[Federal Register Volume 81, Number 164 (Wednesday, August 24, 2016)]
[Proposed Rules]
[Pages 57812-57816]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-19876]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 16 and 511

[Docket No. FDA-2011-N-0079]


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 for new animal drugs for investigational use to expand 
the scope of clinical investigator disqualification to include 
ineligibility to conduct nonclinical laboratory studies. Currently, 
when the Commissioner of Food and Drugs (the Commissioner) determines 
that an investigator is ineligible to receive a new animal drug for 
investigational use, the investigator also is ineligible to conduct any 
clinical investigation that supports an application for a research or 
marketing permit for products regulated by FDA. Under this proposal, 
when the Commissioner determines that an investigator is ineligible to 
receive a new animal drug for investigational use, the investigator 
also will be ineligible to conduct any nonclinical study intended to 
support an application for a research or marketing permit for a new 
animal drug. This proposal is intended to help ensure adequate 
protection of animal research subjects and the quality and integrity of 
data submitted to FDA.

DATES: Submit either electronic or written comments on the proposed 
rule by November 22, 2016. See section VII of this document for the 
proposed effective date of a final rule based on this document.

ADDRESSES: You may submit comments as follows:

Electronic Submissions

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

[[Page 57813]]

instructions for submitting comments. Comments submitted 
electronically, including attachments, to http://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on http://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Division of 
Dockets Management, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2011-N-0079 for ``Disqualification of a Clinical Investigator.'' 
Received comments will be placed in the docket and, except for those 
submitted as ``Confidential Submissions,'' publicly viewable at http://www.regulations.gov or at the Division of Dockets Management between 9 
a.m. and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on http://www.regulations.gov. 
Submit both copies to the Division of Dockets Management. If you do not 
wish your name and contact information to be made publicly available, 
you can provide this information on the cover sheet and not in the body 
of your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: http://www.fda.gov/regulatoryinformation/dockets/default.htm.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper 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.
    Submit written requests for single copies of the guidance to the 
Policy and Regulations Staff (HFV-6), Center for Veterinary Medicine, 
Food and Drug Administration, 7519 Standish Pl., Rockville, MD 20855. 
Send one self-addressed adhesive label to assist that office in 
processing your requests. See the SUPPLEMENTARY INFORMATION section for 
electronic access to the guidance document.

FOR FURTHER INFORMATION CONTACT: Vernon Toelle, Center for Veterinary 
Medicine (HFV-230), 7519 Standish Pl., Rockville, MD 20855, 240-402-
5637.

SUPPLEMENTARY INFORMATION:

I. Introduction

    The current regulations in part 511 (21 CFR part 511) prohibit a 
disqualified clinical investigator from conducting any clinical 
investigation that supports an application for a research or marketing 
permit for products regulated by FDA. We propose to expand the current 
clinical investigator disqualification regulations in part 511 by 
providing that a disqualified investigator also is ineligible to 
conduct any nonclinical laboratory study intended to support an 
application for a research or marketing permit for a new animal drug. 
In this document, consistent with our proposal in part 58 (21 CFR part 
58) published elsewhere in this issue of the Federal Register, the term 
``nonclinical laboratory study'' means in vivo or in vitro experiments 
in which test articles are studied prospectively in test systems under 
laboratory conditions or in the applicable environment to determine 
their safety or toxicity or both. The term does not include studies 
involving human subjects, clinical studies, or clinical investigational 
use in animals. The term does not include basic exploratory studies 
carried out to determine whether a test article has any potential 
utility or basic exploratory studies to determine the physical or 
chemical characteristics of a test article.
    Under current Sec.  511.1(c) (21 CFR 511.1(c)), a clinical 
investigator disqualified by the Commissioner is ineligible to receive 
the test article regulated in part 511 (i.e., a new animal drug for 
investigational use). Also, under the current regulations in Sec.  
511.1(c), a disqualified clinical investigator is ineligible to conduct 
any clinical investigation that supports an application for a research 
or marketing permit for products regulated by FDA. However, under the 
current regulations, a disqualified clinical investigator continues to 
be eligible to conduct a nonclinical laboratory study intended to 
support an application for a research or marketing permit for a new 
animal drug.
    In order to conclude that a clinical investigator is no longer 
eligible to receive new animal drugs for investigational use, the 
Commissioner must find that the investigator repeatedly or deliberately 
failed to comply with the conditions of the exempting regulations or 
repeatedly or deliberately submitted to FDA or to the sponsor false 
information in any required report (Sec.  511.1(c)(2)). When a clinical 
investigator is disqualified under part 511, the basis for 
disqualification typically is the repeated or deliberate submission of 
false information to FDA or a sponsor in a required report. For new 
animal drugs, the same clinical investigator could conduct both 
nonclinical laboratory studies and clinical investigations.
    In the new animal drug approval process, nonclinical laboratory 
studies such as those for target animal safety and human food safety 
may be essential in determining whether to approve an application for a 
research or marketing permit for a new animal drug. Therefore, this 
proposal to expand Sec.  511.1(c) to include nonclinical laboratory 
studies is intended to help ensure adequate protection of animal 
research subjects and the quality and integrity of data submitted to 
FDA for the approval of a new animal drug.

