Federal Register, Volume 76 Issue 71 (Wednesday, April 13, 2011)

[Federal Register Volume 76, Number 71 (Wednesday, April 13, 2011)]
[Proposed Rules]
[Pages 20575-20588]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2011-8786]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 16, 312, 511, and 812

[Docket No. FDA-2011-N-0079]
RIN 0910-AG49

Disqualification of a Clinical Investigator

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
the regulations to expand the scope of clinical investigator
disqualification. Under this proposal, when the Commissioner of Food
and Drugs determines that an investigator is

[[Page 20576]]

ineligible to receive certain test articles (drugs, devices, or new
animal drugs), the investigator also will be ineligible to conduct any
clinical investigation that supports an application for a research or
marketing permit for products regulated by FDA. This proposal is based
in part upon recommendations from the Government Accountability Office,
and is intended to help ensure adequate protection of research subjects
and the quality and integrity of data submitted to FDA. FDA also is
amending the list of regulatory provisions under which an informal
regulatory hearing is available by changing the scope of certain
provisions and adding regulatory provisions that were inadvertently
omitted.

DATES: Submit either electronic or written comments on the proposed
rule by July 12, 2011. See section VII of this document for the
proposed effective date of a final rule based on this document.

ADDRESSES: You may submit comments, identified by Docket No. FDA-2011-
N-0079 and/or RIN number 0910-AG49, by any of the following methods:

Electronic Submissions

Submit electronic comments in the following way:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.

Written Submissions

Submit written submissions in the following ways:
FAX: 301-827-6870.
Mail/Hand delivery/Courier (for paper, disk, or CD-ROM
submissions): Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
Instructions: All submissions received must include the Agency name
and Docket No. FDA-2011-N-0079 and Regulatory Information Number (RIN)
for this rulemaking. All comments received may be posted without change
to http://www.regulations.gov, including any personal information
provided. For additional information on submitting comments, see the
``Comments'' heading of the SUPPLEMENTARY INFORMATION section of this
document.
Docket: For access to the docket to read background documents or
comments received, go to http://www.regulations.gov and insert the
docket number, found in brackets in the heading of this document, into
the ``Search'' box and follow the prompts and/or go to the Division of
Dockets Management, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Kathleen E. Pfaender, Office of Good
Clinical Practice, Food and Drug Administration, 10903 New Hampshire
Ave., Bldg. 32, rm. 5129, Silver Spring, MD 20993, 301-796-8340.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Introduction
II. Background
III. Description of the Proposed Rule
A. Disqualification Proceedings (Sec. Sec. 312.70(a),
511.1(c)(1), and 812.119(a))
B. Ineligibility To Receive Any Test Article (Sec. Sec.
312.70(b), 511.1(c)(2), and 812.119(b))
C. Disqualified Investigator's Data in Applications and
Submissions to FDA (Sec. Sec. 312.70(c), 511.1(c)(3), and
812.119(c))
D. Disqualified Investigator's Data in Applications and
Submissions to FDA--Sponsor Notification, Opportunities, and
Responsibilities (Sec. Sec. 312.70(d), 511.1(c)(4), and 812.119(d))
E. Disqualified Investigator's Data in Applications and
Submissions to FDA--Withdrawal of Product Approval (Sec. Sec.
312.70(e), 511.1(c)(5), and 812.119(e))
F. Other Proceedings
G. Reinstatement (Sec. Sec. 312.70(f), 511.1(c)(6), and
812.119(f))
H. Part 511 Definitions (Sec. 511.3)
IV. Regulatory Hearing Before the Food and Drug Administration
V. Environmental Impact
VI. Legal Authority
VII. Proposed Implementation Plan
VIII. Analysis of Impacts
A. Objective
B. Background
C. Baseline
D. Costs of the Proposed Rule
E. Benefit
F. Alternatives
G. Small Business Impact
IX. Paperwork Reduction Act of 1995
X. Federalism
XI. Request for Comments
XII. References

I. Introduction

Under current regulations, a clinical investigator disqualified by
the Commissioner of Food and Drugs (the Commissioner) is ineligible to
receive a particular type of FDA-regulated test article only; i.e.,
drugs (including biologics) in Sec. 312.70 (21 CFR 312.70); new animal
drugs in Sec. 511.1(c) (21 CFR 511.1(c)); or devices in Sec. 812.119
(21 CFR 812.119). The proposed rulemaking will amend Sec. Sec. 312.70,
511.1(c), and 812.119 to provide that when the Commissioner determines
that a clinical investigator is ineligible to receive the test article
under that provision (e.g., drugs in Sec. 312.70), the clinical
investigator also will be ineligible to conduct any clinical
investigation that supports an application for a research or marketing
permit for products regulated by FDA, including drugs, biologics,
devices, new animal drugs, foods, including dietary supplements, that
bear a nutrient content claim or a health claim, infant formulas, food
and color additives, and tobacco products.
Other proposed revisions are intended to clarify and harmonize the
clinical investigator disqualification regulations in parts 312, 511,
and 812 (21 CFR parts 312, 511, and 812). FDA proposes this rulemaking
to help protect the rights and safety of subjects involved in FDA-
regulated investigations and to help ensure the reliability and
integrity of the data used to support marketing of products regulated
by FDA.

II. Background

FDA inspects the records of a clinical investigator to evaluate the
quality and integrity of clinical data used to support applications
under review by FDA and to evaluate whether protections are afforded to
participating research subjects, where required. FDA may consider
disqualification of a clinical investigator when FDA has information
that an investigator has repeatedly or deliberately failed to comply
with applicable requirements for the conduct of clinical
investigations, or has repeatedly or deliberately submitted to FDA or
to the sponsor false information in any required report.
Disqualification of an investigator is initiated by the appropriate
FDA Center depending upon the particular type of test article under
study by the investigator in the clinical investigation. For example,
the Center for Devices and Radiological Health may pursue
disqualification of a clinical investigator who conducted a device
study and allegedly violated the regulations. The regulations provide
the investigator, who is subject to disqualification, an opportunity to
be heard and explain the matter(s) complained of; i.e., explain the
alleged violation(s). If the explanation offered is not accepted by the
Center, the investigator will be given an opportunity for an informal
regulatory hearing under part 16 (21 CFR part 16). After evaluating all
available information, including any explanation presented by the
investigator, the Commissioner issues a Commissioner's decision
regarding the eligibility of the investigator to receive a particular
type of test article. When disqualified by a Commissioner's decision,
the investigator is no longer eligible to receive the particular type
of test article (drugs, devices, or new animal drugs) under study when
the violations occurred. Under current regulations, an

[[Page 20577]]

investigator disqualified by a Commissioner's decision as ineligible to
receive investigational devices, for example, may still be eligible to
receive investigational drugs (including biologics), because the
regulations do not specifically prohibit such an investigator from
receiving other types of test articles.
In September 2009, the Government Accountability Office (GAO)
released a final report on FDA's oversight of clinical investigators
(Ref. 1). In that report, the GAO recommended, among other things, that
FDA extend disqualification by a Commissioner's decision to include
ineligibility to receive drugs, biologics, and medical devices. The GAO
noted that FDA's disqualification regulations are included in separate
sets of regulations and, as a result, the regulations as currently
written limit the types of test articles to which disqualification
applies and consequently, limits FDA's oversight of clinical
investigators (Ref. 1 at page 40, under ``FDA's Regulations Allow
Disqualified Clinical Investigators to Conduct Trials for Other Medical
Products''). The GAO elaborated, comparing disqualifications that
resulted from a Commissioner's decision with those resulting from a
consent agreement between FDA and the investigator. That is, a consent
agreement may contain ``more extensive restrictions by disqualifying
the investigator from receiving any FDA-regulated investigational
products (including drugs, biologics, devices, animal drugs, and food
additives)'' (Ref. 1 at page 41). The GAO concluded that it is critical
for FDA to take action and to have the authority to take action to
prevent clinical investigators who engaged in serious misconduct from
doing so again, whether in research that involves drugs, biologics, or
devices (Ref. 1 at page 42).
In past investigator disqualification actions, there is little, if
any, evidence that an investigator disqualified from receiving one type
of test article (e.g., drugs) later conducted a clinical investigation
studying a different type of test article (e.g., devices). Even so, FDA
agrees with the GAO's recommendation and its underlying rationale to
expand the scope of articles covered when an investigator is
disqualified by a Commissioner's decision. This proposed action of
explicitly extending a disqualified investigator's ineligibility to
receive any FDA-regulated test article would help to reduce the risk of
additional violations in other FDA-regulated investigations and thus,
would help to ensure the integrity of clinical trial data and help
reduce the risk to human subjects who participate in FDA-regulated
investigations. This proposed rule may also lead to improved public
confidence in the clinical data supporting FDA decisions.
We therefore propose that a clinical investigator disqualified by a
Commissioner's decision will be ineligible to receive any test article
under the disqualification regulations in parts 312, 511, or 812, and,
in addition, the investigator will be ineligible to conduct any
clinical investigation that supports an application for a research or
marketing permit for products regulated by FDA. Those products include
drugs, biologics, devices, new animal drugs, foods, including dietary
supplements, that bear a nutrient content claim or a health claim,
infant formulas, food and color additives, and tobacco products. To
effect this change, FDA proposes to amend the current regulations in
Sec. Sec. 312.70, 511.1(c), and 812.119.

