
[Federal Register: July 15, 2008 (Volume 73, Number 136)]
[Rules and Regulations]               
[Page 40453-40463]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr15jy08-1]                         


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Rules and Regulations
                                                Federal Register
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[[Page 40453]]



DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 210

[Docket No. FDA-2005-N-0170] (formerly Docket No. 2005N-0285)

 
Current Good Manufacturing Practice and Investigational New Drugs 
Intended for Use in Clinical Trials

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending the current 
good manufacturing practice (CGMP) regulations for human drugs, 
including biological products, to exempt most phase 1 investigational 
drugs from complying with the regulatory CGMP requirements. FDA will 
continue to exercise oversight of the manufacture of these drugs under 
FDA's general statutory CGMP authority and through review of the 
investigational new drug applications (IND).
    In addition, elsewhere in this issue of the Federal Register, FDA 
is announcing the availability of a guidance document entitled 
``Guidance for Industry: CGMP for Phase 1 Investigational Drugs'' dated 
November 2007 (the companion guidance). This guidance document sets 
forth recommendations on approaches to compliance with statutory CGMP 
for the exempted phase 1 investigational drugs.
    FDA is taking this action to focus a manufacturer's effort on 
applying CGMP that is appropriate and meaningful for the manufacture of 
the earliest stage investigational drug products intended for use in 
phase 1 clinical trials while ensuring safety and quality. This action 
will also streamline and promote the drug development process.

DATES: This rule is effective September 15, 2008.

FOR FURTHER INFORMATION CONTACT: Monica Caphart, Center for Drug 
Evaluation and Research (HFD-320), Food and Drug Administration, 10903 
New Hampshire Ave., Silver Spring, MD 20993, 301-796-3248, or
    Christopher Joneckis, Center for Biologics Evaluation and Research 
(HFM-1), Food and Drug Administration, 1401 Rockville Pike, Rockville, 
MD 20852, 301-827-5000.

SUPPLEMENTARY INFORMATION:

I. Rulemaking Procedure

    In the Federal Register of January 17, 2006 (71 FR 2458), FDA 
published a direct final rule to amend Sec.  210.2 (21 CFR 210.2) to 
exempt most phase 1 investigational drugs from complying with the CGMP 
requirements in parts 210 and 211 (21 CFR parts 210 and 211). We 
explained that we issued this rule as a direct final rule because we 
believed it was non-controversial and that there was little likelihood 
of receiving significant adverse comments. We concurrently published in 
the Federal Register of January 17, 2006 (71 FR 2494) a companion 
proposed rule, identical in substance to the direct final rule, that 
provided a procedural framework from which to proceed with standard 
notice-and-comment rulemaking in the event we were required to withdraw 
the direct final rule because of significant adverse comments. A 
significant adverse comment is defined as a comment 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 change. Any comments received under the companion proposed rule 
were treated as comments regarding the direct final rule and vice 
versa. A full description of FDA's policy on direct final rule 
procedures may be found in a guidance document published in the Federal 
Register of November 21, 1997 (62 FR 62466).
    We received 14 comments on the proposed rule, of which several were 
considered to be significant adverse comments. Therefore, in the 
Federal Register of May 2, 2006 (71 FR 25747), we withdrew the direct 
final rule. This final rule summarizes and responds to the comments 
received on the direct final rule and proposed rule. See section V of 
this document for a discussion of the comments and FDA's responses.
    Together with the companion guidance, this final rule will assist 
the drug development process by streamlining the application of CGMP 
that is more appropriate to the manufacture of the earliest stage 
investigational drug products--those intended for use in phase 1 
clinical trials.

II. Background

    A phase 1 clinical trial includes the initial introduction of an 
investigational new drug product, including biological drug products, 
into humans. Such studies are conducted to establish the basic safety 
of the drug, and are designed to determine the metabolism and 
pharmacologic actions of the drug in humans. The total number of 
subjects in a phase 1 clinical trial is limited generally to no more 
than 80 subjects. This is in contrast to phase 2 and phase 3 clinical 
trials when a substantially greater number of subjects are involved, 
more subjects are exposed to the drug product, and the effectiveness of 
the drug product is also tested in addition to safety. During phase 2 
or phase 3, drug products may also be made available for treatment use 
through one of several mechanisms for expanded access to 
investigational drugs.
    FDA's general CGMP regulations for human drugs are set forth in 
parts 210 and 211. Although the preamble to a final rule published in 
the Federal Register of September 29, 1978 (43 FR 45014) (the 1978 
final rule) issuing these regulations expressly stated that the CGMP 
regulations applied to investigational drug products, it also raised 
the possibility of proposing an additional CGMP regulation to cover 
drugs being used in research: ``The Commissioner finds that, as stated 
in Sec.  211.1, these CGMP regulations apply to the preparation of any 
drug product for administration to humans or animals, including those 
still in investigational stages. It is appropriate that the process by 
which a drug product is manufactured in the development phase be well 
documented and controlled in order to assure the reproducibility of the 
product for further testing and for ultimate commercial production. The 
Commissioner is considering proposing

[[Page 40454]]

