------
Type of Application No. of Sponsors
------------------------------------------------------------------------
Drugs
New drug application (NDA) 135
NDA supplement 100
Abbreviated new drug application (ANDA) 240
ANDA supplement 120
Rx to over-the-counter switch 10
------------------------------------------------------------------------
Biologics
Product license application (PLA) 25
PLA supplement 10
------------------------------------------------------------------------
Devices
Premarket approval (PMA) 50
PMA supplement 10
Reclassification petitions 4
510(k) 300
------------------------------------------------------------------------
There is no firm basis for estimating the frequency of disclosure
by applicants. FDA assumes that from 1 to 10 percent of applicants
would need to submit disclosure for one or more clinical investigators.
In estimating the total burden hours for this activity, FDA has assumed
a 10 percent rate, which is the maximum number of applicants that might
be estimated to disclose annually. The agency believes this figure will
in all likelihood be smaller, perhaps markedly so.
The conforming amendments to drug, biologics, and medical device
regulations that accompany this rule provide for sponsors of the
covered studies to obtain the necessary financial information (e.g.,
equity interests) from investigators at the time the investigator is
retained by the sponsor of the covered study, along with other required
information. FDA concludes that it is reasonable to assume that a
sponsor could incorporate financial disclosure information into the
sponsor's existing system for maintaining investigator information, and
the addition of this information would represent a negligible
expenditure of time. It is estimated that 15 minutes will be required
to add this information to an application record.
The agency estimates that to comply with information collection
activities under this final rule, applicants will spend a total of
1,000 hours annually for certification activities (1,000 applicants
multiplied by 1 hour) and 400 hours for disclosure (100 applicants
multiplied by 4 hours). The total time estimated to be spent by
clinical investigators is 4,600 hours (46,000 clinical investigators
multiplied by 6 minutes). The total estimated annual burden is 6,000
hours for the drug, biologics, and device industries and all clinical
investigators. Once again, FDA has reached this total after carefully
analyzing the activities involved, and using high-end assumptions for
both the amount of time that would be required for each activity and
the number of applicants who would disclose. As noted in section V of
this document, FDA invites comments on these estimates.
14. Several comments alleged that FDA has failed to comply with the
requirements of the Regulatory Flexibility Act. These comments stated
that FDA should conduct a Regulatory Flexibility Analysis under the
Regulatory Flexibility Act, because ``the impact of the rule will fall
disproportionately on small firms, since they may not be able to pay
clinical investigators on a fee-for-service basis.'' These comments
said the rule would significantly affect small firms because of such
factors as ``the thousands of investigators who would need to provide
information to sponsors,'' the composition of the medical device
industry, 98 percent of which is made of small businesses, and the
``severe paperwork burden.''
Included in this final rule is a Regulatory Flexibility Analysis to
assess the impact of the regulation on the industries subject to this
rule. In this analysis, which is included in section IV of this
document, the agency concludes that this final rule does not have a
significant impact on a substantial number of small businesses.
15. Several comments recommended that FDA limit the scope of the
rule with respect to covered studies. One comment said that Phase 1
safety studies should be exempted because they are ``preliminary in
nature and not as pivotal as state 2 or 3 trials.'' Another comment
said that the rule should cover only those studies that the applicant
considers to be ``adequate and well controlled investigations intended
to provide substantial evidence of effectiveness for new drugs.'' A
third comment urged that the rule exempt bioavailability/
pharmacokinetic studies, which, the comment said, generally result in
objective, quantitative results based on tangible data. This comment
recommended limiting the studies covered by the regulation to studies
of a non-pharmacokinetic nature, studies with subjective endpoints, and
single-investigator studies. A comment from a pharmaceutical firm said
that the regulation should target specific types of investigations,
such as unblinded device studies. Another comment stated that, based on
the definition in new Sec. 54.2(e), the rule would appear to encompass
large-scale open-label studies, such as studies involving some
cardiovascular therapies, compassionate use studies, and parallel track
studies, all of which might be submitted in support of an NDA. The
comment noted that investigators in such studies could number in the
thousands and said that it would be an unwarranted administrative
burden to require an applicant to obtain financial information from
each clinical investigator.
The definition of covered clinical study in the rule refers to
studies on which the sponsor relies to support efficacy and studies
where a single investigator makes a significant contribution to safety.
That generally would not include Phase 1 tolerance studies or
pharmacokinetic studies (except for bioequivalence studies) and would
include clinical pharmacology studies only when they are critical to an
efficacy determination. In general, large open studies, treatment
protocols and other studies with large numbers of investigators would
not be covered. In these studies, the large number of investigators
generally means that no single investigator has a major responsibility
for the data. In addition, important adverse events will generally be
apparent because they lead to cessation of therapy and submission of
the case report form. Although it is not impossible that a financial
interest could be important in these studies, it is relatively unlikely
and the agency has concluded that the effort needed to obtain financial
information for the investigators in these studies should not be
undertaken.
16. Some comments maintained that the regulation would deter
investigators from participating in clinical research and would be a
hindrance to clinical research. One comment stated, ``while
investigators will initially see no issue, as soon as FDA takes the
first action to set a precedent, some investigators will become
reluctant to participate in clinical studies.''
FDA does not agree. The agency estimates that the majority of
clinical investigators will have no financial arrangements or interests
subject to disclosure under the terms of the regulation. For those
investigators who have such interests, FDA is not prohibiting or
requiring divestiture of any financial interests, nor does FDA believe
an investigator should be penalized in any way for holding such
[[Page 5240]]
interests. It is, therefore, difficult to see why investigators would
be deterred by this regulation from participating in clinical research.
As for those comments suggesting that the regulation would hinder
clinical research, FDA does not believe the final regulation will
impose a significant burden and certainly not a burden sufficient to
hinder clinical research.
17. In the preamble to the proposed rule, FDA requested comment on
whether the agency should require disclosure of interests held by a
clinical investigator in a firm considered to be a competitor of the
sponsor of the covered study. Comment received was almost equally
divided with respect to such disclosure. One comment in support of
disclosure of competing interests stated that competing interests are
just as likely to result in bias; others said that if the purpose of
financial disclosure is to detect bias, it shouldn't matter whether the
bias is positive or negative. Comments opposed to disclosure of such
interests said that such a requirement might not be realistic inasmuch
as it is often not possible to identify every company that is in
competition with the sponsor of the covered study. A comment from one
trade association stated that such interests should not concern FDA,
and a comment from another trade association said that, in this regard,
it should be sufficient to FDA for a sponsor of a covered study to be
willing to use an investigator.
FDA agrees with the arguments presented by the comments opposing a
requirement for disclosure of competing interests, and such a
requirement is not included in this final rule.
18. In the preamble to the proposed rule, FDA asked for comment on
whether the definition of a clinical investigator should include
business partners of the investigator, who might share in profits from
the investigator's arrangements or financial interests. The majority of
comments on this issue opposed the inclusion of business partners, but
these and other comments addressed other aspects of the definition. One
comment concurred with the definition. Several comments found the
definition to be too broad and stated that, as proposed, the definition
would involve all study personnel and, thus, pose an enormous
administrative burden. Two comments recommended limiting the scope of
the definition to the principal investigator only, and one comment
recommended that the definition include the principal investigator and
the principal investigator's immediate family. Other comments argued
that the definition should not include the investigator's immediate
family. Some comments suggested that the definition of clinical
investigator for the purposes of this rule should be consistent with
the definitions of clinical investigator in various agency regulations,
including regulations governing investigational drugs and devices, as
well as 21 CFR part 50, Protection of Human Subjects, and 21 CFR part
56, Institutional Review Boards, or consistent with the definition in
the PHS rule.