[[Page 57814]]

    Consistent with the proposed changes to the provisions in part 511, 
we propose amending the list of regulatory provisions under which a 
part 16 (21 CFR part 16) informal regulatory hearing is available. In 
part 16, we propose changing the scope of the relevant provision for 
part 511 to add ``any nonclinical laboratory study intended to support 
an application for a research or marketing permit for a new animal 
drug.''
    Concurrent with this proposal, FDA is publishing elsewhere in this 
issue of the Federal Register a related provision in part 58. We 
propose in Sec.  58.206 (21 CFR 58.206) that a disqualified person 
under part 58, who is a clinical investigator, would be notified that 
they are ineligible to receive a test article under part 511. Thus, 
where this part 511 proposal would make a disqualified clinical 
investigator ineligible to conduct any nonclinical laboratory study 
intended to support an application for a research or marketing permit 
for a new animal drug, the proposal in Sec.  58.206 would make a 
disqualified person under part 58, who is a clinical investigator, 
ineligible to receive a test article under part 511. An investigator 
ineligible to receive a test article under part 511 also would be 
ineligible to conduct any nonclinical laboratory study intended to 
support an application for a research or marketing permit for a new 
animal drug. We propose this action in Sec.  58.206 to help protect the 
safety and welfare of animal research subjects involved in FDA-
regulated nonclinical laboratory studies and clinical investigations, 
and to help ensure the reliability and integrity of the data submitted 
to FDA to support FDA decisions concerning new animal drugs.

II. Background

    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 (e.g., new 
animal drug for investigational use) under study by the investigator in 
the clinical investigation. For example, the Center for Veterinary 
Medicine (CVM) may pursue disqualification of a clinical investigator 
who conducted a new animal drug clinical investigation and allegedly 
submitted to FDA or the sponsor false information in a required report.
    The regulations provide the investigator, who is subject to 
disqualification, an opportunity to be heard and explain the matter 
complained of, i.e., explain the alleged violations. 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. 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 (e.g., a new animal drug for 
investigational use). When disqualified by a Commissioner's decision, 
the investigator is no longer eligible to receive the particular type 
of test article under study when the violations occurred (e.g., new 
animal drugs). Also, under current regulations, an investigator 
disqualified by a Commissioner's decision is ineligible to conduct any 
clinical investigation that supports an application for a research or 
marketing permit for products regulated by FDA.
    Because CVM regulates drugs for animal use, the study subjects are 
animals in both nonclinical laboratory studies and clinical 
investigations intended to support the approval of a new animal drug. 
Nonclinical laboratory studies such as those for target animal safety 
and human food safety may be essential in determining whether to 
approve an application for a research or marketing permit for a new 
animal drug. For animal drug products regulated by CVM, the same 
investigator may conduct both nonclinical laboratory studies and 
clinical investigations. For example, CVM's two most recent clinical 
investigator disqualification matters involved investigators who were 
also study directors on nonclinical laboratory studies submitted to CVM 
in support of applications for a new animal drug. In addition, CVM is 
aware of multiple persons that conduct both clinical investigations and 
nonclinical laboratory studies intended to support an application for a 
research or marketing permit for a new animal drug. Therefore, it is 
critical for CVM to have the authority to disqualify an investigator 
from conducting nonclinical laboratory studies when that same 
investigator is disqualified from conducting clinical investigations, 
particularly when the basis for disqualification is the repeated or 
deliberate submission of false information to FDA or the sponsor in a 
required report.
    This proposal to amend part 511 to expand a disqualified 
investigator's ineligibility to conduct any nonclinical laboratory 
study intended to support an application for a research or marketing 
permit for a new animal drug would help to ensure adequate protection 
of animal research subjects and data integrity. This action also may 
lead to improved public confidence in the nonclinical and clinical data 
supporting FDA decisions for new animal drug approvals.
    We therefore propose that when the Commissioner determines that a 
clinical investigator is ineligible to receive the test article under 
the disqualification regulations in part 511 and is therefore 
ineligible to conduct any clinical investigation that supports an 
application for a research or marketing permit for products regulated 
by FDA, the investigator also would be ineligible to conduct any 
nonclinical laboratory study intended to support an application for a 
research or marketing permit for a new animal drug.
    To effect this change, FDA proposes to amend the current 
regulations in Sec.  511.1(c).

