[Federal Register Volume 71, Number 10 (Tuesday, January 17, 2006)]
[Proposed Rules]
[Pages 2494-2496]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 06-350]


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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Register, FDA is announcing the availability of a draft guidance for 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://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

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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]
BILLING CODE 4160-01-S