FDA agrees with the comments opposing the inclusion of business
partners as unnecessary and potentially burdensome. With regard to
making the definition of clinical investigator consistent with the PHS
regulation on objectivity in research and various other agency
regulations, FDA believes that those definitions are broader than
needed to achieve the goals of this regulation. For example, the
definition of investigator in the PHS final rule on objectivity in
research means the principal investigator and any other persons
responsible for the design, conduct, or reporting of research funded by
PHS, or proposed for such funding. FDA agrees with those comments
supporting a more narrow definition of clinical investigator and
defines clinical investigator for the purpose of this rulemaking to be
any listed or identified investigator or subinvestigator who is
directly involved in the evaluation of research subjects. As in the PHS
rule, FDA's definition of clinical investigator, in new Sec. 54.2(d),
also includes the investigator's spouse and dependent children.
19. FDA did not propose to require disclosure of financial
interests in, and arrangements with, the sponsor of the covered study
by full-time employees of the sponsor of the covered study, explaining
that the agency gives an appropriate level of scrutiny to the submitted
data in such instances on the assumption that such employees have a
clear financial as well as other interests in the outcome of the
research. The majority of comments agreed that the rule should not
cover such full-time employees. Some comments, however, did not support
a blanket exemption for such employees. One comment argued that
employee incentives such as promotion or termination could depend on
product approval. Another comment said that full-time employees should
be subject to disclosure requirements if they meet the equity
threshold. A third comment stated that if all employees are treated
with maximum scrutiny, further disclosure ``may not be necessary.'' One
comment said that employees who are part-time employees of the
applicant should also be exempt.
The agency treats data from clinical investigators who are the
employees of sponsors with maximum scrutiny and will continue to do so
because such employees can be assumed to have significant financial
interests in the outcome of studies, often including stock options and
significant equity interest in their employers. Because part-time
employees also may receive such incentives, FDA would apply similar
scrutiny to them. Thus, FDA has changed the language in new Sec. 54.4
with respect to identifying clinical investigators who are full-time
employees of the sponsor to read ``full-or part-time employees of the
sponsor of a covered study,''clarifying that the agency will not
require certification or disclosure for part-time employees.
20. Several comments argued that refusal to file a marketing
application is an overly harsh response to an investigator's financial
interests. One comment noted that applications may contain reports of
studies not conducted by the sponsor and asked whether such studies
would be excluded from the refusal-to-file provision. Another
questioned whether the agency would refuse to file an application if
one disclosure statement should be missing in the face of hundreds
being provided.
In new Sec. 54.2(e) FDA has defined a covered clinical study as one
the applicant or FDA relies on to establish that the product is
effective or that make a significant contribution to the demonstration
of safety. This generally would not include studies reported only
briefly or in the form of a publication, unless the latter were
intended to be the critical supportive study. The rule emphasizes that
an applicant may consult with FDA as to which clinical studies
constitute ``covered clinical studies.'' Although most marketing
studies that meet this definition will have been conducted by the
applicant, some critical studies may have been conducted by an academic
or governmental organization (e.g., by the National Institutes of
Health or Veteran's Administration) or by another firm. In these cases,
the relevant financial interests are those that are sponsor-independent
(patent ownership) or that relate to the sponsor of the study (e.g.,
payment in options or significant payments of other sorts). The
applicant should be aware of all interests that investigators might
have (e.g., patent rights) but the applicant may not be aware of prior
arrangements with the study sponsor such as an expectation of a royalty
payment, significant payments of other sorts, or of
[[Page 5241]]
an ownership interest in a nonpublicly traded study sponsor. It is
possible that some of this information cannot be obtained.
The conforming amendments to parts 312 and 812 (21 CFR parts 312
and 812) require clinical investigators to provide sponsors the
information needed to allow an applicant to submit certification and
disclosure statements. FDA has given further consideration to the
application of the refusal-to-file provision, however, and concludes
that where circumstances make it impossible for an applicant of an
application to obtain the information needed for certification or
disclosure for one or more clinical investigators, and the applicant
explains these circumstances adequately, the agency will not refuse to
file an application. The refusal to file provision is not based on the
investigator's financial interest but on failure of the applicant to
disclose them.
21. Two comments suggested that, before the final rule becomes
effective, FDA conduct a series of educational fora on these new
requirements to ensure that they are understood by the industry that
must comply with them.
FDA welcomes the suggestion. Just as the agency has opened the
development of the regulation to public participation in a number of
ways, it will now seek opportunities to describe the provisions of the
final rule to all segments of the public. FDA will take these steps in
addition to working with applicants, as the agency has indicated
consistently it will do, to help ensure that their clinical research is
carefully managed with respect to protection from potential bias.
III. Conforming Amendments
At the time the regulations in new part 54 were proposed, FDA
proposed conforming amendments to certain regulations for drugs,
biologics, and devices. The final amendments to these regulations have
been modified as necessary to ensure continuing conformity with the
final regulations and will take effect at the time those regulations
become effective. The amendments are described in detail in the
following sections.
A. Amendments to Regulations for Human Drug Products
In its regulations governing investigational new drug applications,
FDA is amending Sec. 312.53(c), which applies to the selection of
investigators, to require sponsors to obtain financial information from
clinical investigators. As noted in the preamble to the proposed rule,
this amendment provides for sponsors to acquire financial information
from clinical investigators before starting clinical investigations.
This will enable the sponsor, and any future potential applicant, to
discover potential bias on the part of the clinical investigator before
the investigation begins and permit the sponsor to consult with FDA on
management of the situation. As noted previously, the sponsor of a
clinical study and the applicant for a marketing application would be
the same entity in the majority of cases. However, in some cases, an
applicant would have obtained the product and related studies from the
study sponsor, including the relevant information as to financial
interests of clinical investigators.
Section 312.57 is amended to require sponsors to maintain records
on financial interests and arrangements of investigators and
investigators' immediate families as required in new part 54.
The agency is amending Secs. 314.50 and 314.60 (21 CFR 314.50 and
314.60) to require that all NDA's, amendments to applications, and
supplements that contain new data from a previously unreported study
include certification and disclosure statements as required in new part
54. FDA is amending Sec. 314.94 (21 CFR 314.94) to require
certification or disclosure statements in ANDA's. The agency originally
proposed that the certification and disclosure statements be included
on the application form. The agency has determined that this would be
impractical, and is therefore amending Secs. 314.60 and 314.94 to
require that the financial certification or disclosure statement be
part of the application submission, but not be included on the
application form.
Under 21 CFR 314.101(d), the agency may refuse to file or receive
an application that is incomplete. Failure to include a financial
certification or disclosure statement, as required by amended
Secs. 314.50(l) and 314.94(a)(13), would give the agency grounds to
refuse to file or receive the application. Similarly, amended
Sec. 314.60(a) gives the agency authority to refuse to accept any
amendment to an unapproved application when that amendment contains new
clinical data from an unreported study and does not include a financial
certification or disclosure statement. These provisions incorporate the
requirement for a financial certification or disclosure statement found
in new part 54. In some situations, a certification or disclosure
statement is not required under new part 54, and thus the agency would
not refuse to file or receive the application, or refuse to accept the
amendment for failure to include the statement. For example, new
Sec. 54.4(c) in this final rule. FDA recognizes that it would not
refuse to file an application that contains a certification from the
applicant stating that it was not possible to obtain the information
required for certification and disclosure and the reason, e.g., if a
covered study were concluded prior to the requirement for a study
sponsor to obtain this information from investigators and the
investigators could not be reached or were unwilling to provide the
information voluntarily.
