[Federal Register: January 16, 2009 (Volume 74, Number 11)]
[Rules and Regulations]
[Page 2849-2862]
[DOCID:fr16ja09-16]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 314 and 320

[Docket No. FDA-2003-N-0209] (Formerly Docket No. 2003N-0341)
RIN 0910-AC23

Requirements for Submission of Bioequivalence Data; Final Rule

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending its
regulations on the submission of bioequivalence data to require an
abbreviated new drug application (ANDA) applicant to submit data from
all bioequivalence (BE) studies the applicant conducts on a drug
product formulation submitted for approval. In the past, ANDA
applicants have submitted BE studies demonstrating that a generic
product meets bioequivalence criteria in order for FDA to approve the
ANDA, but have not typically submitted additional BE studies conducted
on the same drug product formulation, such as studies that do not show
that the product meets these criteria. FDA is amending the regulation
because we now believe that data from additional BE studies may be
important in our determination of whether the proposed formulation is
bioequivalent to the reference listed drug (RLD), and are relevant to
our evaluation of ANDAs in general. In addition, such data will
increase our understanding of how changes in components, composition,
and methods of manufacture may affect product formulation performance.

DATES: The rule is effective July 15, 2009.

FOR FURTHER INFORMATION CONTACT: Aida L. Sanchez, Center for Drug
Evaluation and Research (HFD-650), Food and Drug Administration, 7520
Standish Pl., Rockville, MD 20855,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of October 29, 2003 (68 FR 61640), FDA
proposed to amend its regulations in parts 314 and 320 (21 CFR parts
314 and 320) to require an ANDA applicant to submit data from all BE
studies that the applicant conducts on a drug product formulation
submitted for approval. Section 505(j)(2)(A)(iv) of the Federal Food,
Drug, and Cosmetic Act (the act) (21 U.S.C. 355(j)(2)(A)(iv)) requires
that ANDA applicants submit, among other things, information showing
that the applicant's drug is bioequivalent to a drug that has
previously been approved by FDA. Under the regulations at Sec.
314.3(b), the approved drug product identified by FDA as the drug
product on which an ANDA applicant relies for approval is the RLD. The
requirement that an ANDA applicant submit information that shows the
proposed product is bioequivalent to the RLD is described in FDA's
regulations at Sec.  314.94(a)(7). Section 320.24 sets forth the types
of evidence acceptable to establish BE. The most common BE studies are
those performed on solid oral dosage forms of drugs that are absorbed
into the systemic circulation. BE data provide an estimate of the rate
and extent of drug absorption for a test and reference product. These
data are examined, using statistical procedures, to determine whether
the test product meets BE limits.
    A BE study may fail to show that a test product meets BE limits
because the test product has significantly higher or lower relative
bioavailability (i.e., measures of rate and extent of absorption
compared to the reference product). In some cases, BE will not be
demonstrated because there are inadequate numbers of subjects in the
study relative to the magnitude of intrasubject variability, and not
because

of either significantly high or low relative bioavailability of the
product. Where the relative bioavailability of a product is too low,
the concern is that not enough of the active ingredient is reaching the
site of action, and therefore the product may not be as therapeutically
effective as the RLD. Where the relative bioavailability of a test
product is too high, the concern with the product is not its
therapeutic efficacy, but rather its safety relative to the RLD. When
the variability of the test product is high, the concern relates to
both safety and efficacy. The variability may suggest that the test
product does not perform as consistently as the reference product, and
the test product may be too variable to be clinically useful.
    The act and FDA regulations require that an ANDA applicant submit
information demonstrating BE of a proposed drug to the RLD, but do not
specify whether all BE studies must be submitted. It has been the
practice of ANDA applicants to submit evidence of bioequivalence
consisting of studies demonstrating that the rate and extent of
absorption of the test product meet BE limits. Thus, ANDA applicants
that have conducted multiple studies on a final formulation, producing
both passing and nonpassing results, have generally not submitted the
results of the nonpassing study or studies to FDA. Similarly, ANDA
applicants that have conducted multiple studies on a final formulation,
producing more than one passing result, have generally not submitted
the results of all of the passing studies to FDA. As a result, FDA
infrequently sees data from such additional studies and is generally
unaware of the existence of such studies. In rare instances, ANDA
applicants have submitted additional BE studies, or the agency has
learned about such studies through other means.