additional CGMP regulations specifically designed to cover drugs in 
research stages'' (43 FR 45014 at 45029). Such additional regulations 
have never been issued.
    On February 21, 1991, FDA issued a guidance document entitled 
``Preparation of Investigational New Drug Products (Human and Animal)'' 
(56 FR 7048) (the 1991 guidance). That document, however, did not 
discuss all manufacturing scenarios, and did not clearly address small- 
or laboratory-scale production of drug products for use in phase 1 
clinical trials. Additionally, the 1991 guidance did not fully discuss 
FDA's expectations on appropriate approaches to manufacturing controls 
for batches produced during drug development.
    For several reasons, FDA believes that production of human drug 
products, including biological drug products, intended for use in phase 
1 clinical trials (phase 1 investigational drugs) should be exempted 
from complying with the specific regulatory requirements set forth in 
parts 210 and 211. First, even if exempted from the requirements of 
parts 210 and 211, investigational drugs remain subject to the 
statutory requirement that deems a drug adulterated if ``* * * the 
facilities or controls used for, its manufacture, processing, packing, 
or holding do not conform to or are not operated or administered in 
conformity with current good manufacturing practices to assure that 
such drug meets the requirements of this chapter [of the Federal Food, 
Drug, and Cosmetic Act (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'' (section 501(a)(2)(B) of the 
act (21 U.S.C. 351(a)(2)(B))). Second, FDA oversees drugs for use in 
phase 1 trials through its 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 (Sec.  312.23(a)(7) (21 CFR 
312.23(a)(7))). Submission of this information, along with other 
information required in the IND, informs FDA of the steps that the 
manufacturer is taking to ensure the safety and quality of the 
investigational drug. Under this IND authority, FDA has the option to 
place an IND on clinical hold if the study subjects would be exposed to 
unreasonable and significant risk or if the IND does not contain 
sufficient information to assess the risks to subjects (21 CFR 312.42). 
FDA also may terminate an IND if the methods, facilities, and controls 
used for the manufacturing, processing, and packing of the 
investigational drug are inadequate to establish and maintain 
appropriate standards of identity, strength, quality, and purity as 
needed for subject safety (21 CFR 312.44(b)(1)(iii)).
    Thus, even though FDA is exempting phase 1 drug products from 
compliance with the specific requirements of the CGMP regulations, FDA 
retains the ability to take appropriate actions to address 
manufacturing issues. For example, in addition to the authority to put 
an IND on clinical hold or terminate an IND, FDA may initiate an action 
to seize an investigational drug or enjoin its production if its 
production does not occur under conditions sufficient to ensure the 
identity, strength, quality, and purity of the drug, which may 
adversely affect its safety.
    FDA believes this change in the CGMP regulations (parts 210 and 
211) is appropriate because many of the issues presented by the 
production of investigational drugs intended for use in the relatively 
small phase 1 clinical trials are different from issues presented by 
the production of drug products for use in the larger phase 2 and phase 
3 clinical trials or for commercial marketing. We are considering 
additional guidance and regulations to clarify FDA's expectations with 
regard to fulfilling CGMP requirements when producing investigational 
drugs for phase 2 and phase 3 clinical trials.
    Additionally, many of the specific requirements in the regulations 
in part 211 do not apply to the conditions under which many drugs for 
use in phase 1 clinical trials are produced. For example, the concerns 
underlying the regulations' requirement for fully validated 
manufacturing processes, rotation of the stock for drug product 
containers, the repackaging and relabeling of drug products, and 
separate packaging and production areas are generally not concerns for 
these very limited production investigational drug products used in 
phase 1 clinical trials.
    Consequently, in this final rule, FDA is amending the scope section 
of the drug CGMP regulations in part 210 to make clear that production 
of investigational drugs for use in phase 1 clinical trials conducted 
under an IND does not need to comply with the regulations in part 211. 
However, once an investigational drug product has been manufactured by, 
or for, a sponsor and is available for use in a phase 2 or phase 3 
study, thus demonstrating an intent to expose more subjects to the 
investigational drug and requiring that the regulations' CGMP 
requirements be met, the same investigational drug product used in any 
subsequent phase 1 study by the same sponsor must be manufactured in 
compliance with part 211. In addition to drug products that, if 
eventually approved, would be approved under section 505 of the act (21 
U.S.C. 355), this rule applies to investigational biological products 
that are subject to the CGMP requirements of section 501(a)(2)(B) of 
the act. Examples of such products include recombinant and non-
recombinant therapeutic products, vaccine products, allergenic 
products, in vivo diagnostics, plasma derivative products, blood and 
blood products, gene therapy products, and somatic cellular therapy 
products (including xenotransplantation products) that are subject to 
the CGMP requirements of section 501(a)(2)(B) of the act. Therefore, 
this final rule exempts the production of phase 1 investigational drugs 
from complying with the regulatory requirements set forth in parts 210 
and 211.

III. Legal Authority

    Under section 501(a)(2)(B) of the act, 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 FDA to amend its 
regulations as contemplated by this final rule. Section 701(a) of the 
act (21 U.S.C. 371(a)) gives FDA, through delegation from the Secretary 
of the Department of Health and Human Services, general rulemaking 
authority to issue regulations for the efficient enforcement of the 
act. We refer readers to section V of the preamble of the 1978 final 
rule for a fuller discussion of our CGMP rulemaking authority (43 FR 
45014 at 45020-45026).

IV. Summary of the Final Rule

    This final rule adds paragraph (c) to Sec.  210.2, exempting 
certain investigational drugs for use in a phase 1 clinical trial 
(including biological drugs) from compliance with part 211. However, 
these drugs remain subject to the statutory requirements under section 
501(a)(2)(B) of the act, i.e., CGMP. The regulation also explains that 
the exemption from compliance with part 211 does not apply to an 
investigational drug that a sponsor has made available

[[Page 40455]]

for a phase 2 or phase 3 clinical trial, or has lawfully been marketed, 
and is being used for a phase 1 clinical trial. Such investigational 
drug products used for a phase 1 clinical trial must comply with part 
211.
    We have also changed the term ``defined'' to ``described'' for 
clarification.

V. Comments on the Proposed Rule and FDA's Responses

    We received approximately 14 comments on the proposed rule. Several 
comments were duplicate submissions by the same entity; several other 
comments submitted to the docket pertained to the draft guidance under 
a separate docket number. These comments were also considered in 
revising the draft guidance. The following responses are specific to 
the comments on the proposed rule.

A. General Comments

    (Comment 1) Several comments welcome the proposed changes and 
commend FDA for revising the regulations to exempt phase 1 
investigational drugs from regulatory CGMP under part 211. One comment 
adds that, because most products do not proceed beyond the clinical 
trial phase of development, the burden of full compliance with CGMP at 
the phase 1 stage far outweighs any perceived benefit and suggests that 
FDA devise a progressive scale for CGMP compliance beginning with phase 
1 clinical trials through approval to market the product.
    (Response) We appreciate these supportive comments. Our expectation 
in issuing this final rule is that sponsors will take an appropriate 
approach to instituting manufacturing controls appropriate for the 
stage of investigational drug development.
    (Comment 2) Some comments oppose exempting phase 1 investigational 
drugs from compliance with part 211 because they are concerned that 
there could be an effect on product safety and human subject 
protection. Another comment believes that FDA's proposed approach to 
exempt phase 1 investigational drugs from the applicability of part 211 
not only invites greatly reduced product standards, but affects FDA's 
ability to take remedial action. One reason given was that FDA does not 
have the personnel to monitor the manufacture of phase 1 
investigational drugs during clinical trials. Another comment believes 
that if the phase 1 investigational drugs are not reproducible, not 
well-documented, or not well-controlled, the results of the trial will 
be meaningless and delay availability of new drugs for commercial use. 
The comment continued to state that an establishment could interpret 
FDA's proposal as loosening the basic requirements needed for phase 1 
material, which would not only jeopardize patients and the results of 
the phase 1 clinical trial, but also the investigational stages of 
development that follow.
    (Response) We are confident that exempting phase 1 investigational 
drugs from the CGMP regulations in part 211 will not jeopardize product 
safety or human subject protection. This action is intended to focus a 
manufacturer's effort on applying CGMP that is appropriate and 
meaningful for the manufacture of the earliest stage investigational 
drug products intended for use in phase 1 clinical trials, while also 
ensuring the products' safety and quality. An additional consequence of 
this action is to streamline and promote the drug development process. 
The companion guidance provides our current thinking on ways to comply, 
through the use of specified quality controls, with statutory CGMP for 
the production of phase 1 investigational drugs. As previously 
described, we will continue to oversee product safety and human subject 
protection through articulation of statutory CGMP requirements, 
clarified in the companion guidance, and a thorough review of the 
chemistry, manufacturing, and control information submitted in the IND 
application for identity, quality, purity, strength, and potency of the 
investigational drug necessary to ensure the safety of the subjects in 
the phase 1 clinical trial. We believe that this exemption does not 
``loosen'' the requirements, but establishes quality control principles 
that are appropriate and comprehensive for the manufacture of phase 1 
investigational drugs, i.e., interpreting and implementing CGMP 
consistent with good scientific methodology.
    We also believe that the exemption will not affect or change our 
ability to take remedial action if necessary, or to monitor the 
manufacture of such investigational drugs; nor do we believe that this 
action will delay availability of new drugs for commercial use. As 
stated elsewhere in this document and in the proposed rule, compliance 
with CGMP is required by section 501(a)(2)(B) of the act and a drug can 
be deemed adulterated by FDA for failure to comply with statutorily 
mandated CGMP.
    (Comment 3) One comment states that the proposed rule was 
misleading and unclear. The comment asserts, correctly, that a phase 1 
investigational drug used in phase 2 and phase 3 clinical trials must 
comply with part 211, but argues that the progression of the study to 
phase 2 and phase 3 is unknown at the time of the phase 1 
investigational drug production. Therefore, the sponsor will most 
likely produce the phase 1 investigational drug in compliance with part 
211 in lieu of not being able to use data from the phase 1 study for 
phase 2 and phase 3.
    (Response) We disagree that the proposed rule was misleading and 
unclear. In the preamble to the direct final rule (71 FR 2458 at 2459), 
we explained that we believe the exemption for phase 1 investigational 
drugs ``is appropriate because many of the issues presented by the 
production of investigational drugs intended for use in the relatively 
small Phase 1 clinical trials are different from issues presented by 
the production of drug products for use in the larger Phase 2 and Phase 
3 clinical trials or for commercial marketing.'' Given the differences 
between phase 1 clinical trials and phase 2 and phase 3 clinical trials 
discussed in section II of this document, we believe compliance with 
the particular regulations in part 211 is not appropriate for phase 1 
investigational drugs because many of the specific requirements in part 
211 do not apply to the manufacture of phase 1 investigational drugs in 
the same manner because they were intended to apply to commercial drug 
manufacture. For example, rotation of the stock for drug product 
containers, the repackaging and relabeling of drug products, and 
separate packaging and manufacturing areas are generally not of concern 
for the limited production of phase 1 investigational drugs. 
Additionally, the requirement for fully validated manufacturing 
processes may not be appropriate for this early stage of development. 
We believe that recommending approaches and considerations, and 
allowing the manufacturer to develop specific controls appropriate for 
the particular product, manufacturing process, and facility in order to 
comply with statutory CGMP requirement is less burdensome and more 
efficient for the sponsor. We agree that drug products used in phase 2 
and phase 3 clinical trials may be improved or refined (i.e., 
manufacturing process and/or product) based on the results of the phase 
1 clinical trial. However, limiting the exemption from compliance with 
the regulations in part 211 to drugs for use in phase 1 clinical trials 
(and not extending it to drugs that a sponsor has made available for a 
phase 2 or phase 3 clinical trial, or has lawfully marketed) does not 
preclude the use of