FDA is amending 21 CFR 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, or ANDA's, or the hearing process for
issuing, amending, and withdrawing antibiotic regulations, to submit a
certification or disclosure statement.
Amendments to 21 CFR 320.36 require similar reporting and
recordkeeping for certification and disclosure statements accompanying
bioequivalence studies as would be required under part 312.
Amendments to 21 CFR 330.10 require certification or disclosure
statements to accompany clinical data submitted as part of the over-
the-counter drug monograph process.
B. Amendments to Regulations for Biologicals
FDA is amending the regulations at 21 CFR 601.2(a) governing the
filing of applications for product licenses to require the inclusion of
certification or disclosure statements, or both, as required in new
part 54.
C. Amendments to Regulations for Medical Devices
FDA is adding a new paragraph to 21 CFR 807.87 to require the
inclusion of certification or disclosure statements, or both, in a
premarket notification submission. A paragraph is added to Sec. 807.100
to allow FDA to withhold a decision on a premarket notification
submission until certification or disclosure statements are submitted
to FDA as required under new part 54.
FDA is amending 21 CFR 807.31 to require that certification and
disclosure statements be retained at the establishment maintaining the
historical file. Section 812.110 is amended to require clinical
investigators to provide sponsors with sufficient accurate financial
information (see 812.110) for the preparation of certification or
disclosure statements.
FDA is amending Sec. 812.43(c), which applies to the selection of
monitors and investigators, to require sponsors to
[[Page 5242]]
obtain financial information from clinical investigators. Although not
identified in the proposed rule as a conforming amendment to the device
regulations, this revision is consistent with the requirement in
Sec. 812.110(d) that investigators provide financial information to
sponsors to obtain the information. This amendment provides for
sponsors to acquire financial information from clinical investigators
before starting clinical investigations. This will enable the sponsor
(and any future applicant) to discover potential bias on the part of
the investigator before the investigation begins and permit the sponsor
to consult with FDA on management of the situation. This conforming
amendment parallels the drug conforming amendment in Sec. 312.53(c).
FDA is amending Sec. 812.140(b)(3) to require sponsors to maintain
records on financial interests and arrangements of investigators and
investigators' immediate families as required in new part 54. This
conforming amendment is consistent with the recordkeeping requirements
in new part 54.
FDA is amending 21 CFR 814.20 to require the inclusion of
certification or disclosure statements in premarket approval
applications. The agency is also amending 21 CFR 814.42 to provide that
the agency may refuse to file an application or amendments that contain
clinical data unless certifications or disclosure statements are
included as required by new part 54.
FDA is amending 21 CFR 814.112 to require applicants of
humanitarian device exemption (HDE) applications to submit
certification or disclosure statements. The regulation on HDE's was
issued after publication of the financial disclosure proposal. This
amendment is consistent with the other conforming amendments requiring
financial disclosure information for premarket approval applications.
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 amending 21 CFR 860.123 to require
any sponsor who submits clinical data as part of a reclassification
petition to include certification or disclosure statements, or both, as
required by new part 54.
IV. Summary of Changes
FDA has made the following changes in the final rule in response to
comments received on the proposed rule as discussed previously in this
preamble and to clarify the intent of the regulation:
1. Recognizing that the firm submitting a marketing application
might not have sponsored the covered studies, FDA has changed the term
defined in new Sec. 54.2(b) from ``Significant equity interest in the
applicant'' to ``Significant equity interest in the sponsor of a
covered study'' and has revised new Sec. 54.2(f) (``Significant
payments of other sorts'') to contain similar clarifying language. FDA
has defined ``applicant'' and sponsor of the covered study at new
Sec. 54.2(g) and (h) and has added language to the purpose statement in
21 CFR 51.1 to distinguish a sponsor of a covered study from a sponsor
of a marketing application (i.e., applicant). The agency has also added
language to the scope of the regulation in new Sec. 54.3, to make it
clear that the requirements of the regulation apply to applicants
whether or not the applicant was the sponsor of the studies submitted.
The applicant is responsible for obtaining the information required by
the regulation or for demonstrating conclusively why it is not possible
to do so. The agency has added similar clarifying language to
appropriate sections of the disclosure requirements in new Sec. 54.4
and requirements for recordkeeping and record retention in new
Sec. 54.6.
2. FDA has made one further change in the definition of a
significant equity interest in new Sec. 54.2(b). In the proposed rule,
a disclosable equity interest in a publicly traded corporation was
defined as ``any equity interest in a publicly traded corporation that
exceeds 5 percent of total equity, and no applicable time period was
stated. In the final rule, FDA has defined an equity interest in a
publicly traded corporation as one that exceeds $50,000 during the time
the clinical investigator is carrying out the study and for 1 year
following completion of the study.'' FDA has eliminated the 5 percent
equity holding provision and has replaced it with the $50,000 threshold
because FDA recognizes that for many corporations, a 5 percent equity
interest represents an unrealistically large threshold interest. FDA
has clarified the time period whereby applicants are required to
disclose information to FDA for 1 year following completion of the
study (i.e., after enrollment of all the subjects and followup subjects
in accordance with the clinical protocol) to further reduce the
possibility that clinical investigators could exert undue influence
during final data analysis.
3. In response to comments that the definition of ``clinical
investigator'' in new Sec. 54.2 (d) of FDA's proposed rule was too
broad, FDA has revised this definition to clarify that it includes only
principal and subinvestigators who are directly involved in the
treatment and evaluation of research subjects and their spouses and
dependent children.
4. In the final rule, FDA has shortened and clarified the
definition of covered clinical study in new Sec. 54.2(e).
5. In new Sec. 54.2(f) of the proposed rule, FDA defined
``significant payments of other sorts'' as ``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.'' In the final rule, FDA has set the threshold for
disclosure of such payments at a value of more than $25,000 and has
further revised and clarified this definition so that it reads as
follows:
Significant payments of other sorts means payments made by the
sponsor of a covered study to the investigator or the institution to
support activities of the investigator that have a monetary value of
more than $25,000, exclusive of the costs of conducting the clinical
study or other clinical studies (e.g., a grant to fund ongoing
research, compensation in the form of equipment or retainers for
ongoing consultation or honoraria), during the time the clinical
investigator is carrying out the study and for 1 year following
completion of the study.
6. The opening paragraph of proposed Sec. 54.4 required the
applicant to ``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 * * *''. In
response to a comment, FDA is changing this phrase to read ``not a
full-time or part-time employee of the sponsor for each covered
clinical study.''
7. Section 54.4(a) of the proposed rule stated that an applicant
shall submit for each covered clinical study either a certification or
disclosure statement. FDA has revised this statement to make it clear
that the applicant must submit a certification or disclosure statement
for each investigator who participated in a covered clinical study, as
opposed to each covered clinical study. FDA recognizes that, in some
instances, an applicant might need to submit both certification and
disclosure statements to cover the interests of all clinical
investigators who participated in one covered study. The agency has
also changed this statement to make it clear that the applicant may
submit one certification statement to cover all investigators for whom
certification is made.
8. FDA has also made provision in new Sec. 54.4 of the final rule
for an
[[Page 5243]]
applicant who can demonstrate that it was not possible to obtain the
information required for certification and disclosure to certify that
the applicant, acted with due diligence, to obtain the information
needed to certify or disclose but was unable to do so. For example, if
the laws of a foreign country preclude the applicant from obtaining the
financial information, a statement submitted to FDA referencing such
laws would be appropriate.