III. Description of the Proposed Rule

To harmonize the headings for the clinical investigator
disqualification regulations in parts 312, 511, and 812, FDA proposes
to change the heading in Sec. 511.1(c) to match those currently in
Sec. Sec. 312.70 and 812.119. Therefore, we propose to change the
heading in Sec. 511.1(c) from ``Withdrawal of eligibility to receive
investigational-use new animal drugs'' to ``Disqualification of a
clinical investigator''. This revision will help to identify the
investigator disqualification regulations pertaining to new animal
drugs.

A. Disqualification Proceedings (Sec. Sec. 312.70(a), 511.1(c)(1), and
812.119(a))

FDA proposes to revise the provisions currently in Sec. Sec.
312.70(a), 511.1(c)(1), and 812.119(a), to clarify, simplify, and to
harmonize those provisions. Also, for consistency with other proposed
changes to the disqualification regulations, FDA proposes to change the
scope of the question addressed during a part 16 hearing, should the
investigator request and be granted an informal regulatory hearing.
1. Proposed Revisions to Sec. 312.70(a)
To harmonize the provisions in Sec. 312.70(a) with those
currently in Sec. 812.119(a), we propose to add ``repeatedly or
deliberately'' before the reference to submitting false information in
any required report. The addition of ``repeatedly or deliberately''
before ``submitted to FDA or to the sponsor false information in any
required report,'' codifies FDA's current policies and makes consistent
the clinical investigator disqualification regulations.
To harmonize the provisions in Sec. 312.70(a) with those
currently in Sec. 812.119(a), we propose to add a provision for
accepting an investigator's explanation concerning the alleged
misconduct. That is, if the investigator offers an explanation in
writing or during an informal conference and the explanation is
accepted by the applicable Center, the Center will discontinue pursuit
of the disqualification proceeding. This proposed revision clarifies
FDA's current policies and makes consistent the clinical investigator
disqualification regulations.
To simplify the regulations, we propose to change ``Center
for Drug Evaluation and Research or the Center for Biologics Evaluation
and Research'' to ``applicable Center'' after ``If an explanation is
offered but not accepted by the * * *''.
We propose to add ``of this chapter'' after ``the
investigator will be given an opportunity for a regulatory hearing
under part 16 * * *'', for clarity and to harmonize Sec. 312.70(a)
with the provisions currently in Sec. 812.119(a).
Regarding the question of whether the investigator is
entitled to receive test articles, we propose to change ``entitled'' to
``eligible'' because ``eligible'' is the correct term for this
provision.
We propose to change the scope of the question addressed
during a part 16 hearing, should the investigator request and be
granted an informal hearing, from whether the investigator is eligible
to receive ``investigational new drugs'' to whether the investigator is
eligible to receive ``test articles under this part and eligible to
conduct any clinical investigation that supports an application for a
research or marketing permit for products regulated by FDA''. Those
FDA-regulated products include drugs, biologics, devices, new animal
drugs, foods, including dietary supplements, that bear a nutrient
content claim or a health claim, infant formulas, food and color
additives, and tobacco products.
2. Proposed Revisions to Sec. 511.1(c)(1)
To harmonize the investigator disqualification
regulations, we propose to change the first words in the first sentence
in Sec. 511.1(c)(1) from ``Whenever the Food and Drug Administration''
to ``If FDA''.
Although already applicable, we propose to add explicit
provisions in Sec. 511.1(c)(1), consistent with the current
regulations in Sec. 312.70(a), that a clinical investigator includes a
sponsor-investigator. Because sponsor-

[[Page 20578]]

investigators must meet an investigator's regulatory responsibilities
as well as a sponsor's, FDA has consistently considered sponsor-
investigators to be subject to the clinical investigator
disqualification provisions in studies of drugs, animal drugs, and
devices.\1\
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\1\ See, for example, the final rule at 62 FR 46875, September
5, 1997; clarifying FDA's authority to reach sponsor-investigators
under the regulations for disqualification of a clinical
investigator.
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To harmonize the provisions in Sec. 511.1(c)(1) with the
provisions currently in Sec. 812.119(a), we propose to add
``repeatedly or deliberately'' before the reference to submitting false
information in any required report. The addition of ``repeatedly or
deliberately'' codifies FDA's current policies and makes consistent the
clinical investigator disqualification regulations.
To make the investigator disqualification regulations
consistent, we propose to change the wording of the first sentence in
Sec. 511.1(c)(1) to read as follows, ``If FDA has information
indicating that an investigator (including a sponsor-investigator) has
repeatedly or deliberately failed to comply with the conditions of
these exempting regulations or has repeatedly or deliberately submitted
to FDA or to the sponsor false information in any required report, the
Center for Veterinary Medicine will furnish the investigator written
notice of the matter complained of and offer the investigator an
opportunity to explain the matter in writing, or, at the option of the
investigator, in an informal conference.'' For this first sentence,
this proposal removes the reference to ``in general terms'' concerning
the Center's written notice of the matter to the investigator. This
proposal also replaces offering ``him'' with offering ``the
investigator'' an opportunity to explain. At the end of this first
sentence, the wording is changed from ``in an informal conference and/
or in writing'' to ``in writing, or, at the option of the investigator,
in an informal conference.''
To harmonize the provisions in Sec. 511.1(c)(1) with
those currently in Sec. 812.119(a), we propose to add a provision for
accepting an investigator's explanation concerning the alleged
misconduct. That is, if the investigator offers an explanation in
writing or during an informal conference and the explanation is
accepted by the affected Center, the Center will discontinue pursuit of
the disqualification proceeding. This proposed revision clarifies FDA's
current policies and makes consistent the clinical investigator
disqualification regulations.
For consistency with the regulations currently in
Sec. Sec. 312.70(a) and 812.119(a), we propose to change in the second
sentence in Sec. 511.1(c)(1) (the third sentence in this proposal),
``shall have'' to ``will be given'', and remove after ``an opportunity
for a regulatory hearing * * *'' the clause, ``before the Food and Drug
Administration pursuant to * * *'' Also, in this sentence, we propose
to change the term ``entitled'' to the term ``eligible''.
We propose to change the scope of the question addressed
during a part 16 hearing, should the investigator request and be
granted an informal hearing, from whether the investigator is eligible
to receive ``investigational new animal drugs'' to whether the
investigator is eligible to receive ``test articles under this part and
eligible to conduct any clinical investigation that supports an
application for a research or marketing permit for products regulated
by FDA''. Those FDA-regulated products include drugs, biologics,
devices, new animal drugs, foods, including dietary supplements, that
bear a nutrient content claim or a health claim, infant formulas, food
and color additives, and tobacco products.
3. Proposed Revisions to Sec. 812.119(a)
Although already applicable, we propose to add explicit
provisions in Sec. 812.119(a), consistent with the current regulations
in Sec. 312.70(a), that a clinical investigator includes a sponsor-
investigator. Because sponsor-investigators must meet an investigator's
regulatory responsibilities as well as a sponsor's, FDA has
consistently considered sponsor-investigators to be subject to the
clinical investigator disqualification provisions in studies of drugs,
animal drugs, and devices.\2\
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\2\ See, for example, the final rule at 62 FR 46875, September
5, 1997; clarifying FDA's authority to reach sponsor-investigators
under the regulations for disqualification of a clinical
investigator.
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To harmonize the provisions in Sec. 812.119(a) with those
currently in Sec. 312.70(a), we propose to change after repeatedly or
deliberately submitted ``false information either to the sponsor of the
investigation or * * *'', to read instead, ``to FDA or to the sponsor
false information in any required report, * * *''
To harmonize the provisions in Sec. 812.119(a) with those
currently in Sec. 312.70(a), we propose to change the matter ``under
complaint'' to the matter ``complained of''.
For clarity and consistency with our current procedures
and the proposed changes to Sec. Sec. 312.70(a) and 511.1(c)(1), we
propose to change the language in Sec. 812.119(a) from ``the
disqualification process will be terminated'' to ``the Center will
discontinue pursuit of the disqualification proceeding.''
For consistency with the proposed revisions to Sec. Sec.
312.70(a) and 511.1(c)(1), we propose to add ``applicable'' before
``Center'' to read, ``If an explanation is offered but not accepted by
the applicable Center''.
Regarding the question of whether the investigator is
entitled to receive test articles, we propose to change the term
``entitled'' to ``eligible''.
We propose to change the scope of the question addressed
during a part 16 hearing, should the investigator request and be
granted an informal hearing, from whether the investigator is eligible
to receive investigational devices to whether the investigator is
eligible to receive ``test articles under this part and eligible to
conduct any clinical investigation that supports an application for a
research or marketing permit for products regulated by FDA''. Those
FDA-regulated products include drugs, biologics, devices, new animal
drugs, foods, including dietary supplements, that bear a nutrient
content claim or a health claim, infant formulas, food and color
additives, and tobacco products.
In summary, the proposed harmonized provisions in Sec. Sec.
312.70(a), 511.1(c)(1), and 812.119(a) provide that when FDA has
information indicating that a clinical investigator, including a
sponsor-investigator, has repeatedly or deliberately failed to comply
with the relevant regulatory requirements or has repeatedly or
deliberately submitted to FDA or to the sponsor of the investigation
false information in any required report, the applicable FDA Center
notifies the investigator in writing of the alleged violations. This
written notice offers the investigator an opportunity to explain the
matter in writing, or, at the option of the investigator, during an
informal conference. If the investigator offers an explanation that is
accepted by the applicable Center, that Center will discontinue pursuit
of the disqualification proceeding. If, however, the investigator
offers an explanation not accepted by the applicable Center, the
investigator will be offered an opportunity to request an informal
regulatory hearing \3\ under part 16 \4\ on the question of whether the
investigator is eligible to receive test articles under

