Federal Register, Volume 77 Issue 83 (Monday, April 30, 2012)

[Federal Register Volume 77, Number 83 (Monday, April 30, 2012)]
[Rules and Regulations]
[Pages 25353-25361]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2012-10292]

=======================================================================
-----------------------------------------------------------------------

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: Final rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is amending the
regulations to expand the scope of clinical investigator
disqualification. Under this rulemaking, when the Commissioner of Food
and Drugs (the Commissioner) determines that an investigator is
ineligible to receive one kind of test article (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 other kinds of products regulated by FDA. This
final rule is based in part upon recommendations from the Government
Accountability Office (GAO), 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: This rule is effective May 30, 2012.

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:

I. Background

In the Federal Register of April 13, 2011 (76 FR 20575), FDA
proposed to amend its regulations to expand the scope of clinical
investigator disqualification (the April 2011 proposed rule). As
discussed in greater detail in the preamble to the proposed rule (76 FR
20575 at 20576 to 20585), when disqualified by a Commissioner's
decision under one part of the former regulations a clinical
investigator continued to be eligible to receive other types of test
articles and conduct

[[Page 25354]]

clinical investigations studying those other test articles.
The GAO, in its September 2009 final report on FDA's oversight of
clinical investigators (Ref. 1), recognized FDA's regulatory
limitations regarding clinical investigator disqualification. In its
September 2009 final report, the GAO recommended, among other things,
that FDA extend disqualification by a Commissioner's decision to
include ineligibility to receive unapproved drugs, biologics, and
medical devices. 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). Among other amended provisions, this
final rule responds to that GAO report and prevents clinical
investigators who are disqualified by a Commissioner's decision
(whether related to drugs, biologics, devices, or animal drugs) from
conducting any clinical investigations that support an application for
a research or marketing permit for products regulated by FDA. The other
amended provisions in this final rule provide for clarity and
harmonization of the clinical investigator disqualification regulations
and the addition of inadvertently omitted regulatory provisions under
which a part 16 (21 CFR part 16) regulatory hearing is available.

II. Overview of the Final Rule

This final rule amends part 312 (21 CFR part 312) in Sec. 312.70,
part 511 (21 CFR part 511) in Sec. 511.1(c), and part 812 (21 CFR part
812) in Sec. 812.119) to provide that when the Commissioner determines
that a clinical investigator is ineligible to receive the test article
under that part (e.g., new animal drugs in part 511 or drugs in part
312), the clinical investigator also is 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 amendments in this final rule, as explained in the preamble
to the proposed rule, help to clarify and harmonize the clinical
investigator disqualification regulations in parts 312, 511, and 812
(21 CFR part 812). Also, this final rule amends certain provisions in
part 16 (21 CFR part 16) by:
Adding to Sec. 16.1(b)(2) an entry for Sec. 812.119;
Revising the entries for Sec. Sec. 312.70 and
511.1(c)(1); and
Adding to the list of regulatory provisions under which a
part 16 regulatory hearing is available, provisions for:
[cir] Sec. 58.204(b) (21 CFR 58.204(b)), relating to disqualifying
a testing facility, and
[cir] 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 Federal Food Drug and Cosmetic Act (FD&C Act) (21 U.S.C.
3601).
On its own initiative, FDA modified the codified language published
in the April 2011 proposed rule (76 FR 20575), to remove ``pursuit of''
from the proposed provisions in Sec. Sec. 312.70(a), 511.1(c)(1), and
812.119(a). FDA made this change to clarify the rule and eliminate
unnecessary language. In this final rule, therefore, the relevant
language is ``If an explanation is offered and accepted by the
applicable Center, the Center will discontinue the disqualification
proceeding'' (see in this document codified Sec. Sec. 312.70(a),
511.1(c)(1), and 812.119(a)).
This final rule helps to protect the rights and safety of subjects
involved in FDA-regulated investigations, and helps to ensure the
reliability and integrity of the data used to support marketing of
products regulated by FDA.