9. FDA has deleted the statement in new Sec. 54.6 of the proposed
rule that if the application is not approved, a sponsor shall retain
covered records ``for 2 years after the product, for which the
application was submitted, was shipped and delivered to clinical
investigators for testing.'' FDA has deleted this statement because it
is inconsistent with other recordkeeping requirements.
10. Also in new Sec. 54.6(a)(1) and (a)(2), FDA has deleted the
requirement from the proposed rule that sponsors must show all
compensation paid to clinical investigators and has replaced it with a
statement requiring applicants to complete records showing any
financial arrangement as described in new Sec. 54.4(a)(3)(i) and
(a)(3)(ii). FDA has made the change in order to ease recordkeeping
requirements and require applicants to maintain records that may raise
potential problematic financial arrangements. Similarly, FDA has
revised the conforming amendments in Sec. 312.57 to ease recordkeeping
requirements and has added Sec. 812.43(c)(5) to identify the device
sponsors' requirements.
V. Analysis of Impacts
FDA has examined the impacts of the final rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612).
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; and distributive impacts and equity). The agency believes
that this final rule is consistent with the regulatory philosophy and
principles identified in the Executive Order. The agency concludes that
the rule is a significant regulatory action as defined by the Executive
Order. The following discussion summarizes the agency's economic
assessment, and where possible, presents quantitative estimates of the
impact of the regulation on the industries subject to this rule.
A. Regulatory Flexibility Analysis
The Regulatory Flexibility Act requires agencies to prepare a
Regulatory Flexibility Analysis for each rule unless the agency
certifies that the rule would not have a significant economic impact on
a substantial number of entities. As explained in section IV.B of this
document, the agency believes that this final rule will not have a
significant economic impact on a substantial number of small entities.
Nevertheless, the rule may impose significant costs on a few small
businesses. Because FDA cannot adequately quantify all of this impact,
it has prepared a Regulatory Flexibility Analysis as part of its
economic assessment. This analysis, which is summarized in section IV.B
of this document, is available for review at the Dockets Management
Branch (address above).
FDA finds that it is important to the public health to ensure, as
much as possible, that the safety and efficacy data submitted to the
agency in support of marketing applications are free of the effects of
any bias that may result from the financial interests of investigators.
The information received through the reporting requirements in the
final rule will help the agency to determine the reliability of data
submitted in marketing applications. In addition, the reporting
requirements will help to ensure that sponsors of covered studies
consider potentially problematic financial arrangements and interests
in the early stages of product development and, if necessary, consider
how best to minimize such potential sources of bias in their clinical
studies.
The final rule will affect firms that sponsor marketing
applications containing clinical data in the human drug, biologic, and
medical device industries. Although FDA receives about 1,000 marketing
applications and supplements per year that will be subject to this
rule, the agency believes that only a few of these applications will be
more than minimally affected. Public comments in response to the
proposed rule indicate that potentially problematic financial
arrangements occur only occasionally, although perhaps more often
within the small biotechnology and medical device firms that choose to
utilize, for example, the inventor of a product as a clinical
investigator, or to make payments to the clinical investigator in the
form of equity interests such as stock options. While FDA cannot
determine the precise number of such arrangements, representatives from
the drug and device industries (Science Board Meeting, March 29, 1996)
report that sponsors only rarely reimbursed clinical investigators by
those means described as problematic in the final rule.
The rule will create costs in three areas: Reporting,
recordkeeping, and research. Reporting and recordkeeping are discussed
in section V of this document. The agency estimates that total
reporting costs of sponsors and investigators will be less that
$450,000 annually and estimates no additional costs for recordkeeping.
However, these costs are offset by the significant public health
benefits of FDA's being able to adequately assess the reliability of
clinical trial data and thus ensure the safety and efficacy of
regulated products. As described previously, financial interests
especially if combined with 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.
Research costs can be incurred either before the product
application has been submitted to the agency or after the agency begins
its review. Costs may be incurred before an application is submitted
when a clinical investigator has a disclosable interest and the sponsor
modifies a trial protocol or alters procedures to minimize the
potential for investigator bias. However, even where the investigator
has a disclosable interest or arrangement, many clinical protocols will
not need to be modified because they already are designed to minimize
potential for investigator bias. (Sponsors are encouraged to meet with
FDA to discuss protocol design and this is common practice with
sponsors of covered clinical studies of human drugs and biologics).
Although a few protocols may require some adjustment to the design,
such as having a blinded observer carry out critical observations, most
changes would be minor and not costly. In some cases, sponsors might
choose a different investigator. Where a protocol is altered, however,
sponsors would incur costs for modifying the protocol, preparing
additional analyses, or hiring additional investigators. This would
occur, however, only where there was a potentially important problem to
resolve.
Costs could also occur after a marketing application is submitted
if FDA determined that the financial interests of an investigator raise
serious questions about the integrity of the data. In such a case, the
agency may audit the data derived from the investigator, request that
the applicant submit further analyses of the data, request that the
[[Page 5244]]
applicant conduct additional independent studies to confirm the results
of the questioned study, or refuse to accept the result of the covered
clinical study. The likelihood that this rule would require additional
research will decline rapidly, however, as applicants adjust to the new
requirements by designing studies that minimize the potential bias.
Because relevant clinical trials for most new drug and biological
products are blinded and involve multiple sites and multiple
investigators, the agency does not anticipate significant modifications
to protocols for most of these products. Clinical trials for medical
devices, however, tend to be smaller, involving fewer sites and fewer
investigators. In addition, there is a higher possibility of
``inventor/ investigator'' relationships in this industry and,
therefore, the sponsors of medical device marketing applications may be
more likely than sponsors of applications in other industries to
require protocol modifications that could lead to higher costs.
Unfortunately, until the agency collects the financial disclosure
information that could be used to determine the frequency and type of
future research protocol adjustments, it cannot project the likely
magnitude of these research costs. That is, because FDA does not know
which clinical protocols may have unacceptable potential biases, the
agency has no means of quantifying the number of the research protocols
that might be modified or the associated costs of such modifications.
FDA notes, however, that such costs would occur only in the presence of
potentially biased clinical trial data that would otherwise be used to
support new product approval decisions and would therefore be
worthwhile. Because such occurrences would be quite uncommon, FDA
concludes that, in aggregate, these costs would be small.
B. Small Business Impact
The Small Business Administration (SBA) uses employment size
criteria to identify small businesses in the industries affected by
this rule. SBA defines a drug company (Standard Industrial Code (SIC)
2834) as small if there are fewer than 750 employees; whereas biologic
(SIC's 2835 and 2836) and medical device companies (SIC's 3841, 3842,
3843, 3844, 3845, and 3851) are considered small if employment is less
than 500. Table 2 displays the distribution of companies by employment
size. Even if the employment size category of 500+, which is the
largest category reported by SBA, were considered as the small business
threshold, approximately 87 percent of drug companies, 85 percent of
biologic companies and 94 percent of device companies would be
considered small. On this basis, most of the firms affected by this
rule are small businesses.
Table 2.--Number of Firms by Employment Size for 1993\1\
----------------------------------------------------------------------------------------------------------------
Employment Size
Industry -------------------------------------------------------------------------------
<20 20 to 99 100 to 499 Total
----------------------------------------------------------------------------------------------------------------
Drug 332 155 80 85 652
Biologic 208 92 50 65 415
Medical device 2,936 835 381 273 4,425
----------------------------------------------------------------------------------------------------------------
\1\ Source: Special Census Tabulation prepared by U.S. Bureau of Census for U.S. Small Business Administration,
Tab 3 - United States.