[[Page 40456]]

data from a phase 1 clinical trial for phase 2 and phase 3. While it is 
true that some sponsors may choose to manufacture phase 1 
investigational drugs in compliance with the regulatory requirements in 
part 211 in anticipation of expansion of the product into phase 2 
clinical trials, this rule does not require that they do so, and it is 
up to the manufacturer to determine whether it makes sense in their 
particular case to manufacture the phase 1 drug in compliance with the 
regulations in part 211.
    (Comment 4) One comment states that FDA is ignoring past reports of 
phase 1 clinical trial failure, i.e., the two subject deaths in phase 1 
clinical trials conducted at Johns Hopkins University and the 
University of Pennsylvania, and the six subjects who experienced major 
organ failure in a phase 1 clinical trial in England. The comment also 
adds that there have been several deaths and recalls due to drugs 
compounded by pharmacists and an increase of recalls of medical devices 
due to CGMP noncompliance. The comment also makes the statement that 
FDA should not assume that a medical researcher or other employee would 
be able to make safe phase 1 materials following guidance.
    (Response) We disagree with the comment highlighting the cases as a 
reason for not issuing this final rule. Investigations of the 
referenced cases found no evidence to suggest that the adverse events 
were caused by the manufacturing of the phase 1 investigational drug 
(Refs. 1, 2, and 3), and neither the British not the Johns Hopkins 
studies had been submitted to FDA under IND, and so had consequently 
not been prospectively reviewed by FDA (See http://www.fda.gov/cder/
warn/2003/02-hfd-45-0303.pdf), and thus, we are of the opinion that 
nothing in this final rule would have affected the outcome of any of 
the specific cases mentioned as we are not aware that CGMP was 
deficient or contributed to the deaths. As to the implication in the 
comment that these three cases indicate that there are risks in the 
manufacture of drugs for use in phase 1 clinical trials, we believe 
that there is risk in the manufacture of any drug, whether 
investigational or not and regardless of the stage of testing. We note, 
again, that investigational drugs for use in phase 1 clinical trials 
remain subject to statutory CGMP, and a companion guidance is being 
issued concurrent with this rule to provide suggested approaches for 
complying with statutory CGMP for phase 1 investigational drugs.
    With regard to the comment on pharmacy compounding errors, the 
reported instances of recalls due to drugs compounded by pharmacists 
are not analogous to producing drugs for phase 1 clinical trials, which 
is the subject of this rulemaking. Moreover, the comment concerning an 
increase of medical device recalls due to CGMP noncompliance apparently 
assumes that this final rule relieves phase 1 investigational drugs of 
compliance with any CGMP requirements. However, as previously 
discussed, this final rule exempts phase 1 investigational drugs only 
from regulatory CGMP requirements in parts 210 and 211. The statutory 
requirement to comply with CGMP still applies. We note that, in 
addition to the considerations described in the guidance, reference to 
technical information and appropriate training are necessary to comply 
with statutory CGMP.

B. CGMP Regulation Specific to Phase 1 Investigational Drugs

    (Comment 5) Several comments request that FDA engage stakeholders 
and issue a new rulemaking for CGMP specific to phase 1 investigational 
drugs. One comment suggests that FDA apply the comments submitted to 
the docket on the proposed rule and draft guidance in proposing a new 
rule. Another comment suggests that FDA amend only the relevant 
requirements, e.g., on the repackaging and relabeling of drug products, 
retaining the oversight in all phases of a clinical trial of a drug.
    (Response) We appreciate the comments and will consider the 
appropriateness of such a proposed rule. For current purposes, however, 
we intend to proceed directly from the statute, and direct the public 
to the companion guidance that is being issued concurrently with this 
rule, suggesting some approaches to comply with statutory CGMP for 
phase 1 investigational drugs.

C. Scope

    (Comment 6) One comment requests FDA to clarify the scope of the 
rulemaking, i.e., that the scope does not include active pharmaceutical 
ingredients (API).
    (Response) The scope of the exemption from compliance with part 211 
includes investigational new human drug and biological products, 
including finished dosage forms used as placebos, for human use in a 
phase 1 study or trial. Examples of such investigational drugs include, 
but are not limited to, the following:
     Investigational recombinant and non-recombinant 
therapeutic products,
     Vaccine products,
     Allergenic products,
     In vivo diagnostic products,
     Plasma derivative products,
     Blood and blood components\1\,
     Gene therapy products, and
     Somatic cellular therapy products (including 
xenotransplantation products).
    However, if such products have already been manufactured by an IND 
sponsor for use during phase 2 or phase 3 clinical trials or have been 
lawfully marketed, the manufacture of such a product must comply with 
the appropriate requirements of part 211 for the product to be used in 
any subsequent phase 1 clinical trial, irrespective of the trial size 
or duration of dosing.
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    \1\ You should consult with the Office of Blood Research and 
Review, Center for Biologics Evaluation and Research (CBER), to 
determine circumstances when an IND would be required for blood or a 
blood component. Manufacturers of blood and blood components 
intended for transfusion and for further manufacture must still 
comply with the applicable regulations in 21 CFR parts 600 through 
660.
---------------------------------------------------------------------------