III. Description of the Proposed Rule

A. Disqualification Proceedings (Sec.  511.1(c)(1))

    Proposed Revisions to Sec.  511.1(c)(1): 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, also to 
include whether the investigator is eligible to conduct any nonclinical 
laboratory study that is intended to support an application for a 
research or marketing permit for a new animal drug.

B. Ineligibility To Receive Any Test Article (Sec.  511.1(c)(2))

    Proposed Revisions to Sec.  511.1(c)(2): We propose that an 
investigator disqualified by a Commissioner's decision also will be 
ineligible to conduct any nonclinical laboratory study that is intended 
to support an application for a research or marketing permit for a new 
animal drug.
    Therefore, as proposed, an investigator determined to be ineligible 
to receive a test article under part 511 also would be ineligible to 
conduct any nonclinical laboratory study intended to support an 
application for a research or marketing permit for a new animal drug. 
This proposal expands the scope of the current regulations in Sec.  
511.1(c)(2) which states that a disqualified clinical investigator is 
ineligible to conduct any

[[Page 57815]]

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. Reinstatement (Sec.  511.1(c)(6))

    FDA proposes amending Sec.  511.1(c)(6) for consistency with our 
proposal to add ``any nonclinical laboratory study intended to support 
an application for a research or marketing permit for a new animal 
drug'' to the part 511 investigator disqualification regulations. 
Therefore, for consistency with the proposed changes in Sec.  
511.1(c)(2), we propose adding in Sec.  511.1(c)(6) that the 
investigator has presented adequate assurances that the investigator 
will conduct any nonclinical laboratory study intended to support an 
application for a research or marketing permit for a new animal drug 
solely in compliance with the applicable provisions of chapter I.

IV. Regulatory Hearing before the Food and Drug Administration

    We propose to revise Sec.  16.1(b)(2) to amend the entry for Sec.  
511.1(c)(1) to add ``any nonclinical laboratory study intended to 
support an application for a research or marketing permit for a new 
animal drug'' to be consistent with the other proposed amendments in 
this rulemaking.

V. Environmental Impact

    We have 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

    Under section 701(a) of the FD&C Act (21 U.S.C. 371(a)), FDA is 
authorized to issue regulations for the efficient enforcement of the 
FD&C Act. Section 512(j) of the FD&C Act (21 U.S.C. 355(j)) authorizes 
FDA to issue regulations for exempting from the operation of section 
512 of the FD&C Act new animal drugs intended solely for 
investigational use by experts qualified by scientific training and 
experience to investigate the safety and effectiveness of animal drugs. 
An investigator who repeatedly or deliberately violates the regulations 
or who repeatedly or deliberately submits to FDA or the sponsor false 
information in a required report would not be considered a qualified 
expert with the experience required to conduct nonclinical laboratory 
studies intended to support an application for a research or marketing 
permit for a new animal drug. This proposed rulemaking would disqualify 
a clinical investigator from conducting nonclinical laboratory studies 
intended to support an application for a research or marketing permit 
for a new animal drug when the Commissioner determines that a clinical 
investigator is ineligible to receive the test article under the 
disqualification regulations in part 511. FDA's legal authority to 
promulgate this proposal regarding clinical investigators exists under 
sections 512(j) 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 201, 501, 502, 503, 512, and 701 of the 
FD&C Act (21 U.S.C. 321, 351, 352, 353, 360b, and 371).