II. Summary of the 2003 Proposed Rule

    FDA determined that the submission of all bioequivalence studies,
both passing and nonpassing, is necessary for the purposes of
evaluating a drug product submitted for approval under an ANDA.
Accordingly, the agency proposed to amend its regulations in parts 314
and 320. Specifically, the agency proposed to amend:
     the ANDA content requirements (Sec.  314.94(a)(7)(i))
     the ANDA amendment requirements (Sec.  314.96(a)(1)), and
     the requirements for submission of in vivo bioavailability
and bioequivalence data (Sec.  320.21(b)(1)).
    The agency did not propose to amend the text of Sec.  320.21(c).
However, because Sec.  320.21(c) references the requirements of Sec.
320.21(b)(1), the proposed changes to Sec.  320.21(b)(1) would also
modify the requirements of Sec.  320.21(c). In addition, FDA explained
how it intended to interpret two of its current regulations to be
consistent with the proposal. Specifically, FDA explained that it
intended to interpret the regulation applicable to an ANDA submitted
under an approved suitability petition (Sec.  314.94(a)(7)(ii)) and the
postmarketing reporting regulation (Sec.  314.81(b)(2)(vi)) to require
the submission of all BE studies, both passing and nonpassing.
    The agency did not propose to amend the section heading of Sec.
320.21 (``Requirements for submission of in vivo bioavailability and
bioequivalence data''), but after reviewing the public comments, the
agency believes that the section heading of Sec.  320.21 may cause
confusion. As explained in the proposed rule, FDA is requiring the
submission of all bioequivalence studies conducted on a drug product
formulation submitted for approval. This requirement includes both in
vivo and in vitro studies that are conducted for the purpose of
establishing bioequivalence. Therefore, FDA is changing the section
heading of Sec.  320.21 to omit the reference to in vivo studies, to
more clearly reflect the fact that both in vivo and in vitro studies
must be submitted.

III. Description of the Final Rule

    We are revising our regulations to require applicants to submit
data on all BE studies, including studies that do not meet passing
bioequivalence criteria, which are performed on a drug product
formulation submitted for approval under an ANDA, or in an amendment or
supplement to an ANDA that contains BE studies. Applicants will also be
required to submit data in an annual report on all postmarketing BE
studies conducted or otherwise obtained on the approved drug product
formulation during the annual reporting period.
    The provisions of the proposed rule stated that BE studies on the
``same drug product formulation'' must be submitted. The proposed rule
did not specifically define the term ``same drug product formulation.''
However, in the preamble to the proposed rule, the agency stated that
``FDA intends that the terminology `same drug product formulation' will
include formulations that have minor differences in composition or
method of manufacture from the formulation submitted for approval, but
are similar enough to be relevant to the agency's determination of
bioequivalence. For example, where an applicant makes formulation or
manufacturing changes of the type that qualify as level 1 or level 2
changes in FDA's current guidances on scale up and postapproval changes
(SUPAC) listed below, the agency will consider the original and
modified products to be similar enough to constitute the same drug
product formulation for the purposes of the proposed rule'' (68 FR
61640 at 61643). The proposed rule then listed six SUPAC guidances.
    FDA received a significant number of comments indicating that using
the SUPAC guidances as a way of explaining which BE studies must be
submitted to the agency did not provide sufficient clarity. For
example, one comment on the proposed rule asked if the rule will
require the submission of pilot studies, including pilot
pharmacokinetic studies in animals, or in vitro studies. Another
comment asked whether it will be necessary to submit prior studies--
such as a pharmacokinetic study on the metabolite only, a
pharmacokinetic study in urine, a pharmacodynamic study, a clinical
endpoint BE study or other clinical study, or a sensitization or
irritation study for transdermal patches--that are not directly
relevant to the assessment of BE by the current criteria.
    The final rule continues to use the term ``same drug product
formulation.'' However, to eliminate the confusion caused by reference
to the SUPAC guidances, we have added a definition of the term ``same
drug product formulation.'' As set forth in Sec.  320.1(g) of this
final rule, the term ``same drug product formulation'' means the
formulation of the drug product submitted for approval and any
formulations that have minor differences in composition or method of
manufacture from the formulation submitted for approval, but are
similar enough to be relevant to the agency's determination of
bioequivalence (Sec.  320.1(g)). This definition is consistent with
FDA's intended meaning for the term ``same drug product formulation,''
as described in the proposed rule (68 FR 61640 at 61643), and
eliminates the need to refer to the SUPAC guidances as discussed
further in this document.
    In addition, as stated in the preamble to the proposed rule, FDA
intends to make available shortly a draft guidance intended to help
affected entities better understand which BE studies should be
submitted, as well as the format FDA recommends for submission.
    FDA is revising Sec. Sec.  314.94(a)(7)(i), 314.96(a)(1), 320.1(g),
320.21 (section heading), and 320.21(b)(1), as well as modifying Sec.
320.21(c) (which references the requirements of Sec.  320.21(b)(1)) to