One industry comment expressed concern that the ``impact of the
rule will fall disproportionately on small firms, since they may not be
able to pay clinical investigators on a fee-for-service basis.'' The
writer was particularly concerned about the adverse effect this rule
will have on the medical device industry and the ``thousands of
investigators who would need to provide information to sponsors.''
FDA agrees that the smallest firms will exhibit the highest
incidence of potentially problematic financial arrangements. Medical
device and biotechnology sponsors that have few resources, especially
new start-up companies, are more likely to engage in unconventional
compensation arrangements than other companies. These smaller firms
would also be more likely than the larger firms to have ``inventor/
investigator'' relationships.
Even among the smallest firms, however, very few will incur
significant costs. In fact, the majority of companies counted in Table
2 will not be affected by this rule. For example, only about 5 percent
of the approximately 6,000 medical device companies will produce any
devices affected by the rule. For those relatively few firms that
sponsor or conduct clinical trials, FDA has been told by industry
representatives that only a small subset will have disclosable
arrangements.
And even a smaller subset of firms may incur increased research
costs, because only in rare cases would sponsors of the covered study
need to modify original protocols, particularly because sponsors of the
covered studies are encouraged to consult with the agency whenever a
questionable financial arrangement or interest emerges. These
consultations are particularly important, because the cost to modify a
clinical trial design before a clinical trial is conducted is far lower
than the cost to address a problem after the trial is completed. For
these few instances where a sponsor of a covered study may need to take
additional steps to minimize the potential for bias, FDA believes that
the benefits of correcting potentially biased results will more than
offset the costs of any needed research modifications.
C. Analysis of Alternatives
FDA has considered various alternatives to publishing this final
rule including not requiring submission of this information to the
agency. After meeting with numerous groups including regulated industry
and others, it was decided that it was necessary for FDA to require
submission of this information in order for FDA to be adequately aware
of influences that could affect data reliability. FDA also considered
the need to prohibit certain financial interests where the original
investigator was compensated in ways that have the potential to
influence the outcome of the study. FDA decided against that option,
however, because FDA recognizes that therapeutic products that benefit
the public health have been developed by these means. Instead, FDA
intends to give these types of financial arrangements close scrutiny.
Changes to the September 1994 proposed rule have been made to
clarify the intent of the regulation and as a result of public comment,
including meetings with industry, consumer groups, health
professionals, and clinical investigators. Table 3 lists
[[Page 5245]]
changes made in the final rule that will reduce the economic impact on
small businesses:
Table 3.--Comparison of the Impact of the Proposed Rule and Final Rule on Financial Disclosure by Clinical
Investigations in Reducing the Economic Impact on Small Businesses
----------------------------------------------------------------------------------------------------------------
Proposed Rule Final Rule
----------------------------------------------------------------------------------------------------------------
(a) Definition of significant equity interest ``any (a) Significant equity defined as exceeding $50,000
ownership interest stock option, or other financial during the time the trial is carried out for 1 year
interest whose value cannot be readily determined following completion of the study.
through reference to public prices, or any equity
interest in a publicly traded corporation that exceeds
5 percent of total equity''.
(b) $5,000 disclosure threshold for significant (b) Increased disclosure threshold to amounts exceeding
payments of other sorts from the sponsor. $25,000.
(c) Broader definition of clinical investigator and (c) Narrowed definition to principal and
asked for comment on the inclusion of business subinvestigators and their immediate families.
partners.
----------------------------------------------------------------------------------------------------------------
VI. Paperwork Reduction Act of 1995
This final rule contains information collection requirements that
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The
title, description, and respondent description of the information
collection requirements are shown below with an estimate of the annual
reporting and recordkeeping burden. Included in the estimate is the
time for reviewing instructions, searching existing data sources,
gathering and maintaining the data needed, and completing and reviewing
each collection of information.
Title: Financial Disclosure by Clinical Investigators
Description: This final rule requires the sponsor of any drug
(including a biological product), or device marketing application to
certify to the absence of certain financial interests of clinical
investigators and/or disclose those financial interests as required,
when covered clinical studies are submitted to FDA in support of
product marketing.
Description of Respondents: Respondents are sponsors of marketing
applications containing clinical data from studies covered by the
regulation. These sponsors represents pharmaceutical, biologic and
medical device firms. Many of these firms are small entities especially
in the areas of medical devices and biologics/biotechnology.
Respondents are also clinical investigators who provide financial
information to sponsors of marketing applications.
FDA received a number of comments on the information collection
estimates in the proposed rule (see comment no. 13 of section II of
this document for a summary and response to these comments). The agency
has added language to the final rule to allow one certification
statement to cover all investigators for which the applicant is
certifying in an application. FDA has also recalculated its estimate of
the total number of hours that will be necessary to complete the
information collection requirements associated with this final rule.
The applicant will incur reporting costs in order to comply with
the final rule. Applicants will be required to submit, for example, a
complete list of clinical investigators for each covered study, a list
that is already required in a marketing application. For investigators
not employed by the applicant and/or the sponsor of the covered study,
the applicant must either certify to the absence of certain financial
arrangements with clinical investigators or disclose those arrangements
to FDA.
The clinical investigator will have to supply information
pertaining to significant stock ownership in that company (e.g.,
whether the clinical investigator, his spouse or dependent child owns
$50,000 or more stock in that company).
Because the sponsor would be aware of any payments to
investigators, patents or licenses held by investigators, and any other
significant financial arrangements with investigators, most of the
information that is necessary to certify or disclose is already
available to the sponsor of the study. Similarly, sponsors that are
nonpublicly traded corporations can easily identify their stockholders.
The only information that the sponsor will need to obtain from the
investigator would be the investigator's stock holdings in the sponsor,
if the sponsor is publicly traded.
FDA expects that almost all applicants will submit a certification
statement in Sec. 54.4(a)(1) and (a)(2). Preparation of the statement
using the following Form FDA 3454 will represent little effort and
should require no more than 1 hour per study (80 percent clerical time,
20 percent managerial).
BILLING CODE 4160-01-F
[[Page 5246]]
[GRAPHIC] [TIFF OMITTED] TR02FE98.004
BILLING CODE 4160-01-C
[[Page 5247]]
Table 4.--Estimated Number of Applications, Clinical Trials, and Investigators Subject to the Proposed Rule by
Type of Application\1\
----------------------------------------------------------------------------------------------------------------
Number of
Application Type Total Number Applications Number of Trials Number of
Applications Affected Investigators
----------------------------------------------------------------------------------------------------------------
Drugs
New drug application (NDA),
new molecular entity (NME) 35 35 3 to 10 3 to 100
NDA nonNME 100 100 1 to 3 10 to 30
NDA efficacy supplement 100 100 1 to 3 10 to 30
Abbreviated new drug
application (ANDA) 400 240 1.1 2
ANDA supplement 2,500 120 1 2
Rx switch 20 10 2 4
----------------------------------------------------------------------------------------------------------------
Biologics
Product license application
(PLA) 25 25 3 to 10 3 to 100
PLA efficacy supplement 10 10 1 to 3 3 to 100
----------------------------------------------------------------------------------------------------------------
Medical Devices
Premarket approval (PMA) 50 50 1 10 to 20
PMA supplement 400 10 1 3 to 10
Reclassification petitions 8 4 1 3 to 10
510(k) 6,000 300 1 20
----------------------------------------------------------------------------------------------------------------
\1\ Source: Agency estimates.
