[Printable PDF]
[Federal Register: January 17, 2006 (Volume 71, Number 10)]
[Proposed Rules]
[Page 2494-2496]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr17ja06-13]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 210
[Docket No. 2005N-0285]
Current Good Manufacturing Practice Regulation and
Investigational New Drugs; Companion Document to Direct Final Rule
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is publishing this
companion proposed rule to the direct final rule, published elsewhere
in this issue of the Federal Register, which is intended to amend our
current good manufacturing practice (CGMP) regulations for human drugs,
including biological products, to exempt most investigational ``Phase
1'' drugs from complying with the regulatory requirements. We will
instead exercise oversight of production of these drugs under the
agency's general statutory CGMP authority and investigational new drug
application (IND) authority. Elsewhere in this issue of the Federal
Register, FDA is announcing the availability of a draft guidance for
industry entitled ``INDs--Approaches to Complying With CGMP During
Phase 1'' to provide further guidance on the subject.
DATES: Submit written or electronic comments by April 3, 2006.
ADDRESSES: Submit written comments to the Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane,
rm. 1061, Rockville, MD 20852. Submit electronic comments to http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/dockets/comments
.
FOR FURTHER INFORMATION CONTACT: Monica Caphart, Center for Drug
Evaluation and Research (HFD-320), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-827-9047; or Christopher
Joneckis, Center for Biologics Evaluation and Research (HFM-1), Food
and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852, 301-
435-5681.
SUPPLEMENTARY INFORMATION:
I. Background
As described more fully in the related direct final rule, a Phase 1
clinical trial includes the initial introduction of an investigational
new drug into humans. Such studies are aimed at establishing basic
safety and are designed to determine the metabolism and pharmacologic
actions of the drug in humans. The total number of subjects in a Phase
1 study is limited--generally no more than 80 subjects. This is in
contrast to Phase 2 and Phase 3 trials, which may involve substantially
greater numbers of subjects, exposing more subjects to the drug
product, and which aim to test the effectiveness of the drug product.
For several reasons, we believe that production of human drug
products, including biological drug products, intended for use in Phase
1 clinical trials should be exempted from complying with the specific
regulatory requirements set forth in parts 210 and 211 (21 CFR parts
210 and 211). First, even if exempted from the requirements of our CGMP
regulations in parts 210 and 211, investigational drugs remain subject
to the statutory provisions that deem a drug adulterated for failure to
comply with CGMPs (21 U.S.C. 351(a)(2)(B)).
Second, we oversee drugs for use in Phase 1 trials through our
existing IND authority. Every IND must contain, among other things, a
section on chemistry, manufacturing, and control information that
describes the composition, manufacture, and control of the
investigational drug product (21 CFR 312.23(a)(7)). This information
should suffice to enable us to
[[Page 2495]]
adequately protect subjects in early Phase 1 trials.
II. Additional Information
This proposed rule is a companion to the direct final rule
published in the final rules section of this issue of the Federal
Register. The proposed rule and the direct final rule are identical.
This companion proposed rule provides the procedural framework to
proceed with standard notice-and-comment rulemaking if the direct final
rule receives significant adverse comment and is withdrawn. The comment
period for the companion proposed rule runs concurrently with the
comment period of the direct final rule. Any comments received on this
companion proposed rule will also be treated as comments on the direct
final rule and vice versa.
For additional information, see the corresponding direct final rule
published in the final rules section of this issue of the Federal
Register. All persons who may wish to comment should review the
rationale for these amendments set out in the preamble discussion of
the direct final rule. A significant adverse comment is one that
explains why the rule would be inappropriate, including challenges to
the rule's underlying premise or approach, or would be ineffective or
unacceptable without a change. A comment recommending a rule change in
addition to this rule will not be considered a significant adverse
comment, unless the comment states why this rule would be ineffective
without the additional change. If no significant adverse comment is
received in response to the direct final rule, no further action will
be taken related to this companion proposed rule. Instead, we will
publish a confirmation notice within 30 days after the comment period
ends, and we intend the direct final rule to become effective 30 days
after publication of the confirmation notice. If we receive significant
adverse comments, we will withdraw the direct final rule. We will
proceed to respond to all of the comments received regarding the direct
final rule, treating those comments as comments to this proposed rule.
The agency will address the comments in a subsequent final rule. We
will not provide additional opportunity for comment.