VII. Proposed Effective Date

    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. Preliminary Economic Analysis

    FDA has examined the impacts of the proposed 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). The Agency believes that this proposed rule is not a 
significant regulatory action as defined by Executive Order 12866.
    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 $144 million, using the most current (2014) 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.
    This proposed rule seeks to expand the scope in part 511 of 
disqualification of a clinical investigator to include ineligibility to 
conduct nonclinical laboratory studies. A final rule (77 FR 25353), 
published on April 30, 2012, prevents a disqualified investigator from 
conducting any clinical investigation, and therefore applies explicitly 
to clinical investigations. However, the rule is silent on nonclinical 
laboratory studies. Thus, under the current regulation in part 511, a 
disqualified investigator could conduct a nonclinical laboratory study 
intended to support an application for a research or marketing permit 
for a new animal drug. Because the reason typically for 
disqualification in part 511 is the repeated or deliberate submission 
of false information to FDA or a sponsor in a required report, 
preventing a disqualified clinical investigator from performing both 
nonclinical laboratory studies and clinical investigations is essential 
to adequate protection of animal research subjects and data integrity.
    The Agency would not incur additional costs by expanding the scope 
in part 511 for disqualification of a clinical investigator. Similarly, 
we do not expect that industry would incur additional costs because the 
proposed rule would not require sponsors to perform additional tasks. 
For instance, upon disqualification, the respective investigator's name 
is posted on FDA's Web page, and this helps mitigate the employment of 
the investigator for clinical investigations or nonclinical laboratory 
studies intended to support an application for a research or marketing 
permit for a new animal drug. Because the typical reason for 
disqualification in part 511 is the repeated or deliberate submission 
of false information to FDA or a sponsor in a required report, the 
benefit of preventing a disqualified clinical investigator from 
performing both nonclinical laboratory studies and clinical 
investigations is enhanced protection of animal research subjects and 
data integrity.

[[Page 57816]]

IX. Paperwork Reduction Act

    FDA tentatively concludes that this proposed rule contains no 
collection of information. Therefore, clearance by OMB under the 
Paperwork Reduction Act of 1995 is not required.

X. Federalism

    We have analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. We have 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.

List of Subjects

21 CFR Part 16

    Administrative practice and procedure.

21 CFR Part 511

    Animal drugs, 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 parts 16 and 511 be amended as follows:

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

0
1. The authority citation for 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. In Sec.  16.1, in paragraph (b)(2), revise the numerically sequenced 
entry for Sec.  511.1(c)(1) to read as follows:


Sec.  16.1  Scope.

* * * * *
    (b) * * *
    (2) * * *
    Sec.  511.1(c)(1), relating to whether an investigator is eligible 
to receive test articles under part 511 and eligible to conduct:
    (i) 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; and
    (ii) Any nonclinical laboratory study intended to support an 
application for a research or marketing permit for a new animal drug.
* * * * *

PART 511--NEW ANIMAL DRUGS FOR INVESTIGATIONAL USE

0
3. The authority citation for part 511 continues to read as follows:

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

0
4. In Sec.  511.1, revise the section heading, the last sentences in 
paragraphs (c)(1) and (2), and revise paragraph (c)(6) to read as 
follows:


Sec.  511.1  New animal drugs for investigational use exempt from 
section 512(a) of the Federal Food, Drug, and Cosmetic Act.

* * * * *
    (c) * * *
    (1) * * * 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:
    (i) Any clinical investigation that supports an application for a 
research or marketing permit for products regulated by FDA; and
    (ii) Any nonclinical laboratory study intended to support an 
application for a research or marketing permit for a new animal drug.
    (2) * * * The notification also will explain that an investigator 
determined to be ineligible to receive a test article under this part 
will be ineligible to conduct
    (i) 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, and
    (ii) Any nonclinical laboratory study intended to support an 
application for a research or marketing permit for a new animal drug.
* * * * *
    (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 and 
any nonclinical laboratory study intended to support an application for 
a research or marketing permit for a new animal drug, solely in 
compliance with the applicable provisions of this chapter.
* * * * *

    Dated: August 16, 2016.
Peter Lurie,
Associate Commissioner for Public Health Strategy and Analysis.
[FR Doc. 2016-19876 Filed 8-23-16; 8:45 am]
 BILLING CODE 4164-01-P