III. Comments on the Proposed Rule

FDA received two comments on the proposed rule: One from a
healthcare professional and the other from regulated industry. Both
submissions supported the proposal to help ensure adequate protection
of research subjects and the quality and integrity of data submitted to
FDA. The healthcare professional supported the proposal and had no
other comment. The following comments and responses summarize and
address the issues found in the submission from regulated industry:
(Comment 1) The comment suggests that FDA either clarify or define
the terms ``repeatedly or deliberately'' or alternatively consider
removing the language from Sec. 812.119(a). The comment further asks
that FDA consider how much data or what frequency constitutes
``repeatedly''; and for ``deliberately'', how FDA proposes to determine
deliberate actions. The comment requests examples.
(Response) The interpretations of the terms ``repeatedly'' and
``deliberately'' in FDA's regulations governing disqualification of
clinical investigators are well established. The term ``repeatedly''
means, simply, more than once.\1\ A violation occurs ``repeatedly'' if
it happens more than once.\2\
---------------------------------------------------------------------------

\1\ See, e.g., Commissioner's Decision, In the Matter of William
H Ziering, M.D. (2008), at page 7. ``The term `repeatedly,' as it is
used in 21 CFR 312.70(b), is given its plain meaning, such that a
clinical investigator may be found to have acted `repeatedly' if he
or she engages in proscribed conduct `more than once.' '' (http://www.fda.gov/downloads/RegulatoryInformation/FOI/ElectronicReadingRoom/UCM144019.pdf).
\2\ See, In The Matter of James A. Halikas, Jr., M.D.,
Commissioner's Decision (January 17, 2001); In The Matter of Huibert
M Vriesendorp, M.D., Commissioner's Decision (December 31, 2001).
See also, Commissioner's Decision, In the Matter of William H
Ziering, M.D. (2008). (http:[sol][sol]www.fda.gov/
RegulatoryInformation/FOI/ElectronicReadingRoom/ucm143242.htm).
---------------------------------------------------------------------------

FDA may consider disqualification if a clinical investigator
commits a regulatory violation more than one time within a single study
(e.g., enrolling in a single study two study subjects who were
ineligible because of concomitant illnesses that put those subjects at
greater risk) or one time in each of two studies (e.g., enrolling in
each of two studies, a study subject who was ineligible because of a
concomitant illness putting the subject at greater risk). The
Commissioner, in past decisions, has determined that multiple
violations within a single study constitute repeated violations
sufficient to support disqualification from receipt of test
articles.\3\
---------------------------------------------------------------------------

\3\ See, e.g., Commissioner's Decision, In the Matter of James
A. Halikas (2001), at page 23 (``[T]o interpret repeatedly to mean
transgressions in more than one study would permit an investigator
to commit as many violations of the regulations as he/she wished
without possibility of disqualification as long as that investigator
limited his/her violations to one study. Such a result * * * would
be absurd.'') (http:[sol][sol]www.fda.gov/RegulatoryInformation/FOI/
ElectronicReadingRoom/ucm143242.htm). See also Commissioner's
Decision, In the Matter of Layne O. Gentry (2008), at page 23.
(http:[sol][sol]www.fda.gov/downloads/RegulatoryInformation/FOI/
ElectronicReadingRoom/UCM143906.pdf).
---------------------------------------------------------------------------

The term ``deliberately'' includes conduct that is ``willful'' as
well as conduct demonstrating reckless disregard.\4\ Accordingly, when
a clinical investigator knowingly fails to comply with FDA's
regulations, the clinical investigator may be found to have
deliberately violated the regulations. FDA could pursue the
disqualification of a clinical investigator, for example, if the
investigator changed a study's results by altering a data field on a
case report form to include false data. Likewise, an investigator who
shows a

[[Page 25355]]

reckless disregard for whether his or her conduct may result in a
regulatory violation may be found to have deliberately violated the
regulations.
---------------------------------------------------------------------------