[[Page 20579]]

the applicable part and eligible to conduct any clinical investigation
that supports an application for a research or marketing permit for
products regulated by FDA. Those FDA-regulated products include drugs,
biologics, devices, new animal drugs, foods, including dietary
supplements, that bear a nutrient content claim or a health claim,
infant formulas, food and color additives, and tobacco products.
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\3\ FDA issues to the investigator a ``Notice of Opportunity for
Hearing''. The investigator must show that there is a genuine and
substantial issue of fact that warrants a hearing (Sec. 16.26(a)).
\4\ See part 16, subpart D--Procedures for Regulatory Hearing.
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B. Ineligibility To Receive Any Test Article (Sec. Sec. 312.70(b),
511.1(c)(2), and 812.119(b))

1. Proposed Revisions to Sec. 312.70(b)
For consistency, we propose to refer to ``repeatedly or
deliberately'' in the same order throughout the provision.
For clarity, we propose to move after ``submitted'' the
clause, ``to FDA or to the sponsor''. Therefore, the proposed provision
reads, ``or has repeatedly or deliberately submitted to FDA or to the
sponsor false information in any required report, * * *''.
We propose to add a notification to the reviewing
institutional review board(s) (IRB(s)) about the investigator's
disqualification. This proposed change will harmonize Sec. 312.70(b)
with FDA's current procedures along with those provisions currently in
Sec. 812.119(b). IRBs play a significant role in ensuring that
clinical investigators meet the applicable statutory and regulatory
requirements.\5\ We therefore propose to add this provision in Sec.
312.70(b) to help ensure that any reviewing IRB is aware of the
clinical investigator's disqualification.
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\5\ 63 FR 55873 at 55874, October 19, 1998.
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We propose to change ``entitled'' to ``eligible''.
FDA proposes to harmonize the disqualification regulations
by changing the investigator's ineligibility from receiving
``investigational drugs'' to ineligibility to receive ``test articles
under this part.'' We are also proposing that an investigator
disqualified by a Commissioner's decision also will be ineligible to
conduct any clinical investigation that supports an application for a
research or marketing permit for products regulated by FDA, including
drugs, biologics, devices, new animal drugs, foods, including dietary
supplements, that bear a nutrient content claim or a health claim,
infant formulas, food and color additives, and tobacco products.
For clarity and consistency with our procedures, we
propose to add an explicit reference concerning notification by FDA
about the investigator's disqualification. That is, the investigator
and sponsor will be notified about the basis for the disqualification
determination. The notification to the sponsor, for example, will
provide a statement of the basis for disqualification such as a list of
the investigator's violations, and also include instructions concerning
ongoing studies and any approved products containing the investigator's
data.
For consistency with our procedures, we propose to add
that the reviewing IRB(s) also will be notified about the basis for the
disqualification determination.
2. Proposed Revisions to Sec. 511.1(c)(2)
To harmonize the investigator disqualification regulations
in Sec. 511.1(c)(2) with those currently in Sec. Sec. 312.70(b) and
812.119(b), we propose to change the first word ``If'' in Sec.
511.1(c)(2) to read instead, ``After evaluating all available
information, including any explanation presented by the investigator,
if the Commissioner determines that * * *''.
We propose to change the term ``section'' to
``subchapter''. The disqualification action is pursuant to the
investigator's failure to comply with the conditions of the exempting
regulations in subchapter E (21 CFR chapter I, subchapter E)--Animal
drugs, feeds, and related products. Therefore, we propose ``this
subchapter'' is the applicable and correct term as opposed to the
narrower reference currently in Sec. 511.1(c)(2) to ``this section''.
For clarity and to harmonize Sec. 511.1(c)(2) with the
proposed investigator disqualification regulations in Sec. Sec.
312.70(b) and 812.119(b), we propose to move and modify the clause ``to
the sponsor of an investigation'' and add ``to FDA'' and ``in any
required report'', to read, ``or has repeatedly or deliberately
submitted to FDA or to the sponsor false information in any required
report, * * *''.
For clarity and to harmonize the investigator
disqualification regulations, we propose to change ``he'' to ``the
investigator''.
We propose to change ``entitled'' to ``eligible''.
FDA proposes to harmonize the disqualification regulations
by changing the investigator's ineligibility from receiving
``investigational use new animal drugs'' to ineligibility to receive
``test articles under this part.'' We are also proposing that an
investigator disqualified by a Commissioner's decision also will be
ineligible to conduct any clinical investigation that supports an
application for a research or marketing permit for products regulated
by FDA, including drugs, biologics, devices, new animal drugs, foods,
including dietary supplements, that bear a nutrient content claim or a
health claim, infant formulas, food and color additives, and tobacco
products.
For clarity and consistency with our procedures, we
propose to add an explicit reference concerning notification by FDA
about the investigator's disqualification. That is, the investigator
and sponsor will be notified about the basis for the disqualification
determination. The notification to the sponsor, for example, will
provide a statement of the basis for disqualification such as a list of
the investigator's violations, and also include instructions concerning
ongoing studies and any approved products containing the investigator's
data.
3. Proposed Revisions to Sec. 812.119(b)
For consistency, we propose to refer to ``repeatedly or
deliberately'' in the same order throughout the provision.
For clarity and to harmonize Sec. 812.119(b) with the
proposed investigator disqualification regulations in Sec. Sec.
312.70(b) and 511.1(c)(2), we propose to move and modify the clause
``to the sponsor of an investigation'', add ``to FDA'', and remove
``either'', to read, ``or has repeatedly or deliberately submitted to
FDA or to the sponsor false information in any required report, * *
*''.
We propose to change ``entitled'' to ``eligible''.
FDA proposes to harmonize the disqualification regulations
by changing the investigator's ineligibility from receiving
``investigational devices'' to ineligibility to receive ``test articles
under this part.'' We are also proposing that an investigator
disqualified by a Commissioner's decision also will be ineligible to
conduct any clinical investigation that supports an application for a
research or marketing permit for products regulated by FDA, including
drugs, biologics, devices, new animal drugs, foods, including dietary
supplements, that bear a nutrient content claim or a health claim,
infant formulas, food and color additives, and tobacco products.
For clarity and consistency with our procedures, we
propose to add an explicit reference concerning notification by FDA
about the investigator's disqualification. That is, the investigator,
sponsor, and reviewing IRB(s) will be notified about the basis for the
disqualification determination. The notification to the sponsor, for
example, will provide a statement of the basis for disqualification
such as a list of the investigator's violations, and also include
instructions concerning ongoing

[[Page 20580]]

studies and any approved or cleared products containing the
investigator's data.
Therefore, as proposed, an investigator determined to be ineligible
to receive test articles under one part of FDA's regulations also would
be ineligible to conduct any clinical investigation that supports an
application for a research or marketing permit for products regulated
by FDA, including drugs, biologics, devices, new animal drugs, foods,
including dietary supplements, that bear a nutrient content claim or a
health claim, infant formulas, food and color additives, and tobacco
products. This proposal is consistent with the underlying rationale for
disqualifying a clinical investigator, which is to preserve the
integrity of study data and to help ensure the safety, rights, and
welfare of study subjects. As proposed, those principles would apply to
all test articles and studies; an investigator who is determined to
have repeatedly or deliberately violated the regulations while
conducting a study of a particular type of test article sufficient to
warrant disqualification would thus be ineligible to receive any FDA-
regulated test article or conduct any clinical investigation that
supports an application for a research or marketing permit for products
regulated by FDA.