When certification is not possible and disclosure is made using the
following Form FDA 3455, the applicant must describe the financial
arrangements or interests and the steps that were taken to minimize the
potential for bias in the affected study. As the applicant will be
fully aware of those arrangements and steps taken, describing them will
be straightforward. The agency estimates that it will take about 4
hours to prepare this narrative, 90 percent management time and 10
percent clerical.
BILLING CODE 4160-01-F
[[Page 5248]]
[GRAPHIC] [TIFF OMITTED] TR02FE98.005
BILLING CODE 4160-01-C
[[Page 5249]]
Until the agency begins to collect information on the financial
arrangements between investigators and applicants, it cannot know the
actual number of disclosable arrangements. Therefore, it is not
possible to predict the total cost to industry of preparing these
explanatory statements with any certainty, although the agency was told
by industry representatives that few would be needed because the
financial arrangements described in this rule are uncommon. FDA
estimates that from 1 percent to 10 percent of the applications would
need disclosure statements, and has used the extremely conservative
estimate of 10 percent in Table 5 below.
Investigators must provide sponsors of the covered studies with
sufficient accurate information to make the required disclosure or
certification. Because much of the information required can be obtained
from the applicant's own records, the costs incurred by the clinical
investigator will be minimal. Clinical investigators are required to do
one of two things: (1) Provide a statement that they, their spouse, and
their dependent children did not have a significant equity interest
(greater than $50,000) in the sponsor of the covered study during the
time of the clinical study and for 1 year after, or (2) disclose such
interest. Most people know the financial holdings of their immediate
family and records of such interests are generally accessible because
they are needed for preparing tax records. The time required for this
task may range from 5 to 15 minutes. Assuming a physician's hourly cost
of $87.69,\1\ a $336,695 estimated cost to investigators was
calculated. Clinical investigators are accustomed to supplying such
information in even greater detail when applying for research grants.
Table 5.--Estimated Annual Reporting Burden
----------------------------------------------------------------------------------------------------------------
Annual
21 CFR Section No. of Frequency per Total Annual Hours per Total Hours
Respondents Response Responses Response
----------------------------------------------------------------------------------------------------------------
54.4(a)(1) and (a)(2) 1,000 1 1 1 1,000
54.4(a)(3) 100 1 1 4 400
54.4 (Clinical investigators) 46,000 1 1 .10 4,600
Total 6,000
----------------------------------------------------------------------------------------------------------------
The sponsors of covered studies will be required to maintain
complete records of compensation agreements with any compensation paid
to nonemployee clinical investigators, including information showing
any financial interests held by the clinical investigator, for a time
period of 2 years after the date of approval of the application. This
time is consistent with the current recordkeeping requirements for
other information related to marketing applications for human drugs,
biologics, and medical devices. FDA judged the incremental costs
associated with this new activity to be negligible because firms
already maintain records of compensation as standard business practice
and the required records pertaining to the financial interests of the
investigators will typically consist of only one additional piece of
paper per investigator. Currently, sponsors of covered studies must
maintain many records with regard to clinical investigators, including
protocol agreements and investigator resumes or curriculum vitae and
the inclusion of information required by this rulemaking would add
little to this recordkeeping burden. FDA estimates that an average 15
minutes will be required for each recordkeeper to add this record to
clinical investigators' files.
Table 6.--Estimated Annual Recordkeeping Burden
----------------------------------------------------------------------------------------------------------------
Annual
21 CFR Section No. of Frequency per Total Annual Hours per Total Hours
Recordkeepers Recordkeeping Records Recordkeeper
----------------------------------------------------------------------------------------------------------------
54.6 1,000 1 1,000 .25 250
----------------------------------------------------------------------------------------------------------------
There are no operating and maintenance costs or capital costs associated with this information collection of
information.
Although the September 22, 1994 (59 FR 48708), proposed rule
provided a 90-day comment period under the Paperwork Reduction Act of
1980, and this final rule responds to the comments received, FDA is
providing an additional opportunity for public comment under the
Paperwork Reduction Act of 1995 that became effective after the
expiration of the comment period and applies to this final rule.
Therefore, FDA now invites comments on: (1) Whether the proposed
collection of information is necessary for the proper performance of
FDA's functions, including whether the information will have practical
utility; (2) the accuracy of FDA's estimate of the burden of the
proposed collection of information, including the validity of the
methodology and assumptions used; (3) ways to enhance the quality,
utility, and clarity of the information to be collected; and (4) ways
to minimize the burden of the collection of information on respondents,
including through the use of automated collection techniques, when
appropriate, and other forms of information technology.
---------------------------------------------------------------------------
\1\ Physician mean net income (after expenses, before taxes) for
all specialties is $182,395.20. Source: American Medical
Association. Wage rate assumes 2,080 hours worked per year.
---------------------------------------------------------------------------
Individuals and organizations may submit comments on the
information collection provisions of this final rule by April 3, 1998..
Comments should be directed to the Dockets Management Branch (address
above). Comments should be identified with the docket number found in
brackets in the heading of this document.
At the close of the 60-day comment period, FDA will review the
comments received, revise the information collection provisions as
necessary, and submit these provisions to OMB for review. FDA will
publish a notice in the Federal Register when the information
collection provisions are submitted to OMB, and an opportunity for
public comment to OMB will be provided at that time. Prior to the
effective date of this final rule, FDA will publish a notice in the
Federal Register of OMB's
[[Page 5250]]
decision to approve, modify, or disapprove the information collection
provisions. An agency may not conduct or sponsor, and a person is not
required to respond to, a collection of information unless it displays
a currently valid OMB control number.
List of Subjects
21 CFR Part 54
Biologics, Drugs, Medical devices, 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
Administrative practice and procedure, Biologics, Confidential
business information.
21 CFR Part 807
Confidential business information, Imports, Medical devices,
Reporting and recordkeeping requirements.
21 CFR Part 812
Health records, Medical devices, Medical research, 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, and
under authority delegated to the Commissioner of Food and Drugs, 21 CFR
chapter I is amended as follows:
1. 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 Certification and disclosure requirements.
54.5 Agency evaluation of financial interests.
54.6 Recordkeeping and record retention.
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357,
360, 360c-360j, 371, 372, 373, 374, 375, 376, 379; 42 U.S.C. 262.
Sec. 54.1 Purpose.
(a) The Food and Drug Administration (FDA) evaluates clinical
studies submitted in marketing applications, required by law, for new
human drugs and biological products and marketing applications and
reclassification petitions for medical devices.
(b) The agency reviews data generated in these clinical studies to
determine whether the applications are approvable under the statutory
requirements. FDA may consider clinical studies inadequate and the data
inadequate if, among other things, appropriate steps have not been
taken in the design, conduct, reporting, and analysis of the studies to
minimize bias. One potential source of bias in clinical studies is a
financial interest of the clinical investigator in the outcome of the
study because of the way payment is arranged (e.g., a royalty) or
because the investigator has a proprietary interest in the product
(e.g., a patent) or because the investigator has an equity interest in
the sponsor of the covered study. This section and conforming
regulations require an applicant whose submission relies in part on
clinical data to disclose certain financial arrangements between
sponsor(s) of the covered studies and the clinical investigators and
certain interests of the clinical investigators in the product under
study or in the sponsor of the covered studies. FDA will use this
information, in conjunction with information about the design and
purpose of the study, as well as information obtained through on-site
inspections, in the agency's assessment of the reliability of the data.