    Manufacturers of new active pharmaceutical ingredients (also 
referred to as ``API'' or ``drug substance'') are already exempt from 
compliance with part 211 and must also conform with CGMP as required in 
section 501(a)(2)(B) of the act. Thus, this rule does not change in any 
way how APIs are regulated with regard to CGMP. As stated in the 
companion guidance, limited guidance on CGMP for the manufacture of new 
API for some IND products used in clinical trials is also available 
(see International Conference on Harmonisation (ICH) Q7A GMP Guide for 
API (ICH Q7A guidance)). Manufacturers of APIs should implement 
controls appropriate to the stage of development and, thus, should also 
consider the recommendations described in the companion guidance for 
manufacture of API used in investigational drug products for phase 1 
clinical trials.
    (Comment 7) In the direct final rule, FDA makes the statement 
``[T]his action is intended to streamline and promote the drug 
development process'' (71 FR 2458 at 2459). One comment believes that 
this proposal is outside the scope of FDA's mission mandated by 
Congress, i.e., to ``promote the public health by promptly and 
efficiently reviewing clinical research and taking appropriate action 
on the marketing of regulated products in a timely manner'' and ``with 
respect to such products, protect the public health by ensuring that * 
* * human and veterinary drugs are safe and effective.'' The comment

[[Page 40457]]

further states that FDA was established to serve as a consumer 
protection agency and a check and balance on regulated industry.
    (Response) As section III of this document notes, CGMP is required 
by section 501(a)(2)(B) of the act, and FDA has been given the general 
authority to issue regulations for the efficient enforcement of the 
act. We note here as well that, under section 505(i) of the act, FDA is 
directed to issue regulations for exempting from the requirements of 
section 505 ``drugs intended solely for investigational use by experts 
qualified by scientific training and experience to investigation the 
safety and effectiveness of drugs,'' which include drugs for use in 
phase 1 clinical trials. While we agree that FDA is an agency whose 
public health mission demands an emphasis on safety, we note that this 
does not require us to impose burdens on drug development that do not 
have a commensurate public health benefit. We believe that this final 
rule is appropriate because many of the regulatory requirements in part 
211 simply are not applicable to the manufacture of products intended 
for use in phase 1 clinical trials, and that the agency can continue to 
protect human subjects via interpretation of statutory CGMP and the IND 
process.

D. Direct Final Rule and Companion Proposed Rule Approach

    (Comment 8) A couple of comments object to the direct final rule/
companion proposed rule approach (rulemaking approach). One comment 
believes that the process did not allow for a discussion regarding the 
quality of clinical trial material, i.e., the establishment of 
meaningful, consistent standards that balance patient protection with 
speed of development. The comment then suggests that FDA work with 
industry to address industry-wide questions about quality for clinical 
trial materials, e.g., equipment qualification, water quality, method 
validation or qualification, sterility assurance, control of 
contractors, complaints, cleaning, and specifications.
    (Response) We disagree with the assertion that we did not allow for 
a discussion regarding the quality of clinical trial material. In 
developing the companion guidance, we utilized our experience with IND 
submissions and facility inspections. In addition, comments submitted 
to the docket were considered in finalizing the rule and the companion 
guidance, as well as stakeholder comments provided in multiple venues 
where FDA representatives discussed the proposed rule and draft 
guidance. Both the companion guidance and relevant IND regulations 
emphasize safety as the primary focus of phase 1 clinical trials. The 
companion guidance is written to allow for flexibility in utilizing 
appropriate CGMP controls for the product, manufacturing process, and 
facility to assure product safety. We will continue to work with 
stakeholders to refine appropriate standards as needed through 
continued discussions and meetings in various venues with stakeholders.
    (Comment 9) One comment states that FDA does not have the expertise 
to issue guidance or regulation without stakeholder input and adds that 
the manufacture of clinical supplies is a complex matter in which FDA 
has almost no experience. The comment also states that FDA lacks 
expertise in clinical GMP compliance because FDA has performed few 
inspections of early clinical supply material.
    (Response) We disagree with this comment. The decision to generate 
guidance for this early phase of clinical trial manufacture was due 
primarily to the constant requests for guidance in this area from the 
pharmaceutical industry, academia, and other research organizations. 
The publication of the draft guidance and the direct final and proposed 
rules in January 2006 was to address this apparent need, and to seek 
broader stakeholder input. Additionally, we have experience from 
numerous sources, such as participation with stakeholders in related 
workshops and conferences, facility inspections, and other interactions 
that result in sufficient understanding necessary to issue rulemaking 
and companion guidance. Contrary to the suggestion of the comment, 
conducting inspections of early clinical trial material is not the 
exclusive source of FDA expertise in this area.
    (Comment 10) One comment believes that FDA's finding that the 
subject is suitable for this rulemaking approach is based on 
assumptions, not data, such as the results of ``for cause'' 
inspections, treatment IND inspections, or reports of adverse drug 
events occurring during phase 1 clinical trials.
    (Response) We disagree with the comment. In the direct final rule, 
we stated that the rulemaking approach is appropriate because many of 
the issues present in the manufacture of phase 1 investigational drugs 
are different from those issues presented by the manufacture of drugs 
for later investigational phases or for commercial marketing, and that 
many of the specific requirements in part 211 are not applicable in the 
manufacture of the smaller batches of investigational drugs usually 
used in phase 1. These statements are not based on assumptions, as the 
comment suggests, but on the knowledge of, and experience with, good 
manufacturing practice for phase 1 investigational drugs.
    (Comment 11) One comment states that the proponents of the 
rulemaking approach cite the successful use of ICH Q7A guidance and its 
use during inspections without the need for a regulation. The comment 
suggests that the possible reason for the successful use is that the 
ICH Q7A guidance is more detailed than the draft guidance and is used 
to manufacture material that is further processed before being 
delivered to patients.
    (Response) We disagree with the comment. Due to the more defined 
routes of manufacture of APIs, and the general application of CGMP to 
APIs in the companion guidance, the ICH Q7A guidance was able to 
provide more detail for the commercial manufacture of APIs. Early phase 
clinical trial material may use many different routes of manufacture, 
some of which may be new and innovative. In addition, the 
recommendations or expectations contained in the ICH Q7A guidance (see 
section XIX of that guidance, on APIs for use in clinical trials) 
utilize an approach to CGMP similar to that outlined in the companion 
guidance. For the reason stated in response to comment 4, we believe 
that the companion guidance provides adequate considerations when 
supplemented with additional technical information and appropriate 
training to comply with CGMP.

