[Federal Register: July 15, 2008 (Volume 73, Number 136)]
[Rules and Regulations]
[Page 40453-40463]
[DOCID:fr15jy08-1]

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Rules and Regulations
                                                Federal Register
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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,<PHONE_NUMBER>, or
    Christopher Joneckis, Center for Biologics Evaluation and Research
(HFM-1), Food and Drug Administration, 1401 Rockville Pike, Rockville,
MD 20852,<PHONE_NUMBER>.

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

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

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

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.
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    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

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

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

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

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

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

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.

* * * * *

    (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


[Federal Register Volume 74, Number 122 (Friday, June 26, 2009)]
[Notices]
[Pages 30562-30563]
[FR Doc No: E9-15150]

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DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Docket No. ES09-36-001]

Upper Peninsula Power Company; Notice of Filing

June 19, 2009.
    Take notice that on June 17, 2009, Upper Peninsula Power Company
(UPPCO) filed a supplement to its application for renewed authorization
to issue short-term debt, with new Exhibits C, D, and E, pursuant to
section 204 of the Federal Power Act and Part 34 of the Commission's
regulations.
    Any person desiring to intervene or to protest this filing must
file in accordance with Rules 211 and 214 of the Commission's Rules of
Practice and Procedure (18 CFR 385.211, 385.214). Protests will be
considered by the Commission in determining the appropriate action to
be taken, but will not serve to make protestants parties to the
proceeding. Any person wishing to become a party must file a notice of
intervention or motion to intervene, as appropriate. Such notices,
motions, or protests must be filed on or before the comment date. On or
before the comment date, it is not necessary to

serve motions to intervene or protests on persons other than the
Applicant.
    The Commission encourages electronic submission of protests and
interventions in lieu of paper using the ``eFiling'' link at http://www.ferc.gov. Persons unable to file electronically should submit an
original and 14 copies of the protest or intervention to the Federal
Energy Regulatory Commission, 888 First Street, NE., Washington, DC
20426.
    This filing is accessible online at http://www.ferc.gov, using the
``eLibrary'' link and is available for review in the Commission's
Public Reference Room in Washington, DC. There is an ``eSubscription''
link on the Web site that enables subscribers to receive e-mail
notification when a document is added to a subscribed docket(s). For
assistance with any FERC Online service, please e-mail
<EMAIL_ADDRESS>or call<PHONE_NUMBER> (toll free). For
TTY, call<PHONE_NUMBER>.
    Comment Date: 5 p.m. Eastern Time on June 29, 2009.

Kimberly D. Bose,
Secretary.
[FR Doc. E9-15150 Filed 6-25-09; 8:45 am]
BILLING CODE 6717-01-P


[Federal Register Volume 82, Number 211 (Thursday, November 2, 2017)]
[Notices]
[Page 50867]
[FR Doc No: 2017-23883]

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DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Project No. 2307-078]

Alaska Electric Light & Power Company: Notice of Availability of
Environmental Assessment

    In accordance with the National Environmental Policy Act of 1969
and the Federal Energy Regulatory Commission's (Commission)
regulations, 18 CFR part 380, the Office of Energy Projects has
reviewed the application for a new license for the Salmon Creek and
Annex Creek Hydroelectric Project, located on Salmon Creek and Annex
Creek in the City and Borough of Juneau, Alaska and has prepared an
Environmental Assessment (EA) for the project. The project occupies
648.45 acres of federal lands administered by the United States
Department of Agriculture, Forest Service.
    The EA contains staff's analysis of the potential environmental
effects of the project and concludes that relicensing the project, with
appropriate environmental protective measures, would not constitute a
major federal action that would significantly affect the quality of the
human environment.
    A copy of the EA is available for review at the Commission in the
Public Reference Room or may be viewed on the Commission's Web site at
http://www.ferc.gov using the eLibrary link. Enter the docket number
excluding the last three digits in the docket number field to access
the document. For assistance, contact FERC Online Support at
[email protected],<PHONE_NUMBER> (toll free), or (202) 502-
8659 (TTY).
    You may also register online at http://www.ferc.gov/docs-filing/esubscription.asp to be notified via email of new filings and issuances
related to this or other pending projects. For assistance, contact FERC
Online Support.
    Any comments should be filed within 30 days from the date of this
notice.
    The Commission strongly encourages electronic filing. Please file
comments using the Commission's eFiling system at http://www.ferc.gov/docs-filing/efiling.asp. Commenters can submit brief comments up to
6,000 characters, without prior registration, using the eComment system
at http://www.ferc.gov/docs-filing/ecomment.asp. You must include your
name and contact information at the end of your comments. For
assistance, please contact FERC Online Support. In lieu of electronic
filing, please send a paper copy to: Secretary, Federal Energy
Regulatory Commission, 888 First Street NE., Washington, DC 20426. The
first page of any filing should include docket number P-2307-078.
    For further information, contact Suzanne Novak at<PHONE_NUMBER>.

