[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

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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

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[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