E. Exemption From Part 211

    (Comment 12) One comment believes that compliance with statutory 
CGMP requirements and exemption of phase 1 investigational drugs from 
the requirements in part 211 subjects phase 1 investigational drugs to 
unwritten standards, developed case-by-case without any input from the 
public or industry. The comment also states that unwritten standards 
would lead to differing interpretations within FDA, e.g., by individual 
investigators, district offices, and review divisions. Inconsistency, 
non-transparency, and uncertainty slow product development as the 
industry tries to comply on a shifting landscape of uncertain legal 
basis.
    (Response) We disagree with the comment. We believe that we have 
provided sufficient opportunity for the public and industry to comment 
on the proposed exemption of phase 1 investigational drugs from 
compliance

[[Page 40458]]

with part 211, the draft guidance, and the impact of such action. The 
purpose of the companion guidance is to provide recommendations for 
compliance with statutory CGMP and to promote consistency in 
compliance. The companion guidance is intended for use not only by 
industry, but also by FDA staff to assist in fulfilling their review 
and enforcement responsibilities. It bears emphasis that, because FDA 
has set forth its interpretation of some acceptable approaches to 
statutory CGMP in the companion guidance, as opposed to a rule, we 
remain open to alternative approaches to compliance, so long as they 
provide comparable safety and protection for human subjects. We believe 
this approach maximizes flexibility and minimizes burden, without 
diminishing safety protections.
    (Comment 13) One comment states that unclear rules erode quality. 
For example, financially strapped companies will not be able to justify 
expenses based on recommendations in a draft guidance. Inevitably, some 
companies will stumble, and quality will drop.
    (Response) Industry is not obligated to implement draft guidance. 
Draft guidance is for the purpose of soliciting comments on FDA's 
current thinking on a subject.
    In Sec.  10.115(d)(1) (21 CFR 10.115(d)(1)), we explain that 
guidance does not legally bind the public or FDA. Therefore, a 
financially strapped company may choose to use a less expensive 
approach other than the one recommended in a guidance, but the 
alternative approach must comply with the relevant statutes and 
regulations in assuring patient safety, and the company would be 
prudent to consult FDA before using the alternative approach. As 
previously stated in our response to comment 12, we believe this rule 
maximizes flexibility and minimizes burden without diminishing safety 
protections.
    (Comment 14) One comment believes that regulatory CGMP provides 
minimum, legal requirements to safely make drugs or biologics made for 
use in humans. Another comment states that, instead of the detailed, 
enforceable standards laid out in part 211, FDA proposes to rely upon 
three sources of authority that are variously lacking in detail and/or 
enforceability, i.e., the statutory authority (section 501(a)(2)(B) of 
the act), the IND submission requirements in Sec.  312.23, and the 
draft guidance.
    (Response) We disagree with this comment, and believe the comment 
confuses the requirements of the statute and the regulations. Many of 
the regulatory requirements in part 211 are not readily applicable to 
the manufacture of investigational drugs for use in phase I clinical 
trials. As previously stated, because such products still must comply 
with statutory CGMP, and because FDA has offered suggestions for 
acceptable methods for complying with statutory CGMP, we believe that 
manufacturers will have sufficient guidance to know what they must do 
to safely make drugs or biologics for such early stage clinical trial 
use in humans. We dispute the assertion that we are eschewing detailed, 
enforceable standards in favor of relying upon three sources of 
authority that are variously lacking in detail and/or enforceability. 
Statutory CGMP remains enforceable and we are issuing a companion 
guidance that details acceptable approaches for complying with 
statutory CGMP, and FDA's authority to place clinical trials on hold 
(under its IND authority) remains unchanged.
    (Comment 15) One comment states that FDA assumes that, once this 
rulemaking is final and phase 1 investigational drugs are exempt from 
complying with part 211, new sponsors would keep proper records, 
perform necessary testing, or keep retention samples for later 
investigations, or that they would take the time to learn and follow 
CGMP if there were no regulations requiring them to do so. Another 
comment states that FDA, without evidence, claims that having to 
actually produce drug or biological products according to accepted 
international standards is a barrier too high for entry into phase 1 
studies. The comment continues to say that such barriers do serve a 
social purpose, i.e., preventing those incapable of following or 
unwilling to follow CGMP from administering investigational products to 
humans.
    (Response) As mentioned in the preamble to the proposed rule and 
draft companion guidance, application of part 211 is not appropriate to 
the production of IND products used in phase 1 studies. The type and 
extent of CGMP for investigational studies differs from those typically 
employed for routine commercial manufacturing, and in some cases may 
even include more stringent controls for certain manufacturing 
operations of investigational products. We believe that the proposed 
rule and the draft companion guidance better communicate FDA 
expectations and facilitates compliance with CGMP for the production of 
phase 1 investigational drugs rather than trying to apply existing part 
211 regulations. Our expectation that phase 1 investigational drugs be 
manufactured following appropriate CGMP in adequate manufacturing 
facilities has not diminished with the adoption of this approach.
    FDA is not claiming that the manufacture of a drug or biological 
product for use in phase 1 studies according to international standards 
presents too high a barrier. FDA's position is that the United States' 
good manufacturing practice regulations were written primarily to 
address commercial manufacturing and do not consider the differences 
between early clinical supply manufacture and commercial manufacture. 
The final rule and companion guidance are intended to address these 
differences, while still requiring all drugs for human consumption, 
including those used in clinical trials, to be manufactured in 
accordance with CGMP as required by section 501(a)(2)(B) of the act.

F. Risk to Patients

    (Comment 16) One comment maintains that FDA understates the risk to 
patients. The comment continues to say that the CGMP regulations are 
designed to protect patients from mishaps that would have major impact 
on the clinical subject, e.g., contamination with bacteria, penicillin, 
or industrial cleaning agents; and product mix-ups. Another comment 
believes that Sec.  312.23, which requires companies to submit 
information about the clinical material, has nonexistent patient 
protections, and that submitting general information is no substitute 
for compliance with CGMP.
    (Response) We disagree with the assertion that we understated the 
risk to subjects (patients). We believe that there is no additional 
risk to subjects with this exemption, and have provided recommendations 
that interpret and implement CGMP consistent with good scientific 
methodology. In complying with section 501(a)(2)(B) of the act, a 
manufacturer must manufacture the drug in conformity with good 
manufacturing practice to assure that the 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. If the drug does not meet these criteria, the 
drug is considered adulterated and therefore a possible risk to 
subjects. Because the statutory requirements allow for flexibility in 
describing CGMP, we have issued the companion guidance to recommend 
CGMP for phase 1 investigational drugs. These recommended quality 
controls for

[[Page 40459]]