III. Legal Authority
Under section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic
Act (the act) (21 U.S.C. 201 et seq.) a drug is deemed adulterated if
the methods used in, or the facilities, or controls used for, its
manufacture, processing, packing, or holding do not conform to or are
not operated in conformity with CGMPs to ensure that such drug meets
the requirements of the act as to safety, and has the identity and
strength, and meets the quality and purity characteristics, which it
purports or is represented to possess. The rulemaking authority
conferred on FDA by Congress under the act permits the agency to amend
its regulations as contemplated by this direct final rule. Section
701(a) of the act (21 U.S.C. 371) gives FDA general rulemaking
authority to issue regulations for the efficient enforcement of the
act. We refer readers to the legal authority section of the preamble of
the 1978 CGMP regulations for a fuller discussion (43 FR 45014 at
45020-45026, September 29, 1978).
IV. Environmental Impact
The agency has determined that under 21 CFR 25.30(h) 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. Analysis of Impacts
FDA examined the impacts of this 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 (Public Law 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.
Under the Regulatory Flexibility Act, if a rule has a significant
impact on a substantial number of small entities, an agency must
analyze regulatory options that would minimize any significant impact
of the rule on small entities. The agency has considered the effect
that this rule would have on small entities. Because exempting
production of drugs for use in Phase 1 studies from compliance with
specific regulatory requirements does not add any burden, the agency
certifies that the rule will not have a significant economic impact on
a substantial number of small entities. Therefore, under the Regulatory
Flexibility Act, no further analysis is required.
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 $115 million using the most current (2003) 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.
For a further discussion of the impacts of this rulemaking, see the
Analysis of Impacts section in the corresponding direct final rule
published in the final rules section of this issue of the Federal
Register.
VI. Paperwork Reduction Act of 1995
This proposed rule contains no new information collection
requirements that are subject to review by the Office of Management and
Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-
3520). Under the proposed rule, the production of human drug products,
including biological drug products, intended for use in Phase 1
clinical trials would be exempted from complying with the specific
regulatory requirements set forth in parts 210 and 211. Parts 210 and
211 contain information collection requirements that have been approved
by OMB under control number 0910-0139. As explained in the following
paragraph, the information collection requirements in parts 210 and 211
would be reduced under this proposed rule.
The OMB-approved hourly burden to comply with the information
collection requirements in parts 210 and 211 (control number 0910-0139)
is 848,625 hours. FDA estimates that, under the proposed rule,
approximately 7,315 drugs would be exempted from complying with the
specific regulatory requirements set forth in parts 210 and 211. Based
on this number and the total number of drugs that are subject to parts
210 and 211, FDA estimates that the burden hours approved under control
number 0910-0139 would be reduced by approximately 50,493 hours. Thus,
as a result of the proposed rule, the amended burden hours in control
number 0910-0139 would be approximately 798,132 hours.
VII. Federalism
FDA has analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. FDA
[[Page 2496]]
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. We invite comments on the federalism implications of this
proposed rule.
VIII. Request for Comments
Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) written or electronic comments regarding this document.
This comment period runs concurrently with the comment period for the
direct final rule; any comments received will be considered as comments
regarding the direct final rule. Submit a single copy of electronic
comments or two paper copies of any mailed comments, except that
individuals may submit one paper copy. Comments are to be identified
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.
List of Subjects in 21 CFR Part 210
Drugs, Packaging and containers.
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 part 210 be amended as follows:
PART 210--CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING,
PROCESSING, PACKING, OR HOLDING OF DRUGS; GENERAL
1. The authority citation for 21 CFR part 210 continues to read as
follows:
Authority: 21 U.S.C. 321, 351, 352, 355, 360b, 371, 374; 42
U.S.C. 216, 262, 263a, 264.
2. Section 210.2 is revised by adding paragraph (c) to read as
follows:
Sec. 210.2 Applicability of current good manufacturing practice
regulations.
* * * * *
(c) An investigational drug for use in a Phase 1 study, as defined
in Sec. 312.21(a) of this chapter, is subject to the statutory
requirements set forth at 21 U.S.C. 351(a)(2)(B). The production of
such drug is exempt from compliance with the regulations in part 211 of
this chapter. However, this exemption does not apply to an
investigational drug for use in a Phase 1 study once the
investigational drug has been made available for use by or for the
sponsor in a Phase 2 or Phase 3 study, as defined in Sec. 312.21(b)
and (c) of this chapter, or the drug has been lawfully marketed. If the
investigational drug has been made available in a Phase 2 or 3 study or
the drug has been lawfully marketed, the drug for use in the Phase 1
study must comply with part 211 of this chapter.
Dated: January 9, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 06-350 Filed 1-12-06; 8:45 am]
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