\4\ In The Matter of James A. Halikas, Jr., M.D., Commissioner's
Decision (January 17, 2001); In The Matter of Huibert M.
Vriesendorp, M.D., Commissioner's Decision (December 31, 2001); In
The Matter of Layne O. Gentry, M.D., Presiding Officer Report
(September 12, 2001). (See http:[sol][sol]www.fda.gov/
RegulatoryInformation/FOI/ElectronicReadingRoom/ucm143242.htm).
---------------------------------------------------------------------------

Decisionmakers in part 16 proceedings have interpreted the term
``deliberately'' in Sec. 312.70(b) as roughly synonymous with the
``deliberate indifference'' or ``willful'' standard of intent.\5\ This
standard does not require specific knowledge that behavior, such as
submission of false data to a study sponsor, violates the law, but
reckless disregard for what the regulations require. The Commissioner's
decision In the Matter of Layne O. Gentry \6\ provides a useful
discussion of the standard for ``deliberate'' behavior in a
disqualification proceeding: \7\
---------------------------------------------------------------------------

\5\ See, e.g., Commissioner's Decision, In the Matter of William
H Ziering, M.D. (2008), at page 8 (``A clinical investigator may be
found to have acted `deliberately' * * * if he or she knowingly or
willfully engaged in conduct that violates FDA's regulations or if
the investigator engaged in conduct that demonstrated a reckless
disregard for compliance with FDA's regulations.'') See
http:[sol][sol]www.fda.gov/downloads/RegulatoryInformation/FOI/
ElectronicReadingRoom/UCM144019.pdf.
\6\ On June 18, 2008, Dr. Gentry was determined ineligible to
receive investigational drugs. See http:[sol][sol]www.fda.gov/
downloads/RegulatoryInformation/FOI/ElectronicReadingRoom/
UCM143906.pdf.
\7\ Id. at pages 20-21.

* * * the term ``deliberate,'' when used to describe a category of
violations that might lead to legal consequences, does not
necessarily require a showing of subjective intent on the part of
the person in question. * * * the purpose of [disqualification] is
to protect the safety of patients and to preserve the integrity of
the data needed to assess the safety and effectiveness of drugs
before being sold to the general public through disqualifying
investigators who do not fulfill the responsibilities imposed on
them.
In the context of such a remedial, as opposed to punitive,
scheme, an objective standard for ``deliberate'' or ``deliberately''
is a better fit because the inquiry should focus on preventing risk
rather than imposing punishment for culpable conduct. Even if the
investigator did not intend for the violations to occur, conduct
demonstrating a reckless disregard for the regulatory requirements
calls into question the investigator's fitness for conducting
clinical trials. * * *

Therefore, to sustain a finding of repeated or deliberate
submission of false information, FDA must show that the clinical
investigator repeatedly submitted to the sponsor or to FDA false
information, whether in a single study or in multiple studies, or
submitted false information to the sponsor or FDA knowingly or
willfully or with reckless disregard for the truthfulness of the data
submitted.
(Comment 2) The comment asks how far back FDA will investigate FDA-
approved products with a disqualified investigator's data; and requests
an explanation of how FDA handles products that have been on the market
for a longer period of time without significant safety concerns.
(Response) FDA uses its best efforts to identify each application
and submission to FDA that may include data from a disqualified
clinical investigator. FDA does not place limits on how far back FDA
will investigate to find those applications and submissions that may be
affected by a disqualified investigator who conducted trials with FDA-
regulated test articles.
Each application or submission identified as containing data
reported by a disqualified investigator is subject to examination to
determine whether the investigator has submitted unreliable data that
are essential to the approval of a marketing application or essential
to the continued marketing of an FDA-regulated product. (See Sec. Sec.
312.70(c), 511.1(c)(3), and 812.119(c)). This examination may be
undertaken by FDA or the study sponsor. 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 rescind clearance or withdraw approval of the product
in accordance with the applicable provisions of the relevant statutes.
(See Sec. Sec. 812.119(e), 511.1(c)(5), and 312.70(e)).
Often, there may be sufficient data from sources other than the
disqualified investigator's data to support the continued approval of
the product. Those products that have been on the market for a longer
period of time without significant safety concerns, even though a
disqualified investigator contributed to the data relied on for
approval, would probably remain on the market if sufficient reliable
product-approval data support the continued approval of the product.
(Comment 3) The comment asks that FDA promptly inform affected
sponsors of an investigator's disqualification.
(Response) FDA agrees that sponsors should be informed promptly
about the disqualification of a clinical investigator. Indeed, FDA
informs sponsors at several stages of the disqualification process.
When FDA initiates a disqualification action, FDA sends to the clinical
investigator a notice of initiation of disqualification proceedings and
opportunity to explain (NIDPOE) letter. Following confirmed receipt of
the NIDPOE letter by the clinical investigator, FDA provides a redacted
copy of the letter to the study sponsor and reviewing institutional
review boards (IRBs) (see Ref. 2, section II.C., at page 8), and posts
the redacted NIDPOE letter on FDA's Web site.\8\ The posted NIDPOE
letter is intended to inform sponsors and others who may have an
interest that FDA is initiating an administrative proceeding to
determine whether the clinical investigator should be disqualified from
receiving test articles.
---------------------------------------------------------------------------