producing a phase 1 investigational drug are specifically designed to 
ensure subject safety.
    (Comment 17) One comment believes that the exemption of phase 1 
investigational drugs from part 211 puts patients at risk because it is 
difficult to prove what CGMP is, and makes it difficult for FDA to 
investigate or prosecute serious cases. The comment also states that a 
quality assurance (QA) unit is required for preclinical studies and a 
quality control (QC) unit is required for phase 2 and phase 3 studies. 
However, the new approach does not provide for a QA or QC unit for 
phase 1 studies.
    (Response) We disagree with this comment. As previously discussed 
in section II of this document, CGMP consists of steps that a 
manufacturer takes to ensure the safety and quality of the 
investigational drug. This information is submitted to FDA in the IND. 
Through FDA's IND authority, FDA has the ability to take appropriate 
actions to address manufacturing issues if there is a safety risk to 
subjects, i.e., place an IND on clinical hold, terminate an IND, seize 
an investigational drug, or prohibit its production.
    The functions performed by QA and/or QC unit(s) appropriate for 
this early phase of clinical trial material manufacture were clearly 
spelled out in the draft companion guidance. We describe in the 
companion guidance the QC functions that should be in effect to 
manufacture in compliance with CGMP for phase 1 clinical trials. It is 
at the discretion of the manufacturer if it wishes to implement these 
responsibilities through separate QA and QC groups.
    (Comment 18) One comment asserts that if the study subjects are 
exposed to unreasonable and significant risk or if the IND does not 
contain sufficient information to assess risk to patients, any action 
by FDA, i.e., placing a clinical hold or terminating an IND, would 
occur after the fact and well after patients are injured in the trial.
    (Response) Sponsors must inform the subjects of clinical trials of 
inherent, unknown risks (21 CFR 50.25). FDA will typically place a 
clinical hold or terminate an IND as a result of evaluating safety 
information provided as part of the IND review. Such evaluations are 
conducted prior to the initiation of the clinical trial. Therefore, we 
can and will, when appropriate, take such actions before the clinical 
trial proceeds. In addition to taking action before the clinical trial 
begins, we also have the ability under statutory CGMP to take 
enforcement actions once the phase 1 clinical trial begins.
    (Comment 19) One comment points out that FDA recognizes that, 
although part 211 applies to phase 2 and phase 3 investigational drugs, 
the extent of the controls varies based on the phase of the clinical 
study. The comments also state that FDA agrees that not all sections of 
part 211 may apply to phase 2 and phase 3 investigational drugs. For 
this reason, the comment suggests revising the last sentence of 
proposed Sec.  210.2(c) to require that the drug for use in phase 1 
study comply with the appropriate sections of part 211. Another comment 
also provided alternative language to Sec.  210.2(c) stating that if 
the investigational drug has been made available for a phase 2 or phase 
3 study or the drug has been lawfully marketed, and the manufacturer 
needs to conduct further phase 1 studies to generate data to support 
the registration of the clinical indication being developed, the drug 
used in the phase 1 clinical trial need not comply with part 211.
    (Response) We disagree with the comment. Because of the wide 
variability in the possible manufacturing processes used to produce 
early phase clinical trial material, it is not feasible to specify what 
parts of part 211 are appropriate in a companion guidance, because what 
may be appropriate for one manufacturing situation may be inappropriate 
for another.
    We decline to use the alternative codified language proposed by the 
comment, which would exempt from the requirements of parts 210 and 211 
investigational drugs used in phase 1 clinical trials where the drugs 
have been lawfully marketed or used in phase 2 or phase 3 clinical 
trials. Because the drug products in question have already been 
manufactured using CGMP as indicated in part 211, the manufacturing 
knowledge is already available and should be fully utilized.
    (Comment 20) One comment reiterates the proposal that phase 1 
investigational drugs would be manufactured following statutory 
requirements and recommendations through guidance for CGMP, and if used 
for a phase 1 clinical trial after available for phase 2 and phase 3 
clinical trials or marketed, the phase 1 material would be manufactured 
using regulatory CGMP. The comment raises the question of the 
possibility that the phase 1 investigational drugs not manufactured per 
the same standard and used on human subjects is unethical. Another 
comment suggests that if only certain phase 1 investigational drugs 
follow CGMP while others are exempt it promotes a situation where 
subject safety may be at risk.
    (Response) We believe that the comment fails to recognize that the 
scope of the specific recommendations for CGMP in support of the 
statutory requirements provides the same, if not additional, protection 
of the phase 1 clinical trial subject. Given that FDA retains oversight 
over these part 211-exempt phase 1 products via the IND mechanism, and 
that the agency is issuing guidance on ways to comply with statutory 
CGMP in the manufacture of such products, we firmly believe that this 
rule presents no safety or ethical issue. However, as discussed 
elsewhere in this preamble, we are requiring that phase 1 
investigational drugs that the sponsor makes available for phase 2 and 
phase 3 clinical trials or as lawfully marketed drugs comply with part 
211. This is because, given the manufacturing scale of a product that 
will be administered beyond a phase 1 trial, such products are more 
like products manufactured for use in phase 2 and phase 3 clinical 
trials or lawfully marketed drugs. The fact that we are requiring 
investigational drugs manufactured in significant enough quantities 
that they are available for phase 2 or phase 3 testing or lawful 
marketing to comply with regulatory CGMP, does not mean that product 
that is manufactured only for use in a phase 1 trial, and is thus 
exempt from complying with regulatory CGMP, is unsafe. The current 
rulemaking exempting products from compliance with part 211 is limited 
to products manufactured exclusively for use in a phase 1 trial and the 
fact that some products used in phase 1 trials will be manufactured in 
compliance with the requirements of part 211 does not mean that 
products that are not so manufactured in compliance with statutory CGMP 
are unsafe.

G. Use of Guidance

    (Comment 21) One comment believes that FDA should not use guidance 
in place of minimum CGMP requirements for the safe manufacture of drugs 
or biologics for human beings. Another comment requests that FDA not 
exempt the manufacture of phase 1 investigational drugs from part 211, 
but instead issue guidance to help manufacturers find innovative, 
simple, and inexpensive approaches to comply with CGMP regulations and 
keep their products safe for the trial subjects.
    (Response) We are not issuing the companion guidance in place of 
minimum CGMP requirements. CGMP is required by statute, and the 
companion guidance provides our current thinking on complying with 
statutory CGMP. As previously stated, this action is

[[Page 40460]]

intended to focus a manufacturer's effort on applying CGMP that is 
appropriate and meaningful for phase 1 investigational drugs, and to 
streamline and promote the drug development process while ensuring the 
safety and quality of the earliest stage investigational drug products. 
We also expect this action to help promote innovative, simple, and 
inexpensive approaches to complying with the statutory CGMP 
requirements. As discussed in our response to comment 13, we are 
willing to discuss with the manufacturer alternative approaches that 
comply with the statutory requirements and that may be more innovative, 
simple, or inexpensive than the recommendations in the companion 
guidance.
    (Comment 22) Several comments express concern that guidance is not 
legally binding and therefore, not enforceable. One of the comments 
states that relying on guidance invites misunderstandings and 
inconsistencies, while another comment believes that if not required 
under part 211, manufacturers may not take the time to read or 
familiarize themselves with guidance related to CGMP, i.e., testing, 
manufacturing sterile or aseptic dosage forms, and employee 
qualification/training. A comment also believes that guidances do not 
undergo the same level of notice and comment, and lacks the complete 
input of interested parties.
    (Response) We agree with the comment that the companion guidance is 
not legally binding and not enforceable. However, the statutory 
requirement that drugs, including investigational drugs for use in 
phase 1 trials, comply with CGMP is legally binding and enforceable. We 
believe that a sponsor, guided by its knowledge, experience, and 
technical information applying good scientific methodology, following 
FDA recommendations, and undertaking appropriate activities (e.g., 
training), can adequately and appropriately comply with statutory CGMP. 
We disagree that relying on guidance invites misunderstandings and 
inconsistencies. In fact, to the contrary, we believe that guidance 
reduces misunderstandings and inconsistencies because guidance provides 
FDA's interpretation of or policy on a regulatory issue, while still 
allowing for flexibility and innovation.
    With regard to adequate notice to, and comment by, interested 
parties on guidance documents, the public can participate in the 
development and issuance of guidance documents as described in Sec.  
10.115(f) and (g), i.e., provide comment on issued draft guidance 
documents, suggest areas for guidance document development, submit 
drafts of proposed guidance documents for FDA to consider, suggest that 
FDA revise or withdraw an already existing guidance document, or 
comment on FDA's annually published list of possible topics for future 
guidance document development or revision. Therefore, we disagree with 
the comment that guidance does not undergo sufficient notice and 
comment, and lacks the complete input of interested parties. Moreover, 
we received extensive comments on the draft companion guidance from 
numerous entities and have considered these comments in preparing the 
companion guidance.
    (Comment 23) Two comments express concern regarding the effect of 
the companion guidance on the 1991 guidance on preparation of INDs, 
which recommends the application of certain sections of parts 210 and 
211 to phase 2 and phase 3 clinical trials. The comments also request 
that FDA clarify the status of the 1991 guidance for phase 2 and phase 
3 materials with regard to complying with CGMP requirements. Another 
comment asks if FDA expects an incremental application of CGMP for the 
production and testing of phase 2 and phase 3 clinical supplies, or if 
the 1991 guidance will remain in effect for phase 2 and phase 3 
materials until the new phase 2 and phase 3 guidance document is 
available.
    (Response) As stated in the introduction of the companion guidance, 
the companion guidance will replace the 1991 guidance only as it 
applies to phase 1 investigational drugs. This action does not affect 
the scope of the 1991 guidance as it applies to phase 2 and phase 3 
investigational drugs, which remains in effect until superseded by a 
subsequent guidance document.
    (Comment 24) One comment states that the guidance would allow the 
same person manufacturing the material (a non-QC unit employee) to also 
release the material to the clinic. The comment further states that the 
release of material by a non-member of the QC unit violates United 
States CGMP and a non-Qualified Person violates European Union CGMP, 
and does not appear to recognize the importance of having an 
experienced and knowledgeable unit or person to safely release the 
materials.
    (Response) We agree with this comment in part. The companion 
guidance recognizes the need to have quality control in this early 
phase of clinical trial material manufacture and has provided 
recommendations for the quality control procedures that should be used. 
We provide flexibility for operations where a very small amount of 
clinical material is produced. While we agree that release of material 
by an untrained person violates United States CGMP, this is not what is 
recommended in the companion guidance, which indicates that, under very 
limited circumstances and where justified, only a person trained in 
CGMP and quality control functions should be given the dual 
responsibility of manufacture and release. The interpretation in the 
companion guidance is consistent with the quality unit functions under 
part 211 and the nature of commercial and investigational products.