require that an applicant submitting BE studies in an ANDA, ANDA
amendment, or ANDA supplement submit: (1) Full reports of BE studies
upon which the applicant relies for approval and (2) either full or
summary reports of all other BE studies conducted on the same drug
product formulation. In addition to amending these provisions, FDA is
also clarifying its interpretation of two regulations, Sec. Sec.
314.94(a)(7)(ii) and 314.81(b)(2)(vi) as follows:
    As currently written, Sec.  314.94(a)(7)(ii) requires an applicant
submitting an ANDA under a petition approved under Sec.  314.93 to
submit the results of any bioavailability or bioequivalence testing
required by the agency to show that the active ingredients of the
proposed drug product are of the same pharmacological or therapeutic
class as those in the RLD, and that the proposed drug product can be
expected to have the same therapeutic effect as the RLD. Consistent
with the regulatory changes described above, FDA intends to interpret
Sec.  314.94(a)(7)(ii) to require the submission of results from all
bioavailability and BE studies, passing and nonpassing, conducted on
the same drug product formulation. An applicant submitting an ANDA
under a petition approved under Sec.  314.93 will now be required to
submit complete reports of the bioavailability or BE studies upon which
the applicant relies for approval, and a complete or summary report for
all other bioavailability or BE studies on the same drug product
formulation.
    As currently written, Sec.  314.81(b)(2)(vi) requires an ANDA
applicant to submit, in an annual report, the results of
``biopharmaceutic, pharmacokinetic, and clinical pharmacology studies *
* * conducted by or otherwise obtained by the applicant'' during the
annual reporting period. FDA intends to interpret this section to
require ANDA applicants with approved ANDAs to submit reports of all BE
studies, both passing and nonpassing, conducted or obtained by the
applicant during the annual reporting period on the approved drug
product.

IV. Comments on the Proposed Rule

    FDA received 11 comments on the proposed rule from manufacturers,
trade associations, and law firms. On June 11, 2004, FDA held a meeting
to discuss the proposed rule with the Generic Pharmaceutical
Association (GPhA). The meeting minutes have been entered into the
docket, and the comments provided by GPhA are included in the comments
we respond to in this document. The majority of the comments supported
the proposed amendments to FDA's regulations. Several comments
requested clarification on various aspects of the rule. The final rule
is described in section III of this document.