\8\ See http:[sol][sol]www.fda.gov/RegulatoryInformation/FOI/
ElectronicReadingRoom/ucm092185.htm.
---------------------------------------------------------------------------

If the investigator's explanation is not accepted by FDA or if the
investigator fails to respond to the NIDPOE letter within the specified
time period, FDA offers the investigator an opportunity for an informal
regulatory hearing under part 16 to determine whether the investigator
should remain eligible to receive test articles. FDA initiates a part
16 hearing by sending to the investigator a Notice of Opportunity for
Hearing (NOOH). The NOOH specifies the facts and other relevant
information that are the subject of the part 16 hearing (see Ref. 2,
id.). FDA posts on its Web site \9\ the names of clinical investigators
who have been issued a NOOH concerning a disqualification proceeding
along with the redacted NOOH.
---------------------------------------------------------------------------

\9\ See http://www.fda.gov/RegulatoryInformation/FOI/ElectronicReadingRoom/ucm143240.htm.
---------------------------------------------------------------------------

If the investigator is disqualified, after receiving confirmation
that the investigator has been notified of his or her disqualification,
FDA promptly posts on its Web site \10\ the investigator's name and the
date of the disqualification action. In addition, FDA notifies the
study sponsor and reviewing IRBs, in writing, about the
disqualification action (Ref. 2, id.). This notification provides a
statement of the basis for the Commissioner's disqualification
determination (see Sec. Sec. 312.70(b), 511.1(c)(2), and 812.119(b)).
---------------------------------------------------------------------------

\10\ See http://www.fda.gov/ICECI/EnforcementActions/DisqualifiedRestrictedAssuranceList/ucm131681.htm.
---------------------------------------------------------------------------

FDA recommends that sponsors routinely check FDA's compliance and
enforcement Web sites \11\ for information about investigator
disqualification proceedings that might affect the sponsor's studies.
Further, in compliance with a sponsor's responsibilities (see, e.g.,
Sec. Sec. 312.53(a), 511.1(b)(7)(i), and 812.43(a)), a sponsor must
select only investigators qualified by training and experience as
appropriate experts to investigate the study. A sponsor therefore must
perform

[[Page 25356]]

due diligence to ensure that an investigator is eligible to receive the
test article. FDA considers checking FDA's Web site for investigator
disqualification to be part of a sponsor's due diligence effort before
selecting a clinical investigator to conduct a sponsor's study.
---------------------------------------------------------------------------

\11\ See http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ComplianceEnforcement/default.htm.
---------------------------------------------------------------------------

(Comment 4) The comment recommends that FDA consider the impact of
investigator disqualification on the submission of results from failed
investigations to ClinicalTrials.gov.
(Response) The comment is beyond the scope of this rulemaking as
the National Institutes of Health (NIH) has the statutory
responsibility for implementing the provisions under the Public Health
Service Act, section 402(j), 42 U.S.C. 282(j)--Expanded Clinical Trial
Registry Data Bank. The NIH proposes to issue new regulations \12\ that
will prescribe procedures for registering and reporting the results of
clinical trials at ClinicalTrials.gov in accordance with section 801 of
the Food and Drug Administration Amendments Act of 2007 (FDAAA, Pub. L.
110-85, September 27, 2007).
---------------------------------------------------------------------------