H. Impact

    (Comment 25) FDA makes the following statement in the direct final 
rule (71 FR 2458 at 2461). ``For drug manufacturers that produce Phase 
1 drug products in-house and also produce approved drug products, this 
direct final rule is expected to reduce the amount of documentation 
they produce and maintain when they manufacture a Phase 1 drug. In some 
cases, it should also reduce the amount of component and product 
testing.'' Two comments state that because it is unknown at the time of 
clinical manufacture if a phase 1 drug will continue to phase 2, 
manufacturers will likely elect to take a conservative approach and 
manufacture a drug to phase 2 requirements (part 211) to allow the 
phase 1 drug to be used in future phase 2 studies. Because of 
availability concerns in the clinical phase, manufacturers would most 
likely elect to not discard phase 1 material that could be used in 
phase 2. Therefore, the statement regarding savings is questionable.
    (Response) We agree with the comment that some manufacturers may 
decide to follow part 211 when manufacturing phase 1 investigational 
drugs. However, the saving estimate was intended to be an estimate of 
incremental savings should manufacturers chose to follow the companion 
guidance, as some manufacturers will.
    (Comment 26) One comment requests that FDA evaluate the cost of 
compliance against the hypothetical public health risk of a product 
that did not reach the market and the likelihood and severity of risks 
to volunteers. Another comment states that the additional risk to 
patients in a phase 1 clinical trial does not justify the proposed 
savings of $1,440 per IND in documentation, training, and other 
``reduced'' requirements. The comment also states that the potential 
costs of $810 per IND is a gross underestimation

[[Page 40461]]

of how much it will cost to manufacture a sterile or aseptic product 
for the first time.
    (Response) In section V.F of this document, the responses to 
comments 16 through 20 state that there will be no change in the risk 
to patients in phase 1 clinical trials as a result of the final rule. 
The cost estimate was intended to capture the incremental cost of 
complying with the proposed rule given current practice under part 211; 
it does not reflect total costs. A cost-benefit analysis of phase 1 
clinical trials or clinical trials in general is beyond the scope of 
this document.
    (Comment 27) One comment believes that the expense is not for 
compliance with CGMP, especially if systems and procedures are simple, 
but for the training of personnel.
    (Response) Training personnel is a cost of complying with the 
current CGMP regulation; the estimate in the proposed rule captured the 
incremental increase in training costs to comply with the proposed 
rule.

VI. Analysis of Impacts

    FDA has examined the impacts of this final 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 final rule is not a significant regulatory action under the 
Executive order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of the 
rule on small entities. Because exempting production of drugs for use 
in phase 1 clinical trials from compliance with specific regulatory 
requirements does not add to the compliance burden of small entities, 
and in most cases reduces it, 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 $127 million, using the most current (2006) 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.
    The purpose of this final rule is to amend our current CGMP 
regulations to exempt the manufacture of investigational drugs used in 
phase 1 clinical trials from compliance with the requirements in part 
211. The rule affects drug manufacturers, chemical manufacturers, and 
laboratories that manufacture drugs on a small scale for use in phase 1 
clinical trials.
    For drug manufacturers that produce in-house investigational drugs 
for use in phase 1 clinical trials and also produce approved drug 
products for marketing, this final rule is expected to reduce the 
amount of documentation they produce and maintain when they manufacture 
an investigational drug for use in a phase 1 clinical trial. In some 
cases, it should also reduce the amount of component and product 
testing.
    Because they currently may not supply the pharmaceutical industry, 
some chemical manufacturers and laboratories may experience a slight 
increase in documentation if they do not have written standard 
operating procedures (SOPs) or if they need to modify existing methods 
of documentation. Although formats may be different, the rule should 
not require more information than is already collected as part of 
standard laboratory practices.
    Because the actual SOPs and manufacturing requirements are 
different for each new drug product and manufacturing facility, the 
procedures to comply with the statutory CGMP requirements for phase 1 
manufacturing are generated as part of product development. The savings 
or costs would be incurred on a per-IND and not per-facility basis.
    This rule is intended to clarify compliance with the statutory 
CGMPs that are necessary in the manufacture of investigational drugs 
used in phase 1 clinical trials, and to exempt certain drugs produced 
under IND and used for phase 1 clinical trials from regulatory CGMP 
requirements under part 211. Some manufacturers may realize savings 
because they no longer must meet certain requirements. The savings to 
drug manufacturers that manufacture in-house the investigational drugs 
used in phase 1 clinical trials will vary greatly from product to 
product. FDA lacks data to estimate where the cost savings will occur 
in the manufacture of investigational drugs. Some substantial savings 
may be realized in testing and analyzing components and in-process 
materials. These costs can typically range from $50 to $1,200 per 
component tested. The extent of the need for SOPs and methods 
validation may also be greatly reduced. We estimate that large drug 
manufacturers that manufacture in-house investigational drugs used in 
phase 1 clinical trials could potentially save between 24 to 40 hours 
per IND\2\. In addition, the clarifications we have made could lead 
some large firms to produce in-house future investigational drugs for 
use in phase 1 clinical trials, rather than contracting the work out.
---------------------------------------------------------------------------