Sec. 54.2 Definitions.
For the purposes of this part:
(a) Compensation affected by the outcome of clinical studies means
compensation that could be higher for a favorable outcome than for an
unfavorable outcome, such as compensation that is explicitly greater
for a favorable result or compensation to the investigator in the form
of an equity interest in the sponsor of a covered study or in the form
of compensation tied to sales of the product, such as a royalty
interest.
(b) Significant equity interest in the sponsor of a covered study
means any ownership interest, stock options, or other financial
interest whose value cannot be readily determined through reference to
public prices (generally, interests in a nonpublicly traded
corporation), or any equity interest in a publicly traded corporation
that exceeds $50,000 during the time the clinical investigator is
carrying out the study and for 1 year following completion of the
study.
(c) Proprietary interest in the tested product means property or
other financial interest in the product including, but not limited to,
a patent, trademark, copyright or licensing agreement.
(d) Clinical investigator means any listed or identified
investigator or subinvestigator who is directly involved in the
treatment or evaluation of research subjects. The term also includes
the spouse and each dependent child of the investigator.
(e) Covered clinical study means any study of a drug or device in
humans submitted in a marketing application or reclassification
petition subject to this part that the applicant or FDA relies on to
establish that the product is effective (including studies that show
equivalence to an effective product) or that make a significant
contribution to the demonstration of safety. An applicant may consult
with FDA as to which clinical studies constitute ``covered clinical
studies'' for purposes of complying with financial disclosure
requirements.
(f) Significant payments of other sorts means payments made by the
sponsor of a covered study to the investigator or the institution to
support activities of the investigator that have a monetary value of
more than $25,000, exclusive of the costs of conducting the clinical
study or other clinical studies, (e.g., a grant to fund ongoing
research, compensation in the form of equipment or retainers for
ongoing consultation or honoraria) during the time the clinical
investigator is carrying out the study and for 1 year following the
completion of the study.
(g) Applicant means the party who submits a marketing application
to FDA for approval of a drug, device, or biologic product. The
applicant is responsible for submitting the appropriate certification
and disclosure statements required in this part.
(h) Sponsor of the covered clinical study means the party
supporting a
[[Page 5251]]
particular study at the time it was carried out.
Sec. 54.3 Scope.
The requirements in this part apply to any applicant who submits a
marketing application for a human drug, biological product, or device
and who submits covered clinical studies. The applicant is responsible
for making the appropriate certification or disclosure statement where
the applicant either contracted with one or more clinical investigators
to conduct the studies or submitted studies conducted by others not
under contract to the applicant.
Sec. 54.4 Certification and disclosure requirements.
For purposes of this part, an applicant must submit a list of all
clinical investigators who conducted covered clinical studies to
determine whether the applicant's product meets FDA's marketing
requirements, identifying those clinical investigators who are full-
time or part-time employees of the sponsor of each covered study. The
applicant must also completely and accurately disclose or certify
information concerning the financial interests of a clinical
investigator who is not a full-time or part-time employee of the
sponsor for each covered clinical study. Clinical investigators subject
to investigational new drug or investigational device exemption
regulations must provide the sponsor of the study with sufficient
accurate information needed to allow subsequent disclosure or
certification. The applicant is required to submit for each clinical
investigator who participates in a covered study, either a
certification that none of the financial arrangements described in
Sec. 54.2 exist, or disclose the nature of those arrangements to the
agency. Where the applicant acts with due diligence to obtain the
information required in this section but is unable to do so, the
applicant shall certify that despite the applicant's due diligence in
attempting to obtain the information, the applicant was unable to
obtain the information and shall include the reason.
(a) The applicant (of an application submitted under sections 505,
506, 507, 519(k), 513, or 515 of the Federal Food, Drug, and Cosmetic
Act, or section 351 of the Public Health Service Act) that relies in
whole or in part on clinical studies shall submit, for each clinical
investigator who participated in a covered clinical study, either a
certification described in paragraph (a)(1) of this section or a
disclosure statement described in paragraph (a)(3) of this section.
(1) Certification: The applicant covered by this section shall
submit for all clinical investigators (as defined in Sec. 54.2(d)), to
whom the certification applies, a completed Form FDA 3454 attesting to
the absence of financial interests and arrangements described in
paragraph (a)(3) of this section. The form shall be dated and signed by
the chief financial officer or other responsible corporate official or
representative.
(2) If the certification covers less than all covered clinical data
in the application, the applicant shall include in the certification a
list of the studies covered by this certification.
(3) Disclosure Statement: For any clinical investigator defined in
Sec. 54.2(d) for whom the applicant does not submit the certification
described in paragraph (a)(1) of this section, the applicant shall
submit a completed Form FDA 3455 disclosing completely and accurately
the following:
(i) Any financial arrangement entered into between the sponsor of
the covered study and the clinical investigator involved in the conduct
of a covered clinical trial, whereby the value of the compensation to
the clinical investigator for conducting the study could be influenced
by the outcome of the study;
(ii) Any significant payments of other sorts from the sponsor of
the covered study, such as a grant to fund ongoing research,
compensation in the form of equipment, retainer for ongoing
consultation, or honoraria;
(iii) Any proprietary interest in the tested product held by any
clinical investigator involved in a study;
(iv) Any significant equity interest in the sponsor of the covered
study held by any clinical investigator involved in any clinical study;
and
(v) Any steps taken to minimize the potential for bias resulting
from any of the disclosed arrangements, interests, or payments.
(b) The clinical investigator shall provide to the sponsor of the
covered study sufficient accurate financial information to allow the
sponsor to submit complete and accurate certification or disclosure
statements as required in paragraph (a) of this section. The
investigator shall promptly update this information if any relevant
changes occur in the course of the investigation or for 1 year
following completion of the study.
(c) Refusal to file application. FDA may refuse to file any
marketing application described in paragraph (a) of this section that
does not contain the information required by this section or a
certification by the applicant that the applicant has acted with due
diligence to obtain the information but was unable to do so and stating
the reason.
Sec. 54.5 Agency evaluation of financial interests.
(a) Evaluation of disclosure statement. FDA will evaluate the
information disclosed under Sec. 54.4(a)(2) about each covered clinical
study in an application to determine the impact of any disclosed
financial interests on the reliability of the study. FDA may consider
both the size and nature of a disclosed financial interest (including
the potential increase in the value of the interest if the product is
approved) and steps that have been taken to minimize the potential for
bias.
(b) Effect of study design. In assessing the potential of an
investigator's financial interests to bias a study, FDA will take into
account the design and purpose of the study. Study designs that utilize
such approaches as multiple investigators (most of whom do not have a
disclosable interest), blinding, objective endpoints, or measurement of
endpoints by someone other than the investigator may adequately protect
against any bias created by a disclosable financial interest.
(c) Agency actions to ensure reliability of data. If FDA determines
that the financial interests of any clinical investigator raise a
serious question about the integrity of the data, FDA will take any
action it deems necessary to ensure the reliability of the data
including:
(1) Initiating agency audits of the data derived from the clinical
investigator in question;
(2) Requesting that the applicant submit further analyses of data,
e.g., to evaluate the effect of the clinical investigator's data on
overall study outcome;
(3) Requesting that the applicant conduct additional independent
studies to confirm the results of the questioned study; and
(4) Refusing to treat the covered clinical study as providing data
that can be the basis for an agency action.
Sec. 54.6 Recordkeeping and record retention.