\12\ See the Fall 2011 Unified Agenda, Expanded Registration and
Results Reporting at ClinicalTrials.gov (RIN 0925-AA55), at http://reginfo.gov/public/do/eAgendaViewRule?pubId=201110&RIN=0925-AA55.
---------------------------------------------------------------------------

(Comment 5) The comment recommends that FDA seek input from
affected sponsors regarding the impact of a clinical investigator's
disqualification on the validity of clinical trial or marketed product
data.
(Response) As discussed in response to Comment 2 in this document,
upon disqualification of a clinical investigator, each application or
submission to FDA containing data reported by a disqualified
investigator is subject to examination (see Sec. Sec. 312.70(c),
511.1(c)(3), and 812.119(c)). We agree that FDA may seek input from an
affected study sponsor; for example, FDA may request from the study
sponsor statistical analyses of study results after eliminating from
the database the disqualified investigator's data.
(Comment 6) The comment asks FDA to clarify whether the rule
applies to ``all sponsors for whom the investigator did work, or only
those that were subject to the problem that caused the
disqualification.''
(Response) This final rule applies to all sponsors who selected the
clinical investigator to conduct their studies. FDA will assess the
reliability of any data developed by a disqualified clinical
investigator.
(Comment 7) The comment recommends that, because clinical
investigator disqualification by a Commissioner's decision is a lengthy
proceeding, FDA consider instituting a process similar to a clinical
hold ``to prevent these individuals from continuing to conduct clinical
trials while the disqualification process is underway.''
(Response) FDA agrees that the use of a clinical hold following
clinical investigator misconduct may be appropriate in some situations
and has issued a guidance document indicating this (see Ref. 3). For
example, FDA may impose a clinical hold on studies where the hold is
necessary to protect human subjects in the study from an unreasonable
and significant risk of illness or injury. In such a case, FDA may
impose a clinical hold based on credible evidence that a clinical
investigator conducting the study has committed serious violations of
FDA regulations on clinical trials of human drugs and biologics,
including parts 312, 50, and 56 (21 CFR parts 50 and 56), or has
submitted false information to FDA or the sponsor in any required
report. Such a clinical hold may be imposed on the study in which the
misconduct occurred or on other studies of drugs or biological products
in which the clinical investigator is directly involved or proposed to
be involved if FDA determines that the investigator's misconduct poses
an ongoing threat to the safety and welfare of such subjects. (See
Sec. Sec. 312.42(b)(1)(i), 312.42(b)(2)(i), 312.42(b)(3)(iii), and
312.42(b)(4)(i)) (Ref. 3).
For medical devices, Sec. 812.30(b) allows for withdrawal of
approval of an application for an investigational device exemption
(IDE). Under this provision, FDA may withdraw approval of an
application if FDA determines that continuation of testing under an IDE
will result in an unreasonable risk to subjects.
(Comment 8) The comment recommends that FDA issue guidance on how a
disqualified investigator's data in applications and submissions to FDA
is to be handled, segregated, analyzed, and reported.
(Response) Because each situation is different, FDA evaluates on a
case-by-case basis the best course of action for handling a
disqualified clinical investigator's data in applications and
submissions. For this reason, FDA does not intend to issue guidance to
address how a disqualified investigator's data should be handled.
(Comment 9) The comment recommends that FDA state explicitly in the
rule that when an investigator is disqualified by FDA from studies of
veterinary drugs the investigator should also be ineligible to
participate in studies of veterinary biologics regulated by the U.S.
Department of Agriculture (USDA) under Title 9 of the Code of Federal
Regulations; and, likewise, that ``USDA should codify a companion rule
to state that investigators disqualified from participation in studies
of goods regulated by FDA will also be disqualified from investigations
of veterinary biologics.''
(Response) As stated in the preamble to the proposed rule, FDA may
refer pertinent matters to another Federal, State, or local government
agency for any action determined appropriate by that agency. Although
FDA agrees that affected agencies should be aware of judicial
proceedings and regulatory actions taken involving clinical
investigators, FDA does not have authority to draft a companion rule to
be administered by USDA.
(Comment 10) The comment recommends that FDA notify sponsors when a
disqualified clinical investigator has been reinstated.
(Response) We agree that FDA should notify interested parties when
a clinical investigator is reinstated as eligible to receive FDA-
regulated test articles. Because FDA has no way of knowing who, in
particular, may be interested in the reinstatement of a certain
investigator, FDA lists on its Web site those investigators who have
been reinstated.\13\
---------------------------------------------------------------------------