A. General Comments

    (Comment 1) Several comments, including comments from
manufacturers, law firms, and trade associations, commended FDA on the
proposal. In particular, these comments noted the importance of
requiring the submission of all bioequivalence data to assess the
safety and effectiveness of ANDA products, and to enhance FDA's
knowledge concerning bioequivalence.
    (Response) We appreciate the support expressed in these comments
and agree that requiring the submission of these data is very
important.
    (Comment 2) One comment specifically commended FDA for stating in
the proposed rule that the agency is not aware of any adverse public
health consequences associated with products for which studies were not
submitted, nor of any information on any currently marketed generic
product suggesting that the product is not bioequivalent to a reference
listed drug to which it has been designated as therapeutically
equivalent.
    (Response) FDA notes that since publication of the proposed rule,
we have not become aware of any such information.
    (Comment 3) In the preamble to the proposed rule we stated: ``Even
when additional BE studies are not critical to the agency's
bioequivalence determination for the specific product being reviewed,
the data provide valuable scientific information that increases the
agency's knowledge and understanding of bioequivalence and generic drug
development and promote further development of science-based
bioequivalence policies'' (68 FR 61640 at 61641). One comment stated
that the goal of increasing FDA's knowledge and understanding of
bioequivalence should not be accomplished by imposing regulatory
requirements on ANDA applicants. This comment suggested that the
appropriate way to achieve this goal will be to hold joint industry-
agency meetings and conferences.
    (Response) We agree with the comment that if the sole purpose of
this rule was to increase the agency's understanding of BE, there would
be alternative means for FDA to achieve this goal. As stated in the
proposal, however, the primary purpose of the requirement to submit
information from all BE studies on the same drug product formulation is
that ``[d]ata contained in additional passing and nonpassing BE studies
can be important to FDA's assessment of bioequivalence for a specific
product'' (68 FR 61640 at 61641). Currently, ANDA applicants are only
required to submit one BE study (or two, if a fed study is required).
Based on one or two studies, FDA might conclude that the product is
bioequivalent to its RLD. If the agency receives other BE studies
conducted by the applicant, and these studies failed to show
bioequivalence, the agency might make a different decision about
whether to approve the ANDA than it would have if the agency had
received only the passing study. In such a case, receipt of additional
BE studies will be critical to FDA's determination as to whether a
generic product is equivalent to its RLD. Unless FDA receives all BE
studies on the same drug product formulation, it is not possible for
the agency to make an informed, scientifically based decision about
bioequivalence. Thus, the rule requires that all BE studies conducted
on the same drug product formulation be submitted. In other cases,
FDA's receipt of additional BE studies might not change the agency's
decision that a product is bioequivalent to its RLD. In both cases,
however, review of the additional studies will serve the ancillary
purpose of increasing the agency's understanding of bioequivalence, and
provide added confidence in the agency's BE determination. In setting
out the second purpose (that of increasing the agency's knowledge of
bioequivalence), we note in the preamble to the proposed rule that this
ancillary purpose is served even when the additional BE studies do not
prove to be critical to the agency's bioequivalence determination for
the specific product being reviewed (68 FR 61640 at 61641).
    (Comment 4) One comment suggested that FDA amend Sec.  314.127(b)
of its regulations to reflect that failure to submit all required BE
study reports is grounds for receiving an ``unapprovable'' letter.
    (Response) FDA generally disagrees with the comment. Failure to
submit all BE studies will be grounds for refusing to receive the ANDA
under Sec.  314.101(b)(1) of FDA's regulations because the ANDA will
not be complete. It should be noted that section 505(j)(4) of the act
describes the grounds for refusing to approve an ANDA. Under certain
circumstances, one or more unreported BE studies might provide the
basis for refusing to approve an ANDA under section 505(j)(4)(F) of the
act (``information submitted in the application is insufficient to show
that the drug is bioequivalent * * *''). See also Sec.  314.127(a)(6).
For example, if,

while an ANDA is pending, FDA discovers that the ANDA omitted one or
more studies that failed to demonstrate BE, FDA might conclude that the
BE information in the application is insufficient.
    (Comment 5) Several comments expressed concern about the burden
that will be imposed on the ANDA review process and agency resources
(e.g., reviewers and inspectors) when the rule is implemented. One
comment expressed concern that the workload created by this rule will
slow action on pending ANDAs. Another comment noted that FDA has been
trying to reduce the time both for BE review and response to
correspondence by the Office of Generic Drug's (OGD's) Division of
Bioequivalence. This comment suggested that adequate hiring and
retention should be established in the Division of Bioequivalence
before implementing the rule.
    (Response) FDA crafted the requirements of the rule mindful of
balancing its need for additional BE information with the need to
ensure that the ANDA review process is not unnecessarily burdened. It
was the desire to achieve this balance that, in part, led FDA to
require only the submission of BE studies conducted with the ``same
drug product formulation'' as that submitted for approval, rather than
requiring the submission of all BE studies conducted with all
developmental formulations, as some comments suggested. FDA
appreciates, however, that the final rule will increase the number of
studies reviewed by the Division of Bioequivalence, and the agency is
working on hiring additional staff to handle this increase. FDA is also
developing databases that will help decrease the amount of
correspondence received by OGD. We believe these steps will ensure that
the ANDA review process continues to be efficient.
    (Comment 6) In the preamble to the proposed rule, FDA stated that
an applicant ``will rarely, if ever, conduct a postmarketing BE study
other than one required for an ANDA supplement'' (68 FR 61640 at
61643). One comment suggested that requiring applicants to submit
failing BE studies will create an additional disincentive to perform
postmarketing BE studies, which may discourage applicants from
considering ways to improve their manufacturing processes.
    (Response) FDA believes that the concern expressed in the comment
is unfounded. The major disincentives to performing postmarketing BE
studies are the financial costs and resource expenditures for the
applicant. That is why such studies are rarely performed, except when
required for an ANDA supplement. In any event, FDA believes that any
potential disincentive created by requiring that such studies be
submitted to the agency will be negligible. Moreover, FDA believes that
industry will agree that because the drug will already be on the
market, in the event that a postmarketing study fails to demonstrate
bioequivalence, it would be particularly important for the agency and
the applicant to examine the reason for the failure.
    (Comment 7) One comment stated that if ANDA holders are going to be
required to submit failed studies performed in accordance with the
SUPAC guidances, new drug application (NDA) holders should also be
required to submit such studies.
    (Response) NDA applicants and NDA holders are already required to
submit failed BE studies. Section 314.50(d)(3) of FDA regulations
requires an NDA to contain a description of all bioavailability and
pharmacokinetic studies in humans performed by or on behalf of the
applicant. The requirement to submit bioavailability studies includes
reports of any bioequivalence studies performed by or on behalf of the
applicant.