(a) Financial records of clinical investigators to be retained. An
applicant who has submitted a marketing application containing covered
clinical studies shall keep on file certain information pertaining to
the financial interests of clinical investigators who conducted studies
on which the application relies and who are not full or part-time
employees of the applicant, as follows:
[[Page 5252]]
(1) Complete records showing any financial interest or arrangement
as described in Sec. 54.4(a)(3)(i) paid to such clinical investigators
by the sponsor of the covered study.
(2) Complete records showing significant payments of other sorts,
as described in Sec. 54.4(a)(3)(ii), made by the sponsor of the covered
clinical study to the clinical investigator.
(3) Complete records showing any financial interests held by
clinical investigators as set forth in Sec. 54.4(a)(3)(iii) and
(a)(3)(iv).
(b) Requirements for maintenance of clinical investigators'
financial records.
(1) For any application submitted for a covered product, an
applicant shall retain records as described in paragraph (a) of this
section for 2 years after the date of approval of the application.
(2) The person maintaining these records shall, upon request from
any properly authorized officer or employee of FDA, at reasonable
times, permit such officer or employee to have access to and copy and
verify these records.
PART 312--INVESTIGATIONAL NEW DRUG APPLICATION
2. The authority citation for 21 CFR part 312 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357,
371; 42 U.S.C. 262.
3. Section 312.53 is amended by adding new paragraph (c)(4) to read
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 sponsor shall obtain a commitment from the clinical
investigator to promptly update this information if any relevant
changes occur during the course of the investigation and for 1 year
following the completion of the study.
* * * * *
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
any financial interest in Sec. 54.4(a)(3)(i), (a)(3)(ii), (a)(3)(iii),
and (a)(3)(iv) of this chapter paid to clinical investigators by the
sponsor of the covered study. 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 clinical investigator shall
provide the sponsor with sufficient accurate financial information to
allow an applicant to submit complete and accurate certification or
disclosure statements as required under part 54 of this chapter. The
clinical investigator shall promptly update this information if any
relevant changes occur during the course of the investigation and for 1
year following the completion of the study.
PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG OR AN
ANTIBIOTIC DRUG
6. The authority citation for 21 CFR part 314 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357,
371, 374, 379e.
7. Section 314.50 is amended by redesignating paragraph (k) as
paragraph (l) and by adding new paragraph (k) to read as follows:
Sec. 314.50 Content and format of an application.
* * * * *
(k) Financial certification or disclosure statement. The
application shall contain a financial certification or disclosure
statement or both 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 or both as required by part 54 of this chapter, or
FDA may refuse to accept any such amendment.
* * * * *
9. Section 314.94 is amended by adding new paragraph (a)(13) to
read as follows:
Sec. 314.94 Content and format of an abbreviated application.
* * * * *
(a) * * *
(13) Financial certification or disclosure statement. An
abbreviated application shall contain a financial certification or
disclosure statement as required by part 54 of this chapter.
* * * * *
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 or both
as required by part 54 of this chapter must accompany all clinical data
submitted. * * *
* * * * *
11. Section 314.300 is amended in the introductory text of
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 or both
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: 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 from which the data 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
[[Page 5253]]
required under part 54 of this chapter and shall 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 of the
application. The person maintaining these records shall, upon request
for any properly authorized officer or employee of the Food and Drug
Administration, at reasonable time, 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: 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 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 or both as 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: 21 U.S.C. 321, 351, 352, 353, 355, 360, 360c-360f,
360h-360j, 371, 374, 379e, 381; 42 U.S.C. 216, 241, 262, 263; 15
U.S.C. 1451-1461.
17. The introductory test of section 601.2 is amended in the
introductory text of 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(s) or both for clinical
investigators 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: 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 and disclosure statements 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 redesignating paragraphs (i)
through (k) as paragraphs (j) through (l), respectively, and by adding
a new paragraph (i) to read as follows:
Sec. 807.87 Information required in a premarket notification
submission.
* * * * *
(i) A financial certification or disclosure statement or both, as
required by part 54 of this chapter.
* * * * *
21. Section 807.100 is amended by redesignating paragraph (a)(4) as
paragraph (a)(5) and by 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 under 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: 21 U.S.C. 331, 351, 352, 353, 355, 356, 357, 360,
360c-360f, 360h-360j, 371, 372, 374, 379e, 381, 382, 383; 42 U.S.C.
216, 241, 262, 263b-263n.
23. Section 812.43 is amended by adding new paragraph (c)(5) to
read as follows:
Sec. 812.43 Selecting investigators and monitors.
* * * * *
(c) * * *
(5) Sufficient accurate financial disclosure information to allow
the sponsor to submit a complete and accurate certification or
disclosure statement as required under part 54 of this chapter. The
sponsor shall obtain a commitment from the clinical investigator to
promptly update this information if any relevant changes occur during
the course of the investigation and for 1 year following completion of
the study. This information shall not be submitted in an
investigational device exemption application, but shall be submitted in
any marketing application involving the device.
* * * * *
24. Section 812.110 is amended by redesignating paragraph (d) as
paragraph (e) and adding new paragraph (d) to read as follows:
Sec. 812.110 Specific responsibilities of investigators.
* * * * *
(d) Financial disclosure. A clinical investigator shall disclose to
the sponsor sufficient accurate financial information to allow the
applicant 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 and for 1 year following
completion of the study.
* * * * *
25. Section 812.140 is amended by revising paragraph (b)(3) to read
as follows:
Sec. 812.140 Records.
* * * * *
(b) * * *
(3) Signed investigator agreements including the financial
disclosure information required to be collected under Sec. 812.43(c)(5)
in accordance with part 54 of this chapter.
* * * * *
PART 814--PREMARKET APPROVAL OF MEDICAL DEVICES
26. The authority citation for 21 CFR part 814 continues to read as
follows:
Authority: 21 U.S.C. 351, 352, 353, 360, 360c-360j, 371, 372,
373, 374, 375, 379, 379e, 381.
27. Section 814.20 is amended by redesignating paragraph (b)(12) as
paragraph (b)(13) and adding new paragraph (b)(12) to read as follows:
Sec. 814.20 Application.
* * * * *
(b) * * *
(12) A financial certification or disclosure statement or both as
required by part 54 of this chapter.
* * * * *
28. Section 814.42 is amended by adding new paragraph (e)(5) to
read as follows:
[[Page 5254]]
Sec. 814.42 Filing a PMA.
* * * * *
(e) * * *
(5) The PMA is not accompanied by a statement of either
certification or disclosure as required by part 54 of this chapter.
29. Section 814.112 is amended by adding new paragraph (a)(4) to
read as follows:
Sec. 814.112 Filing an HDE.
(a) * * *
(4) The HDE is not accompanied by a statement of either
certification or disclosure, or both, as required by part 54 of this
chapter.
* * * * *
PART 860--MEDICAL DEVICE CLASSIFICATION PROCEDURES
30. The authority citation for 21 CFR part 860 continues to read as
follows:
Authority: 21 U.S.C. 360c, 360d, 360e, 360i, 360j, 371, 374.
31. Section 860.123 is amended by adding new paragraph (a)(10) to
read as follows:
Sec. 860.123 Reclassification petition: Content and form.
(a) * * *
(10) A financial certification or disclosure statement or both as
required by part 54 of this chapter.
* * * * *
Dated: October 15, 1997.
Michael A. Friedman,
Lead Deputy Commissioner for the Food and Drug Administration.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 98-2407 Filed 1-30-98; 8:45 am]
BILLING CODE 4160-01-F