C. Disqualified Investigator's Data in Applications and Submissions to
FDA (Sec. Sec. 312.70(c), 511.1(c)(3), and 812.119(c))

1. Proposed Revisions to Sec. 312.70(c)
Currently, Sec. 312.70(c) provides, ``Each IND and each approved
application submitted under part 314 containing data reported by an
investigator who has been determined to be ineligible to receive
investigational drugs will be examined to determine whether the
investigator has submitted unreliable data that are essential to the
continuation of the investigation or essential to the approval of any
marketing application.'' FDA proposes to revise the current regulations
in Sec. 312.70(c) to clarify the applicability of this provision,
update this provision consistent with Sec. Sec. 312.70(b),
511.1(c)(2), and 812.119(b) of this proposal, and to harmonize the
disqualification regulations in Sec. Sec. 312.70(c), 511.1(c)(3), and
812.119(c). Therefore, we propose to amend Sec. 312.70(c) to change
``Each IND and each approved application submitted under part 314'' to
``Each application or submission to FDA under the provisions of this
chapter''. The ``provisions of this chapter'' refers to chapter I and
includes INDs and approved applications submitted under part 314. Also,
we propose to change ``drugs'' to ``FDA-regulated test articles'';
``continuation of the investigation'' to ``continuation of any
investigation''; and add after ``essential to the approval of any
marketing application'' the phrase ``essential to the continued
marketing of an FDA-regulated product.''
2. Proposed Revisions to Sec. 511.1(c)(3)
Currently, Sec. 511.1(c)(3) provides, ``Each `Notice of Claimed
Investigational Exemption for a New Animal Drug' and each approved new
animal drug application containing data reported by an investigator who
has been determined to be ineligible to receive investigational-use new
animal drugs will be examined to determine whether he has submitted
unreliable data that are essential to the continuation of the
investigation or essential to the approval of any new animal drug
application.'' FDA proposes to revise the current regulations in Sec.
511.1(c)(3) to clarify the applicability of this provision, update this
provision consistent with Sec. Sec. 312.70(b), 511.1(c)(2), and
812.119(b) of this proposal, and to harmonize the disqualification
regulations in Sec. Sec. 312.70(c), 511.1(c)(3), and 812.119(c).
Therefore, we propose to revise Sec. 511.1(c)(3) to provide, ``Each
application or submission to FDA under the provisions of this chapter
and containing data reported by an investigator who has been determined
to be ineligible to receive FDA-regulated test articles will be
examined to determine whether the investigator has submitted unreliable
data that are essential to the continuation of any investigation or
essential to the approval of any marketing application, or essential to
the continued marketing of an FDA-regulated product.'' The ``provisions
of this chapter'' refers to chapter I and includes a notice of claimed
investigational exemption for a new animal drug and an approved new
animal drug application.
3. Proposed Revisions to Sec. 812.119(c)
Currently, Sec. 812.119(c) provides, ``Each investigational device
exemption (IDE) and each cleared or approved application submitted
under this part, subpart E of part 807 of this chapter, or part 814 of
this chapter containing data reported by an investigator who has been
determined to be ineligible to receive investigational devices will be
examined to determine whether the investigator has submitted unreliable
data that are essential to the continuation of the investigation or
essential to the approval or clearance of any marketing application.''
FDA proposes to revise the current regulations in Sec. 812.119(c) to
clarify the applicability of this provision, update this provision
consistent with Sec. Sec. 312.70(b), 511.1(c)(2), and 812.119(b) of
this proposal, and to harmonize the disqualification regulations in
Sec. Sec. 312.70(c), 511.1(c)(3), and 812.119(c). Therefore, we
propose to revise Sec. 812.119(c) to provide, ``Each application or
submission to FDA under the provisions of this chapter and containing
data reported by an investigator who has been determined to be
ineligible to receive FDA-regulated test articles will be examined to
determine whether the investigator has submitted unreliable data that
are essential to the continuation of any investigation or essential to
the clearance or approval of any marketing application, or essential to
the continued marketing of an FDA-regulated product.'' The ``provisions
of this chapter'' refers to chapter I and includes investigational
device exemptions (IDEs), and cleared or approved applications
submitted under part 812; 21 CFR part 807, subpart E; or part 814 (21
CFR part 814).

D. Disqualified Investigator's Data in Applications and Submissions to
FDA--Sponsor Notification, Opportunities, and Responsibilities
(Sec. Sec. 312.70(d), 511.1(c)(4), and 812.119(d))

1. Proposed Revisions to Sec. 312.70(d)
In accordance with FDA's procedures and for consistency
with the provisions currently in Sec. 812.119(d), we propose to add
``and the reviewing IRB(s)'' after ``shall terminate the IND
immediately and notify the sponsor * * *''.
We propose to change ``determination'' to ``termination''.
This correction is consistent with the regulations currently in
Sec. Sec. 511.1(c)(4) and 312.44 and, therefore, will harmonize and
clarify the regulations. This proposal provides, ``If a danger to the
public health exists * * * the Commissioner shall terminate the IND
immediately and notify the sponsor and the reviewing IRB(s) of the
termination.''
We propose to add a new sentence at the end of Sec.
312.70(d), to clarify and emphasize the sponsor's responsibilities
under this provision. That is, we propose to add that when the
Commissioner determines that an investigation may not be considered in
support of a research or marketing application, or a notification or
petition submission, this determination does not relieve the sponsor of
any obligation under any other applicable regulation to submit to FDA
the results of the investigation.

[[Page 20581]]

2. Proposed Revisions to Sec. 511.1(c)(4)
For the purpose of plain language and for consistency with
the current and proposed investigator disqualification regulations, FDA
proposes to make corrections to Sec. 511.1(c)(4):
[cir] Change ``he shall first'' to ``the Commissioner will'',
[cir] Change ``before the Food and Drug Administration pursuant
to'' to ``before FDA under'',
[cir] Remove ``on whether the exemption should be terminated'',
[cir] Change ``he'' to ``the Commissioner'',
[cir] Change ``forthwith'' to ``immediately'',
[cir] Change ``event'' to ``case'',
[cir] Change ``the Food and Drug Administration pursuant to'' to
``FDA under'', and
[cir] Remove ``(see 42 FR 15075, March 22, 1977)''.
We propose to add a new sentence at the end of Sec.
511.1(c)(4), to clarify and emphasize the sponsor's responsibilities
under this provision. That is, we propose to add that when the
Commissioner determines that an investigation may not be considered in
support of a research or marketing application, or a notification or
petition submission, this determination does not relieve the sponsor of
any obligation under any other applicable regulation to submit to FDA
the results of the investigation.
3. Proposed Revisions to Sec. 812.119(d)
We propose to change ``determination'' to ``termination''.
This correction is consistent with the regulations currently in Sec.
511.1(c)(4) and therefore will harmonize and clarify the regulations.
Also, we propose to add ``(s)'' at the end of ``IRB'' because there
might be more than one reviewing IRB, to provide that ``the
Commissioner shall terminate the IDE immediately and notify the sponsor
and the reviewing IRB(s) of the termination.''
We propose to add a new sentence at the end of Sec.
812.119(d). As proposed for Sec. Sec. 312.70(d) and 511.1(c)(4), we
propose to add that when the Commissioner determines that an
investigation may not be considered in support of a research or
marketing application, or a notification or petition submission, this
determination does not relieve the sponsor of any obligation under any
other applicable regulation to submit to FDA the results of the
investigation.

E. Disqualified Investigator's Data in Applications and Submissions to
FDA--Withdrawal of Product Approval (Sec. Sec. 312.70(e), 511.1(c)(5),
and 812.119(e))

1. Proposed Revisions to Sec. 312.70(e)
The current investigator disqualification regulations provide that
if the Commissioner determines, after the unreliable data submitted by
the investigator are eliminated from consideration, that the continued
approval of the drug product for which the data were submitted cannot
be justified, the Commissioner will proceed to withdraw approval of the
drug product in accordance with the applicable provisions of the
Federal Food, Drug, and Cosmetic Act as amended (the FD&C Act). We also
note that the Commissioner would revoke any biologics license approved
under the Public Health Service Act. To harmonize the investigator
disqualification regulations in Sec. Sec. 312.70(e), 511.1(c)(5), and
812.119(e), we propose to remove the reference to ``drug''. To keep the
investigator disqualification regulations consistent, this proposal
also changes the reference to the applicable provisions of the FD&C Act
to a reference to the applicable provisions of the relevant statutes.
2. Proposed Revisions to Sec. 511.1(c)(5)
The current investigator disqualification regulations in Sec.
511.1(c)(5) provide that if the Commissioner determines, after the
unreliable data submitted by the investigator are eliminated from
consideration, that the ``data remaining are such that a new animal
drug application would not have been approved, he will proceed to
withdraw approval of the application in accordance with section 512(e)
of the act.'' This proposal does not change the meaning of this
provision, however, for simplicity and to keep the investigator
disqualification regulations consistent, we propose changes to
harmonize the investigator disqualification regulations, as follows:
Change the ``data remaining are such that a new animal
drug application would not have been approved'' to ``continued approval
of the product for which the data were submitted cannot be justified'',
Change ``he'' to ``the Commissioner'',
Change ``application'' to ``product'', and
Change ``in accordance with section 512(e) of the act'' to
``in accordance with the applicable provisions of the relevant
statutes''.
3. Proposed Revisions to Sec. 812.119(e)
The current investigator disqualification regulations provide that
if the Commissioner determines, after the unreliable data submitted by
the investigator are eliminated from consideration, that the continued
clearance or approval of the marketing application for which the data
were submitted cannot be justified, the Commissioner will proceed to
withdraw approval or rescind clearance of the medical device in
accordance with the applicable provisions of the FD&C Act. We propose
to harmonize and simplify the provisions in Sec. Sec. 312.70(e),
511.1(c)(5), and 812.119(e). Therefore, in Sec. 812.119(e), we propose
to change ``marketing application'' and ``medical device'' to
``product'' and change ``in accordance with the applicable provisions
of the act'' to ``in accordance with the applicable provisions of the
relevant statutes''. Also, we propose to change the order of ``withdraw
approval or rescind clearance'' to ``rescind clearance or withdraw
approval'' to match respectively the order at the beginning of the
sentence.