\13\ See http://www.fda.gov/ICECI/EnforcementActions/DisqualifiedRestrictedAssuranceList/ucm131681.htm.
---------------------------------------------------------------------------

IV. 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.

V. Legal Authority

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

[[Page 25357]]

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 (DCCir. 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 (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 (1977); Udall v.
Tallman, 380 U.S. 1, 16 (1965).
Under section 701(a) of the FD&C Act (21 U.S.C. 371(a)), the
Commissioner is empowered to issue regulations for the efficient
enforcement of the FD&C Act. Regulations issued by the Commissioner
under section 701(a) of the FD&C Act 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.2d 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 (21
U.S.C. 355(i), 360b(j), and 360j(g)) regarding clinical investigations
that require prior FDA authorization direct the Commissioner to issue
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 final
rulemaking is intended to fulfill those mandates.
The Commissioner therefore concludes that legal authority to issue
those regulations regarding clinical investigators exists under
sections 505(i), 512(j), 520(g) and 701(a) 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).

VI. Analysis of Impacts

FDA has examined the impacts of the final rule under Executive
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L.
104-4). Executive Orders 12866 and 13563 direct 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). In accordance with Executive Order 12866, FDA has previously
analyzed the potential economic effects of this final rule. As
announced in the proposal, the Agency has determined that the rule is
not a significant regulatory action as defined by Executive Order
12866. The Agency has not received any new information or comments that
would alter its previous determination.
The Regulatory Flexibility Act requires Agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because this final rule does not impose new
requirements on any entity and therefore has no associated compliance
costs, the Agency certifies 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 $136 million, using the most current (2010) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
final rule to result in any 1-year expenditure that would meet or
exceed this amount.

Synopsis

This rule expands the scope of FDA's disqualification actions so
that a disqualified clinical investigator is ineligible to receive any
FDA-regulated test article and ineligible to conduct any clinical
investigation that supports an application for a research or marketing
permit for products regulated by FDA. We estimate that there is an
average of about one matter per year in which clinical investigators
are ultimately disqualified via a Commissioner's decision, and we do
not expect that this final rule will impose additional costs. Non-
quantifiable benefits of this final rule would include helping to
reduce the risk of additional violations in other FDA-regulated
investigations and helping to ensure the integrity of

[[Page 25358]]

clinical trial data. This final rule will help to reduce the risk to
human subjects who participate in FDA-regulated investigations, and may
lead to improved public confidence in the clinical data supporting FDA
decisions. The full analysis of impacts is presented in Ref. 4 of this
document.

VII. Paperwork Reduction Act of 1995

This final 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 No. 0910-0014; expiration date February
28, 2013.\14\ The notification of IRBs in Sec. 312.70 is approved
under OMB Control No. 0910-0130--Protection of Human Subjects;
Recordkeeping Requirements for Institutional Review Boards (IRBs);
expiration date April 30, 2014.\15\ 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
No. 0910-0117; expiration date August 31, 2011 (renewal pending at
OMB).\16\ 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 21 CFR part 812, OMB Control
No. 0910-0078; expiration date February 28, 2013.\17\ 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, 21 CFR part 814, are approved
under OMB control number 0910-0231.
---------------------------------------------------------------------------