    \2\ Eastern Research Group (1195), Economic Threshold and 
Regulatory Flexibility Assessment of Proposed Changes to the Current 
Good Manufacturing Practice Regulations for Manufacturing, 
Processing, Packing, or Holding Drugs (21 CFR 210 and 211), 
submitted to the Office of Planning and Evaluation, FDA. Estimated 
hours to change minor and major SOPs for large establishments (p. 
24, table 7).
---------------------------------------------------------------------------

    For previously described chemical manufacturers and laboratories, 
the requirements in this rule may increase the time required for 
developing SOPs for quality, process, and procedural controls and will 
be incurred on a recurring basis for each new product manufactured. 
There may also be an incremental increase in training costs to educate 
employees on the CGMP requirements. We estimate that an additional 12 
to 24 hours may be required for these activities depending on the 
experience of the entity and its employees with our current CGMP 
rule.\3\
---------------------------------------------------------------------------

    \3\ Eastern Research Group (1995), ibid., Estimated hours to 
change SOPs for small establishments.
---------------------------------------------------------------------------

    The facility that manufactures the investigational drugs used in 
phase 1 clinical trials is identified in the IND. We do not keep a 
database of these facilities and, therefore, we do not have a precise 
number of entities that might be affected by this final rule. To 
estimate the economic impact, we derived an estimate of the number 
affected annually based on the number of INDs we receive.
    We receive an average of 1,410 INDs each year.\4\ However, this 
rule would not apply to the majority of these INDs because they are for 
drug products that already have premarket approvals and, thus, are 
subject to part 211. To derive an estimate of the percentage of INDs 
that would be affected by this rule, we used the percentage of total 
new drug

[[Page 40462]]

applications (NDAs) that were for new molecular entities (NMEs) and 
applied that percentage to the number of annual IND applications. 
Historically, about 30 percent of NDAs are for NMEs each year. Assuming 
the relationship would be the same for the INDs and that the number of 
INDs will remain at about 1,410, this rule would affect about 425 INDs 
per year. A firm may produce multiple drug products for phase 1 
clinical trials in a given year and use different companies to 
manufacture each of these drugs. Therefore, we do not know how many 
individual entities would be affected by this rule each year.
---------------------------------------------------------------------------

    \4\ The annual number of INDs received varies from year to year; 
1,410 is the mean of the total number of research and commercial 
INDs received by the Center for Drug Evaluation and Research and 
CBER between 2001 and 2005.
---------------------------------------------------------------------------

    The Small Business Administration (SBA) defines manufacturers of 
biologic drugs as small entities if they employ fewer than 500 people 
and other drug manufacturers as small if they employ fewer than 750 
people. FDA estimates that about 65 percent of the entities that submit 
NDAs and biologics license applications to the agency meet SBA's 
definition of a small entity. We assume that the distribution of large 
to small entities that submit INDs would be about the same. Although 
many of the entities that produce investigational drugs used in phase 1 
clinical trials are laboratories, they are usually part of much larger 
institutions and are not considered small under SBA's definition. All 
of the entities affected by this rule have personnel with the skills 
necessary to comply with the requirements.
    Because we do not know the experience levels the affected entities 
have with our current CGMP requirements, we used the midpoint of the 
estimated ranges to estimate the potential recurring savings or costs.
    Savings to large manufacturers from reduced SOP and validation 
requirements for phase 1 drug manufacturing in-house, assuming a time 
savings of 32 hours per application, a fully loaded wage rate of $46, 
\5\ and 150 INDs per year (approximately 35 percent of 425) would total 
$220,800 per year or $1,472 per IND. This would be in addition to any 
other savings from decreased component testing.
---------------------------------------------------------------------------

    \5\ Bureau of Labor Statistics, National Compensation Survey, 
2005. Wage rate is the average of the hourly rate for postsecondary 
chemistry teachers ($38.82) and postsecondary biochemistry teachers 
($27.01) plus 40 percent to account for benefits and rounded to the 
nearest whole dollar, www.bls.gov, data accessed September 2006.
---------------------------------------------------------------------------

    The incremental average annual cost to chemical manufacturers and 
laboratories, assuming all would incur costs and assuming an average 
increase of 18 hours per application for writing SOPs and training, a 
fully loaded wage rate of $46, and 275 INDs (approximately 65 percent 
of 425) affected per year, would total $227,700 per year or $828 per 
IND.
    Although we do not know the number and size distribution of the 
entities affected by this rule, the impact on them will be negligible 
and should actually reduce the compliance burden for some. 
Manufacturers of drug products for phase 1 clinical trials are 
currently required to manufacturer them using CGMP, but some of the 
requirements in part 211 are not applicable for the manufacture of 
small quantities used in phase 1 clinical trials. While exempting these 
products from part 211, the companion guidance clarifies FDA's thinking 
on how to manufacture phase 1 investigational drugs under CGMP and does 
not include recommendations that would increase the burden of 
compliance.

VII. Paperwork Reduction Act of 1995

    This final 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 final rule, the production of human drug products, including 
biological drug products, intended for use in phase 1 clinical trials 
are exempted from complying with the requirements under part 211. Part 
211 contains information collection requirements that are approved by 
OMB under control number 0910-0139. As explained in the following 
paragraph, the information collection requirements in part 211 are 
reduced in this final rule.
    The OMB-approved hourly burden to comply with the information 
collection requirements in part 211 (OMB control number 0910-0139) is 
848,625 hours. FDA estimates that, under the final rule, approximately 
425 investigational drugs are exempted from complying with the 
requirements under part 211. Based on this number and the total number 
of drugs that are subject to part 211 (122,795), FDA estimates that the 
burden hours approved under OMB control number 0910-0139 will be 
reduced by approximately 2,936 hours (425/122,795 x 848,625). Thus, as 
a result of the final rule, the amended burden hours in OMB control 
number 0910-0139 are approximately 845,689 hours.

VIII. 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.

IX. 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.

X. References

    The following references have been placed on display in the 
Division of Dockets Management (see ADDRESSES), 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 we are not responsible 
for any subsequent changes to the Web sites after this document 
publishes in the Federal Register.)
    1. Wood, A.J.J., J. Darbyshire, ``Injury to Research 
Volunteers--The Clinical-Research Nightmare,'' The New England 
Journal of Medicine, 354:1869-1871, 2006.
    2. Steinbrook, R., ``Protecting Research Subjects--The Crisis at 
Johns Hopkins,'' The New England Journal of Medicine, 346:716-720, 
2002.
    3. Savulescu, J., ``Harm, Ethics Committees and the Gene Therapy 
Death,'' The Journal of Medical Ethics, 27:148-150, 2001.

List of Subjects in 21 CFR Part 210

    Drugs, Packaging and containers.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act, and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
210 is amended as follows:

PART 210--CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING, 
PROCESSING, PACKING, OR HOLDING OF DRUGS; GENERAL

0
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.

0
2. In Sec.  210.2, add paragraph (c) to read as follows:


Sec.  210.2  Applicability of current good manufacturing practice 
regulations.

* * * * *

[[Page 40463]]

    (c) An investigational drug for use in a phase 1 study, as 
described in Sec.  312.21(a) of this chapter, is subject to the 
statutory requirements set forth in 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 described 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 phase 3 
study or the drug has been lawfully marketed, the drug for use in the 
phase 1 study must comply with part 211.

    Dated: July 9, 2008.
Jeffrey Shuren,
Associate Commissioner for Policy and Planning.
[FR Doc. E8-16011 Filed 7-14-08; 8:45 am]

BILLING CODE 4160-01-S