    Dated: October 24, 2017.
Nathaniel J. Davis, Sr.,
Deputy Secretary.
[FR Doc. 2017-23883 Filed 11-1-17; 8:45 am]
 BILLING CODE 6717-01-P


[Federal Register: February 8, 2010 (Volume 75, Number 25)]
[Notices]
[Page 6229-6231]
[DOCID:fr08fe10-92]

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SECURITIES AND EXCHANGE COMMISSION

[Release No. 34-61457; File No. SR-CTA/CQ-2009-03]

Consolidated Tape Association; Notice of Filing of the Fifteenth
Substantive Amendment to the Second Restatement of the Consolidated
Tape Association Plan and Eleventh Substantive Amendment to the
Restated Consolidated Quotation Plan

February 1, 2010.
    Pursuant to Section 11A of the Securities Exchange Act of 1934
(``Act''),\1\ and Rule 608 thereunder,\2\ notice is hereby given that
on November 2, 2009, the Consolidated Tape Association (``CTA'') Plan
and Consolidated Quotation (``CQ'') Plan participants
(``Participants'') \3\ filed with the Securities and Exchange
Commission (``Commission'') a proposal \4\ to amend the Second
Restatement of the CTA Plan and Restated CQ Plan (collectively, the
``Plans'').\5\ The proposal represents the fifteenth substantive
amendment to the CTA Plan (``Fifteenth Amendment to the CTA Plan'') and
the eleventh substantive amendment to the CQ Plan (``Eleventh Amendment
to the CQ Plan''), and reflects changes unanimously adopted by the
Participants. The Fifteenth Amendment to the CTA Plan and the Eleventh
Amendment to the CQ Plan (``Amendments'') would amend the Plans to
provide that the Participants pay the Network B Administrator a fixed
annual fee in exchange for its performance of Network B administrator
functions under the Plans. In addition, the Amendments seek to
accommodate recent changes in names and addresses of certain
Participants. The Commission is publishing this notice to solicit
comments from interested persons on the proposed Amendments.
---------------------------------------------------------------------------

    \1\ 15 U.S.C. 78k-1.
    \2\ 17 CFR 242.608.
    \3\ Each participant executed the proposed amendment. The
Participants are: BATS Exchange, Inc.; Chicago Board Options
Exchange, Incorporated; Chicago Stock Exchange, Inc.; Financial
Industry Regulatory Authority, Inc.; International Securities
Exchange LLC; NASDAQ OMX BX, Inc.; NASDAQ OMX PHLX, Inc.; The NASDAQ
Stock Market LLC; National Stock Exchange, Inc.; New York Stock
Exchange LLC; NYSE Amex, Inc.; and NYSE Arca, Inc.
    \4\ On January 13, 2010, the CTA filed a revised transmittal
letter indicating, among other technical changes, that the
Participants also proposed to make changes in the names and
addresses of certain Participants (``Transmittal Letter'').
    \5\ See Securities Exchange Act Release Nos. 10787 (May 10,
1974), 39 FR 17799 (May 20, 1974) (declaring the CTA Plan
effective); 15009 (July 28, 1978), 43 FR 34851 (August 7, 1978)
(temporarily authorizing the CQ Plan); and 16518 (January 22, 1980),
45 FR 6521 (January 28, 1980) (permanently authorizing the CQ Plan).
The most recent restatement of both Plans was in 1995. The CTA Plan,
pursuant to which markets collect and disseminate last sale price
information for non-NASDAQ listed securities, is a ``transaction
reporting plan'' under Rule 601 under the Act, 17 CFR 242.601, and a
``national market system plan'' under Rule 608 under the Act, 17 CFR
242.608. The CQ Plan, pursuant to which markets collect and
disseminate bid/ask quotation information for listed securities, is
also a ``national market system plan'' under Rule 608 under the Act,
17 CFR 242.608.
---------------------------------------------------------------------------