\14\ See http://www.reginfo.gov/public/do/PRAViewICR?ref_nbr=200905-0910-005 (accessed on March 30, 2012).
\15\ See http://www.reginfo.gov/public/do/PRAViewICR?ref_nbr=200711-0910-003 (accessed on March 30, 2012).
\16\ See http://www.reginfo.gov/public/do/PRAViewICR?ref_nbr=200806-0910-005 (accessed on March 30, 2012).
\17\ See http://www.reginfo.gov/public/do/PRAViewICR?ref_nbr=201001-0910-010 (accessed on March 30, 2012).
---------------------------------------------------------------------------

VIII. Federalism

FDA has analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. FDA has determined that the rule
does not contain policies that 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 has concluded
that the 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.

IX. References

The following references have been placed on display in the
Division of Dockets Management (HFA-305), Food and Drug Administration,
5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
(FDA has verified the Web site addresses, but FDA is not responsible
for any subsequent changes to the Web sites 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:[sol][sol]www.gao.gov/
new.items/d09807.pdf.
2. See ``Information Sheet Guidance for Institutional Review Boards,
Clinical Investigators, and Sponsors: Clinical Investigator
Administrative Actions--Disqualification,'' May 2010, at
http:[sol][sol]www.fda.gov/downloads/RegulatoryInformation/
Guidances/UCM214008.pdf.
3. See ``Guidance for Industry and Clinical Investigators: The Use
of Clinical Holds Following Clinical Investigator Misconduct,''
September 2004, at http:[sol][sol]www.fda.gov/downloads/
RegulatoryInformation/Guidances/UCM126997.pdf.
4. Full Analysis of Impacts of Final Rule.

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, 21 CFR parts
16, 312, 511, and 812 are amended as follows:

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

0
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.

0
2. Section 16.1 is amended in paragraph (b)(2) by numerically adding
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.
* * * * *

[[Page 25359]]

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

0
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.

0
4. Section 312.70 is revised to read as follows:

Sec. 312.70 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 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
Drug Evaluation and Research or the Center for Biologics 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 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 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
institutional review boards (IRBs) that the investigator is not
eligible to receive test articles under this part. The notification to
the investigator, sponsor, and IRBs 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 containing data reported by an investigator who has been
determined to be ineligible to receive FDA-regulated test articles is
subject to examination to determine whether the investigator has
submitted unreliable data that are essential to the continuation of an
investigation or essential to the approval of a 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 IRBs of the termination. In
such case, the sponsor shall have an opportunity for a regulatory
hearing before FDA under part 16 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

0
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.

0
6. Section 511.1 is amended by:
0
a. Removing ``the Food and Drug Administration'' and adding in its
place ``FDA'' in paragraph (b)(4) introductory text, and paragraphs
(b)(5)(iii), (b)(6), (b)(8)(ii), (b)(9)(i), (d)(2), and (f)(1).
0
b. Revising paragraph (c).
The revisions 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 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

[[Page 25360]]

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 containing data reported by an investigator who has been
determined to be ineligible to receive FDA-regulated test articles is
subject to examination to determine whether the investigator has
submitted unreliable data that are essential to the continuation of an
investigation or essential to the approval of a 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 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.
(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.
* * * * *

0
7. Section 511.3 is added 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 the Food and Drug Administration.
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

0
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.

0
9. Section 812.119 is revised to read as follows:

Sec. 812.119 Disqualification of a clinical investigator.

[[Page 25361]]

requirements of this part, part 50, 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
investigational review boards (IRBs) that the investigator is not
eligible to receive test articles under this part. The notification to
the investigator, sponsor and IRBs 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 containing data reported by an investigator who has been
determined to be ineligible to receive FDA-regulated test articles is
subject to examination to determine whether the investigator has
submitted unreliable data that are essential to the continuation of an
investigation or essential to the clearance or approval of a 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 investigational
device exemption (IDE) immediately and notify the sponsor and the
reviewing IRBs 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 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 24, 2012.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2012-10292 Filed 4-27-12; 8:45 am]
BILLING CODE 4160-01-P