F. Other Proceedings

Although not explicit in the proposed codified, the
disqualification of an investigator is independent of, and neither in
lieu of nor a precondition to, other proceedings or actions authorized
by the FD&C Act. That is, at any time, FDA may, through the Department
of Justice, institute any appropriate judicial proceedings (civil or
criminal) and any other appropriate regulatory action, in addition to
or in lieu of, and before, at the time of, or after, disqualification.
Also, FDA may refer pertinent matters to another Federal, State, or
local government agency for any action determined appropriate by that
agency.

G. Reinstatement (Sec. Sec. 312.70(f), 511.1(c)(6), and 812.119(f))

FDA proposes minor revisions to the regulations currently in
Sec. Sec. 312.70(f), 511.1(c)(6), and 812.119(f), to make the
investigator disqualification regulations consistent. This proposal
changes the references to an investigator who has been determined to be
ineligible to receive ``investigational drugs'', ``investigational-use
new animal drugs'', and ``investigational devices'' currently in those
provisions to, instead, reference an investigator who has been
determined to be ineligible under the appropriate paragraph in the
relevant section (e.g., in proposed Sec. 312.70(f), ``an investigator
who has been determined to be ineligible under paragraph (b) of

[[Page 20582]]

[Sec. 312.70] may be reinstated as eligible * * *''). This proposal
also changes the current references to ``parts 50 and 56'' and to ``the
provisions of this part'' in Sec. Sec. 312.70(f) and 812.119(f), and
the reference to ``the exempting regulations in this section'' in Sec.
511.1(c)(6), to ``the applicable provisions of this chapter'' (i.e.,
chapter I). We also added, for consistency with the proposed changes to
Sec. Sec. 312.70(b), 511.1(c)(2), and 812.119(b), the phrase, ``and
will conduct any clinical investigation that supports an application
for a research or marketing permit for products regulated by FDA''. We
therefore propose that an investigator who has been determined to be
ineligible under Sec. Sec. 312.70(b), 511.1(c)(2), or 812.119(b), may
be reinstated as eligible when the Commissioner determines that the
investigator has presented adequate assurances that the investigator
will employ all test articles, and will conduct any clinical
investigation that supports an application for a research or marketing
permit for products regulated by FDA, solely in compliance with the
applicable provisions of chapter I.

H. Part 511 Definitions (Sec. 511.3)

FDA proposes to amend part 511 by adding a new section that
provides definitions for a contract research organization,
investigator, sponsor, and sponsor-investigator. We propose to add
those definitions to harmonize part 511 with other regulations for the
disqualification of a clinical investigator.

IV. Regulatory Hearing Before the Food and Drug Administration

We propose to add to 16.1(b)(2) an entry for 812.119 and to revise
the entries for 312.70 and 511.1(c)(1). Also, the list of regulatory
provisions under which a part 16 regulatory hearing is available (Sec.
16.1(b)(2)) is incomplete. The provisions for Sec. 58.204(b) (21 CFR
58.204(b)), relating to disqualifying a testing facility, and Sec.
822.7(a)(3) (21 CFR 822.7(a)(3)), relating to an order to conduct
postmarket surveillance of a medical device under section 522 of the
FD&C Act (21 U.S.C. 360l), were inadvertently omitted. We, therefore,
propose to amend part 16 by adding those provisions.

V. Environmental Impact

The agency has determined under 21 CFR 25.30(h) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.

VI. Legal Authority

The disqualification of a clinical investigator is a remedial
measure. The purpose of disqualifying investigators who violate the
regulations is to preserve the integrity of data needed to assess the
safety and effectiveness of an FDA-regulated product before the product
is made available to the public, and to protect the safety of study
subjects during the conduct of a clinical investigation and patient
safety after the approval or clearance of a marketing application.
Although the concept of disqualification is not explicitly
mentioned in the FD&C Act, FDA has the authority to disqualify clinical
investigators who violate FDA's regulations. The Supreme Court in
Weinberger v. Bentex Pharmaceuticals, Inc., 412 U.S. 645, 653 (1973)
has recognized that FDA has authority that ``is implicit in the
regulatory scheme, not spelled out in haec verba'' in the statute. As
stated in Morrow v. Clayton, 326 F.2d 36, 44 (10th Cir. 1963):
[I]t is a fundamental principle of administrative law that the
powers of an administrative agency are not limited to those expressly
granted by the statutes, but include, also, all of the powers that may
fairly be implied therefrom.
See Mourning v. Family Publications Service, Inc., 411 U.S. 356
(1973), and National Petroleum Refiners Association v. FTC, 482 F.2d
672 (DC Cir. 1973). See also Weinberger v. Hynson, Westcott & Dunning,
Inc., 412 U.S. 609 (1973); National Nutritional Foods Association v.
Weinberger, 512 F.2d 688, cert denied, 423 U.S. 827 (1975); United
States v. Nova Scotia Food Products Corp., 568 F.2d 240, 246-248 (2d
Cir. 1977); American Frozen Food Institute v. Mathews 413 F.Supp. 548
(D.D.C. 1976) aff'd per curiam, 555 F.2d 1059 (DC Cir. 1977); National
Confectioners Association v. Califano, 569 F.2d 690 (DC Cir. 1978); and
National Association of Pharmaceutical Manufacturers v. FDA, 637 F.2d
877 (2d Cir. 1981).
``[R]egulatory acts should be given a practical construction, and
one which will enable the agency to perform the duties required of it
by Congress.'' Federal Deposit Ins. Corp. v. Sumner Fin. Corp., 451
F.2d 898, 904 (5th Cir. 1971). Congressional inaction on proposed
legislation that would state expressly an agency's authority to act
does not support an inference that the agency lacks implicit authority
to act under existing legislation. Red Lion Broadcasting Co. v. FCC,
395 U.S. 367, 381-382 n. 11 (1969). See also Leist v. Simplot, 638 F.2d
283, 318 (2d Cir. 1980), affirmed sub nom. Merrill Lynch, Pierce,
Fenner & Smith v. Curran, 456 U.S. 353 (1982). The Supreme Court has
often recognized ``the construction of a statute by those charged with
its administration is entitled to substantial deference.'' United
States v. Rutherford, 442 U.S. 544 (1979). Board of Governors of FRS v.
First Lincolnwood, 439 U.S. 234, 248, 99 S.Ct. 505, 513, 58 L.Ed.2d 484
(1978) (the Court's conclusion ``is influenced by the principle that
courts should defer to an agency's construction of its own statutory
mandate, Red Lion Broadcasting Co. v. FCC, 395 U.S. at 381;
Commissioner v. Sternberger's Estate, 348 U.S. 187, 199 (1955),
particularly when that construction accords with well established
congressional goals.'' 439 U.S. at 251); Bayside Enterprises, Inc. v.
NLRB, 429 U.S. 298, 304, 97 S.Ct. 576, 581, 50 L.Ed.2d 494 (1977);
Udall v. Tallman, 380 U.S. 1, 16, 85 S.Ct. 792, 801, 13 L.Ed.2d 616
(1965).
Under section 701(a) of the FD&C Act (21 U.S.C. 371(a)), the
Commissioner is empowered to promulgate regulations for the efficient
enforcement of the FD&C Act. Regulations issued by the Commissioner
under section 701(a) for determining whether a clinical investigation
of a drug intended for human use, among other things, was
scientifically reliable and valid to support approval of a new drug,
have been upheld by the Supreme Court (Weinberger v. Hynson, Westcott &
Dunning, Inc.); see also Upjohn Co. v. Finch, 422 F.2nd 944 (6th Cir.
1970); and Pharmaceutical Manufacturers Association v. Richardson, 318
F.Supp. 301 (D.Del. 1970)).
Furthermore, sections 505(i), 512(j) and 520(g) of the FD&C Act
regarding clinical investigations that require prior FDA authorization
direct the Commissioner to promulgate regulations to protect the public
health in the course of those investigations. Also, sections 505(i)(1),
512(j), and 520(g)(2)(A) of the FD&C Act require that investigations be
conducted by ``experts qualified by scientific training and
experience.'' An investigator who repeatedly or deliberately violates
the regulations or who repeatedly or deliberately submits false
information would not be considered a qualified expert with the
experience required to conduct investigations of FDA-regulated
articles. Among other stated objectives, the proposed rulemaking is
intended to fulfill those mandates.
The Commissioner therefore concludes that legal authority to
promulgate those regulations regarding clinical investigators exists
under sections 505(i), 512(j), 520(g) and 701(a)

[[Page 20583]]

of the FD&C Act, as essential to protection of the public health and
safety and to enforcement of the agency's responsibilities under
sections 409, 502, 503, 505, 506, 510, 512, 513, 514, 515, 518, 519,
520 and 801 of the FD&C Act (21 U.S.C. 348, 352, 353, 355, 356, 360,
360b, 360c, 360d, 360e, 360h, 360i, 360j and 381), as well as the
responsibilities of FDA under section 351 of the Public Health Service
Act (42 U.S.C. 262).