I. Rule 608(a)

A. Description and Purpose of the Amendments

    Network Administrator Fees under the Plans. Section XII
(``Financial Matters'') of the CTA and Section IX (``Financial
Matters'') of the CQ Plan each provides that a network's Operating
Expenses are to be deducted from the network's Gross Income in
determining the amounts that the network's administrator distributes to
the Participants. Section XII(c)(i) (``Determination of Operating
Expenses'') of the CTA Plan currently provides that a CTA network's
Operating Expenses include all costs and expenses ``associated with,
relating to, or resulting from, the generation, consolidation or
dissemination of the CTA's network's last sale price information.''
Likewise, Section IX(c)(i) (``Determination of Operating Expenses'') of
the CQ Plan currently provide that a network's

Operating Expenses include all costs and expenses that the network's
administrator incurs in ``collecting, processing and making available
that CQ network's quotation information.''
    Proposed Revision. The Network B Administrator has noted that
accounting for operating costs is administratively burdensome,
especially the allocation of organization overhead costs to the Network
B Administrator function. As a result, the Network B Participants have
determined that paying the Network B Administrator a fixed fee in
exchange for its Network B administrative services would be more
efficient.
    Therefore, the Participants propose to replace their payment to the
Network B Administrator of Operating Costs with their payment to the
Network B Administrator of a fixed fee. (The Network A Administrator
similarly receives a fixed fee for its performance of administrative
functions under the CTA and CQ Plans and the Participants understand
that Nasdaq receives a fixed fee for its performance of administrative
functions under the ``Joint Self-Regulatory Organization Plan Governing
the Collection, Consolidation and Dissemination of Quotation and
Transaction Information for Nasdaq-Listed Securities Traded on
Exchanges on an Unlisted Trading Privileges Basis.'')
    For calendar year 2009, the Network B Participants propose to set
the fixed fee at $3,000,000. This amount will compensate the Network B
Administrator for its Network B Administrative services during 2009
under both the CTA Plan and the CQ Plan.
    Annual Increase. For each subsequent calendar year, the Network B
Participants propose to increase (but not decrease) the amount of the
payment by the percentage increase (if any) in the annual cost-of-
living adjustment that the U.S. Social Security Administration applies
to Supplemental Security Income for the calendar year preceding that
subsequent calendar year, subject to a maximum annual increase of five
percent. For example, if the Social Security Administration's cost of
living adjustment for Supplemental Security Income were to be three
percent for calendar year 2010, then the Participants' fixed payment to
the Network B Administrator for 2010 would increase by three percent to
$3,090,000.
    Biannual Review. To assure that the fixed fee bears some
relationship to the costs that the Network B Administrator incurs in
providing Network B administrative services, the Network B
Administrator will provide a report every two years that highlights any
significant changes to CTA Network B and CQ Network B administrative
expenses during the preceding two years. The Participants will review
the report and determine by majority vote whether to continue to pay
the fixed fee at its then current level or to adjust the fee in some
manner.
    Payment of the Fee. In order to pay the fee to the Network B
Administrator, the Participants authorize the Network B Administrator
to deduct, on a quarterly basis, one-quarter of that calendar year's
fixed payment from the aggregate of CTA Network B Gross Income and CQ
Network B Gross Income before determining that quarter's Net Income
under the CTA Plan and the CQ Plan.
    If any Participant's share of Net Income for CTA Network B and CQ
Network B for any calendar year is less than its pro rata share of the
annual fixed payment for that year, the Participant shall be
responsible for the difference.
    Extraordinary Expenses. The Participants' payment of the fixed fee
will compensate the Network B Administrator for all ordinary and
customary operating expenses that it incurs in performing the network
administrator functions under the CTA and CQ Plans. However, it does
not compensate the Network B Administrator for extraordinary expenses
that the Network B Administrator may incur on behalf of the Network B
Participants.
    Extraordinary expenses include such things as that portion of legal
and audit expenses and marketing and consulting fees that are outside
of the ordinary functions that the Network B Administrator performs.
For example, extraordinary expenses would include such costs as legal
fees related to prosecution of a legal proceeding against a vendor that
fails to pay applicable charges and fees relating to a marketing
campaign that the Participants may determine to undertake to popularize
stock trading.\6\
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    \6\ The Commission notes that the Transmittal Letter
accompanying the proposed Amendments included language not voted on
by the Participants and thus not included in the proposed
Amendments: ``Network B Administrator will not incur any
extraordinary expense on behalf of the Network B Participants unless
the Network B Participants determine by majority vote to approve the
incurrence of that extraordinary expense.'' This language is not
part of the proposed Amendments.
---------------------------------------------------------------------------

    In addition, the Participants propose to amend the Plans to reflect
changes in the corporate names and street addresses of NASDAQ OMX BX,
Inc. (formerly Boston Stock Exchange, Inc.), NASDAQ OMX PHLX, Inc.
(formerly Philadelphia Stock Exchange, Inc.) and NYSE Amex, Inc.
(formerly American Stock Exchange LLC). They also propose to conform
the language signifying the status of BATS Exchange, Inc. as a national
securities exchange to the language used for the other Plan
Participants
    The text of the proposed Amendments is available on the CTA's Web
site (http://www.nysedata.com/cta,) at the principal office of the CTA,
and at the Commission's Public Reference Room.