VII. Proposed Implementation Plan

FDA proposes that any final rule that may issue based on this
proposal become effective 30 days after the date of publication of the
final rule in the Federal Register.

VIII. Analysis of Impacts

FDA has examined the impacts of the proposed rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and
the Unfunded Mandates Reform Act of 1995 (Pub. L. 104-4). Executive
Order 12866 directs agencies to assess all costs and benefits of
available regulatory alternatives and, when regulation is necessary, to
select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The Agency believes that
this proposed rule is not a significant regulatory action as defined by
the Executive order.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because this proposed rule does not impose new
requirements on any entity and therefore has no associated compliance
costs, the Agency proposes to certify that the final rule will not have
a significant economic impact on a substantial number of small
entities.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and Tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $135 million, using the most current (2009) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
proposed rule to result in any 1-year expenditure that would meet or
exceed this amount.

A. Objective

The objective of the proposed rule is to strengthen the process for
ensuring the reliability and integrity of the clinical trial data
supporting FDA decision-making on product applications and to help
ensure the adequate protection of research subjects participating in
FDA-regulated clinical investigations. Specifically, this rule would
expand the scope of FDA's disqualification actions so that a
disqualified clinical investigator is ineligible to receive any FDA-
regulated test article. That is, an investigator determined to be
ineligible to receive test articles under parts 312, 511 or 812, will
be ineligible to conduct any clinical investigation that supports an
application for a research or marketing permit for products regulated
by FDA, including drugs, biologics, devices, new animal drugs, foods,
including dietary supplements, that bear a nutrient content claim or a
health claim, infant formulas, food and color additives, and tobacco
products. This action would help reduce the risk to human subjects who
participate in FDA-regulated clinical investigations by explicitly
extending a disqualified investigator's ineligibility to receive any
FDA-regulated test article. In addition, the proposed rulemaking would
establish uniform language across the several existing regulations that
address investigator disqualification.

B. Background

In 2009, the GAO conducted a study of FDA's oversight of clinical
investigators who conduct research involving new drugs, biologics and
medical devices, ``Oversight of Clinical Investigators--Action Needed
To Improve Timeliness and Enhance Scope of FDA's Debarment and
Disqualification Processes for Medical Product Investigators'' (Ref
1.). Among its findings, the GAO recommended that FDA amend its
regulations to ensure that those clinical investigators who have
engaged in misconduct sufficient to warrant disqualification for one
type of investigational medical product are not able to serve as
clinical investigators for other types of medical products.
Currently, FDA regulations provide authority to disqualify
researchers conducting clinical investigations of medical products when
FDA determines that the investigators have not followed the rules
intended to protect study subjects, or who have submitted false
information. The actions to disqualify clinical investigators are
initiated because FDA has evidence that the clinical investigator
repeatedly or deliberately violated FDA's regulations governing the
proper conduct of clinical investigations. However, the regulatory
language may allow a disqualified investigator to participate in
clinical investigations as long as the investigational products studied
are different from the product involved in the disqualification.

C. Baseline

To develop a baseline of the disqualification actions that would be
affected by this proposed rule, FDA's Office of Good Clinical Practice
reviewed all FDA disqualification actions over a 10-year period, 1998-
2007. This time-period was selected to provide a data set large enough
to analyze and to allow sufficient elapsed time from initiation to
final action to characterize completed actions. Over this 10-year
period, FDA has initiated a total of about 60 disqualification actions,
or an average of 6 per year. Of those 60 disqualification actions, 5
percent of the investigators were not disqualified. Approximately 75
percent of clinical investigators entered into a consent agreement or a
restricted agreement that restricts their ability to investigate other
FDA-regulated products, i.e., products different from the one in the
study (or studies) that led to disqualification. A small number of
clinical investigators, about 20 percent of the disqualification
actions, were ultimately disqualified following a Commissioner's
decision. In those matters, FDA does not have regulatory authority to
prohibit those investigators, who are disqualified by a Commissioner's
decision, from conducting investigations involving other FDA-regulated
articles. We have little, if any, evidence that any of the
investigators to date who have been disqualified via a Commissioner's
decision have conducted investigations with other types of FDA-
regulated test articles. Nonetheless, the agency agrees with GAO's
recommendation that FDA have in place uniform and enforceable
regulatory requirements to prevent clinical investigations in other
product areas by disqualified clinical investigators.

D. Costs of the Proposed Rule

We estimate that there may be an average of about 1 or 2 matters
per year of clinical investigators who are ultimately disqualified via
a Commissioner's decision. Because the majority of disqualification
actions are concluded by consent agreements that specifically preclude
the investigator from investigating other FDA-regulated articles and
current practices already

[[Page 20584]]

reduce the risk of such occurrences, we do not expect that this
proposed rule would impose additional costs. Past disqualification
actions show little, if any, evidence that an investigator disqualified
from receiving one type of test article later conducted a clinical
investigation studying a different type of test article. Nonetheless,
based in part on GAO recommendations, we find that explicit regulatory
language is needed to ensure that a disqualified investigator cannot
conduct a clinical investigation with any FDA-regulated test article.
FDA would realize cost savings if there are future disqualification
matters involving clinical investigators who are already disqualified
and then conduct additional research in another FDA-regulated product
area. There would be no need to bring a second action because the first
disqualification would prohibit research by the disqualified
investigator with any test article. We cannot estimate the amount of
savings, but the legal costs avoided would be considerable for each
additional product area.

E. Benefit

The proposed rule would help ensure that disqualified investigators
cannot receive any FDA-regulated article, i.e., disqualified
investigators will be ineligible to conduct any clinical investigation
that supports an application for a research or marketing permit for
products regulated by FDA, including drugs, biologics, devices, new
animal drugs, foods, including dietary supplements, that bear a
nutrient content claim or a health claim, infant formulas, food and
color additives, and tobacco products. Explicitly expanding a
disqualified investigator's ineligibility to receive any FDA-regulated
test article would help to reduce the risk of additional violations in
other FDA-regulated investigations and would help to ensure the
integrity of clinical trial data. This action would help reduce the
risk to human subjects who participate in FDA-regulated investigations.
This proposed rule may also lead to improved public confidence in the
clinical data supporting FDA decisions.

F. Alternatives

This proposed rule constitutes a minor change to existing
regulations to ensure that FDA has the clear regulatory authority it
needs to protect human subjects from exposure to research conducted by
disqualified clinical investigators. We considered not expanding the
scope of FDA's disqualification actions to include the ineligibility of
a disqualified clinical investigator to receive any FDA-regulated test
article. However, this would not meet the objective of helping to
ensure the adequate protection of human subjects in clinical
investigations or helping to ensure the reliability and integrity of
the clinical trial data supporting FDA decision-making on product
applications. There are no other viable alternatives.

G. Small Business Impact

The clinical research community, including clinical investigators,
is composed of many large and small business entities. Clinical
investigators may be associated with government and academic research
institutions, contract research organizations, site-management
organizations, or independent researchers. Investigational product
research is often sponsored by FDA-regulated firms that seek to bring a
new product to market.
The proposed rule is not expected to have a significant economic
impact on a substantial number of small entities as previously
discussed in this document. As stated above in this section of this
document, we do not expect that the proposed rule would impose
additional new costs. This proposed rule is expected to affect an
average of about 1 to 2 clinical investigators per year. Affected
investigators are disqualified because FDA has evidence that the
clinical investigator repeatedly or deliberately violated FDA's
regulations governing the proper conduct of clinical investigations.
FDA is not imposing any additional requirements for the conduct of
clinical investigations used to support marketing applications. It is
clarifying its regulatory authority over disqualified investigators.
Under this proposed rule a disqualified investigator would explicitly
be ineligible to conduct any studies of FDA-regulated articles. We have
little, if any, evidence that a disqualified investigator has conducted
a clinical investigation studying a different type of test article.
For the reasons stated above, we propose to certify that this
proposed rule would not have a significant economic impact on a
substantial number of small entities.

IX. Paperwork Reduction Act of 1995

This proposed rule contains no new collections of information.
Therefore, clearance by the Office of Management and Budget under the
Paperwork Reduction Act of 1995 is not required.
The information collection in Sec. 312.70 pertaining to the
disqualification of a clinical investigator and an investigator's
opportunity to respond to FDA is approved under the investigational new
drug regulations, OMB control number 0910-0014; expiration date August
31, 2011.\6\ The notification of IRB(s) in proposed Sec. 312.70 is
approved under OMB control number 0910-0130--Protection of Human
Subjects; Recordkeeping Requirements for Institutional Review Boards
(IRBs); expiration date December 31, 2010 (renewal pending at OMB).\7\
The information collection in Sec. 511.1(c) pertaining to the
disqualification of a clinical investigator and an investigator's
opportunity to respond to FDA is approved under the new animal drugs
for investigational use regulations OMB control number 0910-0117;
expiration date August 31, 2011.\8\ The information collection in Sec.
812.119 pertaining to the disqualification of a clinical investigator
and an investigator's opportunity to respond to FDA is approved under
the investigational device exemptions reports and records in part 812,
OMB control number 0910-0078; expiration date February 28, 2013.\9\ In
addition, INDs and new drug applications are approved under OMB control
number 0910-0416; animal drug applications, 21 CFR part 514 are
approved under OMB control number 0910-0032; premarket notification
submissions, 510(k), subpart E are approved under OMB control number
0910-0120; and premarket approvals of medical devices, part 814, are
approved under OMB control number 0910-0231.
---------------------------------------------------------------------------

\6\ See http://www.reginfo.gov/public/do/PRAViewICR?ref_nbr=200905-0910-005 (accessed on February 4, 2011).
\7\ See http://www.reginfo.gov/public/do/PRAViewICR?ref_nbr=200711-0910-003 (accessed on February 4, 2011).
\8\ See http://www.reginfo.gov/public/do/PRAViewICR?ref_nbr=200806-0910-005 (accessed on February 4, 2011).
\9\ See http://www.reginfo.gov/public/do/PRAViewICR?ref_nbr=201001-0910-010 (accessed on February 4, 2011).
---------------------------------------------------------------------------

X. Federalism

FDA has analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. FDA has determined that
the proposed rule, if finalized, would not contain policies that would
have substantial direct effects on the States, on the relationship
between the National Government and the States, or on the distribution
of power and responsibilities among the various levels of government.
Accordingly, the Agency tentatively concludes that the proposed rule
does not contain policies that have federalism implications as defined
in the Executive order and, consequently, a federalism summary impact
statement is not required.

[[Page 20585]]

XI. Request for Comments

Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) either electronic or written comments regarding this
document. It is only necessary to send one set of comments. It is no
longer necessary to send two copies of mailed comments. Identify
comments with the docket number found in brackets in the heading of
this document. Received comments may be seen in the Division of Dockets
Management between 9 a.m. and 4 p.m., Monday through Friday.

XII. References

The following reference has been placed on display in the Division
of Dockets Management, Food and Drug Administration, 5630 Fishers Lane,
rm. 1061, Rockville, MD 20857 and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday. We have verified the
Web site address, but we are not responsible for any subsequent changes
to the Web site after this document publishes in the Federal Register.
1. GAO Report to Congressional Requesters--Oversight of Clinical
Investigators, Action Needed to Improve Timeliness and Enhance Scope of
FDA's Debarment and Disqualification Processes for Medical Product
Investigators; GAO-09-807. See http://www.gao.gov/new.items/d09807.pdf
(accessed on February 4, 2011).

List of Subjects

21 CFR Part 16

Administrative practice and procedure.

21 CFR Part 312

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

21 CFR Part 511

Animal drugs, Medical research, Reporting and recordkeeping
requirements.

21 CFR Part 812

Health records, Medical devices, Medical research, Reporting and
recordkeeping requirements.

Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR parts 16, 312, 511, and 812 be amended as follows:

PART 16--REGULATORY HEARING BEFORE THE FOOD AND DRUG ADMINISTRATION

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

Authority: 15 U.S.C. 1451-1461; 21 U.S.C. 141-149, 321-394,
467f, 679, 821, 1034; 28 U.S.C. 2112; 42 U.S.C. 201-262, 263b, 364.

2. Section 16.1 is amended in paragraph (b)(2) by adding in
numerical sequence entries for ``Sec. 58.204(b)'', ``Sec. 812.119'',
and ``Sec. 822.7(a)(3)'' and by revising the entries for ``Sec.
312.70'' and ``Sec. 511.1(c)(1)'' to read as follows:

Sec. 16.1 Scope.

* * * * *
(b) * * *
(2) * * *
Sec. 58.204(b), relating to disqualifying a testing facility.
* * * * *
Sec. 312.70, relating to whether an investigator is eligible to
receive test articles under part 312 of this chapter and eligible to
conduct any clinical investigation that supports an application for a
research or marketing permit for products regulated by FDA, including
drugs, biologics, devices, new animal drugs, foods, including dietary
supplements, that bear a nutrient content claim or a health claim,
infant formulas, food and color additives, and tobacco products.
* * * * *
Sec. 511.1(c)(1), relating to whether an investigator is eligible
to receive test articles under part 511 of this chapter and eligible to
conduct any clinical investigation that supports an application for a
research or marketing permit for products regulated by FDA including
drugs, biologics, devices, new animal drugs, foods, including dietary
supplements, that bear a nutrient content claim or a health claim,
infant formulas, food and color additives, and tobacco products.
* * * * *
Sec. 812.119, relating to whether an investigator is eligible to
receive test articles under part 812 of this chapter and eligible to
conduct any clinical investigation that supports an application for a
research or marketing permit for products regulated by FDA including
drugs, biologics, devices, new animal drugs, foods, including dietary
supplements, that bear a nutrient content claim or a health claim,
infant formulas, food and color additives, and tobacco products.
* * * * *
Sec. 822.7(a)(3), relating to an order to conduct postmarket
surveillance of a medical device under section 522 of the act.
* * * * *

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

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

Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360bbb, 371;
42 U.S.C. 262.

4. Section 312.70 is revised to read as follows:

Sec. 312.70 Disqualification of a clinical investigator.

[[Page 20586]]

determination. The notification also will explain that an investigator
determined to be ineligible to receive test articles under this part
will be ineligible to conduct any clinical investigation that supports
an application for a research or marketing permit for products
regulated by FDA, including drugs, biologics, devices, new animal
drugs, foods, including dietary supplements, that bear a nutrient
content claim or a health claim, infant formulas, food and color
additives, and tobacco products.
(c) Each application or submission to FDA under the provisions of
this chapter and containing data reported by an investigator who has
been determined to be ineligible to receive FDA-regulated test articles
will be examined to determine whether the investigator has submitted
unreliable data that are essential to the continuation of any
investigation or essential to the approval of any marketing
application, or essential to the continued marketing of an FDA-
regulated product.
(d) If the Commissioner determines, after the unreliable data
submitted by the investigator are eliminated from consideration, that
the data remaining are inadequate to support a conclusion that it is
reasonably safe to continue the investigation, the Commissioner will
notify the sponsor who shall have an opportunity for a regulatory
hearing under part 16 of this chapter. If a danger to the public health
exists, however, the Commissioner shall terminate the IND immediately
and notify the sponsor and the reviewing IRB(s) of the termination. In
such case, the sponsor shall have an opportunity for a regulatory
hearing before FDA under part 16 of this chapter on the question of
whether the IND should be reinstated. The determination that an
investigation may not be considered in support of a research or
marketing application or a notification or petition submission does
not, however, relieve the sponsor of any obligation under any other
applicable regulation to submit to FDA the results of the
investigation.
(e) If the Commissioner determines, after the unreliable data
submitted by the investigator are eliminated from consideration, that
the continued approval of the product for which the data were submitted
cannot be justified, the Commissioner will proceed to withdraw approval
of the product in accordance with the applicable provisions of the
relevant statutes.
(f) An investigator who has been determined to be ineligible under
paragraph (b) of this section may be reinstated as eligible when the
Commissioner determines that the investigator has presented adequate
assurances that the investigator will employ all test articles, and
will conduct any clinical investigation that supports an application
for a research or marketing permit for products regulated by FDA,
solely in compliance with the applicable provisions of this chapter.

PART 511--NEW ANIMAL DRUGS FOR INVESTIGATIONAL USE

5. The authority citation for 21 CFR part 511 continues to read as
follows:

Authority: 21 U.S.C. 321, 351, 352, 353, 360b, 371.

6. Section 511.1 is amended by revising paragraph (c) to read as
follows:

Sec. 511.1 New animal drugs for investigational use exempt from
section 512(a) of the act.