B. Additional Information Required by Rule 608(a)

1. Governing or Constituent Documents
    Not applicable.
2. Implementation of the Amendments
    Upon Commission approval of the Amendments, the Participants intend
to implement the fixed fee immediately in order to make it effective
for the 2009 calendar year. That is, for all of 2009, the Network B
Participants would pay the Network B Administrator the fixed fee rather
than operating costs.
3. Development and Implementation Phases
    See Item I(B)(2) above.
4. Analysis of Impact on Competition
    The amendment will impose no burden on competition.
5. Written Understanding or Agreements Relating to Interpretation of,
or Participation in, Plan
    The Participants have no written understandings or agreements
relating to interpretation of the Plans as a result of the Amendments.
6. Approval by Sponsors in Accordance with Plan
    In accordance with Section IV(b) of the CTA Plan and Section IV(c)
of the CQ Plan, each of the Participants must execute a written
amendment to the Plans before the Amendments can become effective. The
Amendments are so executed.
7. Description of Operation of Facility Contemplated by the Proposed
Amendment
a. Terms and Conditions of Access
    Not applicable.
b. Method of Determination and Imposition, and Amount of, Fees and
Charges
    Not applicable.
c. Method of Frequency of Processor Evaluation
    Not applicable.

d. Dispute Resolution
    Not applicable.

II. Rule 601(a)

A. Equity Securities for Which Transaction Reports Shall Be Required by
the Plan

    Not applicable.

B. Reporting Requirements

    Not applicable.

C. Manner of Collecting, Processing, Sequencing, Making Available and
Disseminating Last Sale Information

    Not applicable.

D. Manner of Consolidation

    Not applicable.

E. Standards and Methods Ensuring Promptness, Accuracy and Completeness
of Transaction Reports

    Not applicable.

F. Rules and Procedures Addressed to Fraudulent or Manipulative
Dissemination

    Not applicable.

G. Terms of Access to Transaction Reports

    Not applicable.

H. Identification of Marketplace Execution

    Not applicable.

III. Solicitation of Comments

    Interested persons are invited to submit written data, views, and
arguments concerning the foregoing, including whether the proposed
Amendments are consistent with the Act. Comments may be submitted by
any of the following methods:

Electronic Comments

     Use the Commission's Internet comment form (http://
www.sec.gov/rules/sro.shtml); or
     Send an e-mail to<EMAIL_ADDRESS>Please include
File Number SR-CTA/CQ-2009-03 on the subject line.

Paper Comments

     Send paper comments in triplicate to Elizabeth M. Murphy,
Secretary, Securities and Exchange Commission, 100 F Street, NE.,
Washington, DC 20549-1090.

All submissions should refer to File Number SR-CTA/CQ-2009-03. This
file number should be included on the subject line if e-mail is used.
To help the Commission process and review your comments more
efficiently, please use only one method. The Commission will post all
comments on the Commission's Internet Web site (http://www.sec.gov/
rules/sro.shtml). Copies of the submission, all subsequent amendments,
all written statements with respect to the Amendments that are filed
with the Commission, and all written communications relating to the
Amendments between the Commission and any person, other than those that
may be withheld from the public in accordance with the provisions of 5
U.S.C. 552, will be available for Web site viewing and printing in the
Commission's Public Reference Room, 100 F Street, NE., Washington, DC
20549, on official business days between the hours of 10 a.m. and 3
p.m. Copies of the Amendments also will be available for inspection and
copying at the principal office of the CTA. All comments received will
be posted without change; the Commission does not edit personal
identifying information from submissions. You should submit only
information that you wish to make available publicly. All submissions
should refer to File Number SR-CTA/CQ-2009-03 and should be submitted
on or before March 1, 2010.

    For the Commission, by the Division of Trading and Markets,
pursuant to delegated authority.\7\
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    \7\ 17 CFR 200.30-3(a)(27).
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Florence E. Harmon,
Deputy Secretary.
[FR Doc. 2010-2586 Filed 2-5-10; 8:45 am]
BILLING CODE 8011-01-P