* * * * *
(c) Disqualification of a clinical investigator. (1) If FDA has
information indicating that an investigator (including a sponsor-
investigator) has repeatedly or deliberately failed to comply with the
conditions of these exempting regulations or has repeatedly or
deliberately submitted to FDA or to the sponsor false information in
any required report, the Center for Veterinary Medicine will furnish
the investigator written notice of the matter complained of and offer
the investigator an opportunity to explain the matter in writing, or,
at the option of the investigator, in an informal conference. If an
explanation is offered and accepted by the Center for Veterinary
Medicine, the Center will discontinue pursuit of the disqualification
proceeding. If an explanation is offered but not accepted by the Center
for Veterinary Medicine, the investigator will be given an opportunity
for a regulatory hearing under part 16 of this chapter on the question
of whether the investigator is eligible to receive test articles under
this part and eligible to conduct any clinical investigation that
supports an application for a research or marketing permit for products
regulated by FDA.
(2) After evaluating all available information, including any
explanation presented by the investigator, if the Commissioner
determines that the investigator has repeatedly or deliberately failed
to comply with the conditions of the exempting regulations in this
subchapter, or has repeatedly or deliberately submitted to FDA or to
the sponsor false information in any required report, the Commissioner
will notify the investigator and the sponsor of any investigation in
which the investigator has been named as a participant that the
investigator is not eligible to receive test articles under this part.
The notification to the investigator and sponsor will provide a
statement of the basis for such determination. The notification also
will explain that an investigator determined to be ineligible to
receive test articles under this part will be ineligible to conduct any
clinical investigation that supports an application for a research or
marketing permit for products regulated by FDA, including drugs,
biologics, devices, new animal drugs, foods, including dietary
supplements, that bear a nutrient content claim or a health claim,
infant formulas, food and color additives, and tobacco products.
(3) Each application or submission to FDA under the provisions of
this chapter and containing data reported by an investigator who has
been determined to be ineligible to receive FDA-regulated test articles
will be examined to determine whether the investigator has submitted
unreliable data that are essential to the continuation of any
investigation or essential to the approval of any marketing
application, or essential to the continued marketing of an FDA-
regulated product.
(4) If the Commissioner determines, after the unreliable data
submitted by the investigator are eliminated from consideration, that
the data remaining are inadequate to support a conclusion that it is
reasonably safe to continue the investigation, the Commissioner will
notify the sponsor who shall have an opportunity for a regulatory
hearing under part 16 of this chapter. If a danger to the public health
exists, however, the Commissioner shall terminate the exemption
immediately and notify the sponsor of the termination. In such case,
the sponsor shall have an opportunity for a regulatory hearing before
FDA under part 16 of this chapter on the question of whether the
exemption should be reinstated. The determination that an investigation
may not be considered in support of a research or marketing application
or a notification or petition submission does not, however, relieve the
sponsor of any obligation under any other applicable regulation to
submit to FDA the results of the investigation.
(5) If the Commissioner determines, after the unreliable data
submitted by the investigator are eliminated from consideration, that
the continued approval of the product for which the data were submitted
cannot be justified, the Commissioner will proceed to withdraw approval
of the product in accordance with the applicable provisions of the
relevant statutes.

[[Page 20587]]

(6) An investigator who has been determined to be ineligible under
paragraph (c)(2) of this section may be reinstated as eligible when the
Commissioner determines that the investigator has presented adequate
assurances that the investigator will employ all test articles, and
will conduct any clinical investigation that supports an application
for a research or marketing permit for products regulated by FDA,
solely in compliance with the applicable provisions of this chapter.
* * * * *
7. Part 511 is amended by adding Sec. 511.3 to read as follows:

Sec. 511.3 Definitions.

As used in this part:
Contract research organization means a person that assumes, as an
independent contractor with the sponsor, one or more of the obligations
of a sponsor, e.g., design of a protocol, selection or monitoring of
investigations, evaluation of reports, and preparation of materials to
be submitted to FDA.
Investigator means an individual who actually conducts a clinical
investigation (i.e., under whose immediate direction the drug is
administered or dispensed to a subject). In the event an investigation
is conducted by a team of individuals, the investigator is the
responsible leader of the team. ``Subinvestigator'' includes any other
individual member of that team.
Sponsor means a person who takes responsibility for and initiates a
clinical investigation. The sponsor may be an individual or
pharmaceutical company, governmental agency, academic institution,
private organization, or other organization. The sponsor does not
actually conduct the investigation unless the sponsor is a sponsor-
investigator. A person other than an individual that uses one or more
of its own employees to conduct an investigation that it has initiated
is a sponsor, not a sponsor-investigator, and the employees are
investigators.
Sponsor-investigator means an individual who both initiates and
conducts an investigation, and under whose immediate direction the
investigational drug is administered or dispensed. The term does not
include any person other than an individual. The requirements
applicable to a sponsor-investigator under this part include both those
applicable to an investigator and a sponsor.

PART 812--INVESTIGATIONAL DEVICE EXEMPTIONS

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

Authority: 21 U.S.C. 331, 351, 352, 353, 355, 360, 360c-360f,
360h-360j, 371, 372, 374, 379e, 381, 382, 383; 42 U.S.C. 216, 241,
262, 263b-263n.

9. Section 812.119 is revised to read as follows:

Sec. 812.119 Disqualification of a clinical investigator.

(a) If FDA has information indicating that an investigator
(including a sponsor-investigator) has repeatedly or deliberately
failed to comply with the requirements of this part, part 50 of this
chapter, or part 56 of this chapter, or has repeatedly or deliberately
submitted to FDA or to the sponsor false information in any required
report, the Center for Devices and Radiological Health, the Center for
Biologics Evaluation and Research, or the Center for Drug Evaluation
and Research will furnish the investigator written notice of the matter
complained of and offer the investigator an opportunity to explain the
matter in writing, or, at the option of the investigator, in an
informal conference. If an explanation is offered and accepted by the
applicable Center, the Center will discontinue pursuit of the
disqualification proceeding. If an explanation is offered but not
accepted by the applicable Center, the investigator will be given an
opportunity for a regulatory hearing under part 16 of this chapter on
the question of whether the investigator is eligible to receive test
articles under this part and eligible to conduct any clinical
investigation that supports an application for a research or marketing
permit for products regulated by FDA.
(b) After evaluating all available information, including any
explanation presented by the investigator, if the Commissioner
determines that the investigator has repeatedly or deliberately failed
to comply with the requirements of this part, part 50 of this chapter,
or part 56 of this chapter, or has repeatedly or deliberately submitted
to FDA or to the sponsor false information in any required report, the
Commissioner will notify the investigator, the sponsor of any
investigation in which the investigator has been named as a
participant, and the reviewing IRB(s) that the investigator is not
eligible to receive test articles under this part. The notification to
the investigator, sponsor, and IRB(s) will provide a statement of the
basis for such determination. The notification also will explain that
an investigator determined to be ineligible to receive test articles
under this part will be ineligible to conduct any clinical
investigation that supports an application for a research or marketing
permit for products regulated by FDA, including drugs, biologics,
devices, new animal drugs, foods, including dietary supplements, that
bear a nutrient content claim or a health claim, infant formulas, food
and color additives, and tobacco products.
(c) Each application or submission to FDA under the provisions of
this chapter and containing data reported by an investigator who has
been determined to be ineligible to receive FDA-regulated test articles
will be examined to determine whether the investigator has submitted
unreliable data that are essential to the continuation of any
investigation or essential to the clearance or approval of any
marketing application, or essential to the continued marketing of an
FDA-regulated product.
(d) If the Commissioner determines, after the unreliable data
submitted by the investigator are eliminated from consideration, that
the data remaining are inadequate to support a conclusion that it is
reasonably safe to continue the investigation, the Commissioner will
notify the sponsor who shall have an opportunity for a regulatory
hearing under part 16 of this chapter. If a danger to the public health
exists, however, the Commissioner shall terminate the IDE immediately
and notify the sponsor and the reviewing IRB(s) of the termination. In
such case, the sponsor shall have an opportunity for a regulatory
hearing before FDA under part 16 of this chapter on the question of
whether the IDE should be reinstated. The determination that an
investigation may not be considered in support of a research or
marketing application or a notification or petition submission does
not, however, relieve the sponsor of any obligation under any other
applicable regulation to submit to FDA the results of the
investigation.
(e) If the Commissioner determines, after the unreliable data
submitted by the investigator are eliminated from consideration, that
the continued clearance or approval of the product for which the data
were submitted cannot be justified, the Commissioner will proceed to
rescind clearance or withdraw approval of the product in accordance
with the applicable provisions of the relevant statutes.
(f) An investigator who has been determined to be ineligible under
paragraph (b) of this section may be reinstated as eligible when the
Commissioner determines that the

[[Page 20588]]

investigator has presented adequate assurances that the investigator
will employ all test articles, and will conduct any clinical
investigation that supports an application for a research or marketing
permit for products regulated by FDA, solely in compliance with the
applicable provisions of this chapter.

Dated: April 7, 2011.
David Dorsey,
Acting Deputy Commissioner for Policy, Planning and Budget.
[FR Doc. 2011-8786 Filed 4-12-11; 8:45 am]
BILLING CODE 4160-01-P