B. Same Drug Product Formulation

    (Comment 8) Several comments requested clarification of the term
``same drug product formulation.'' One comment stated that
clarification of the language was important to ensure that it was not
subject to varying interpretations by ANDA applicants.
    (Response) The final rule adds in Sec.  320.1(g) a definition of
the term ``same drug product formulation'' to mean the formulation of
the drug product submitted for approval and any formulations that have
minor differences in composition or method of manufacture from the
formulation submitted for approval, but are similar enough to be
relevant to the agency's determination of bioequivalence. FDA's draft
guidance on the submission of BE data, when available, will expand on
this definition by providing specific examples of formulations that FDA
considers to be the same drug product formulation. For example, FDA
considers two drug products that use different ingredients intended to
affect the color or flavor of the drug product, or use a different
technical grade and/or specification of an excipient, to be the same
drug product formulation. If an applicant has questions that are not
answered by the draft guidance on submission of BE data, the applicant
should contact OGD for assistance in applying the term ``same drug
product formulation.''
    (Comment 9) Two comments asked FDA to revise the concept ``same
drug product formulation.'' One comment requested that the term be
limited to ``studies which are statistically powered correctly and have
a batch size of at least 100,000 packaged units.'' Another comment
asked that the term be broadly interpreted to require the submission of
all BE studies performed on the various formulations of a drug for
which an ANDA is ultimately submitted. For example, the comment
suggested that ANDA applicants should be required to submit BE studies
performed on formulations that differ by SUPAC level 3 changes from the
formulation submitted for approval. The comment suggested that failure
to broadly interpret ``same drug product formulation'' will result in
ANDA applicants making certain SUPAC level 3 changes (such as changing
the manufacturing site) in an attempt to avoid submitting failed study
results. In addition, the comment noted that the submission of all BE
data on all formulations could serve the ancillary purposes of helping
FDA to: (1) Refine the SUPAC levels and (2) establish chemistry,
manufacturing, and controls specifications.
    (Response) FDA disagrees with both of these comments. The term
``same drug product formulation'' is intended to balance competing
concerns. To limit the definition to require only the submission of
studies that are statistically powered correctly and have a particular
batch size could undermine the goals of the rule. Such a limitation
will result in FDA failing to receive results from pilot studies. As
discussed in greater detail below, FDA appreciates that if a pilot
study is underpowered, it cannot be expected to satisfy BE criteria.
Nevertheless, such studies provide valuable information that is
relevant to FDA's bioequivalence determination. Therefore, FDA declines
to limit the scope of the term ``same drug product formulation'' as
suggested in the comment.
    FDA also declines to broadly interpret the definition to include
all formulations tested during the drug's development program. Such an
interpretation would: (1) Increase the burden on ANDA applicants, (2)
likely result in the submission of data irrelevant to the agency's
determination of bioequivalence, and (3) potentially slow the ANDA
review process without enhancing FDA's ability to analyze whether the
formulation submitted for approval is bioequivalent to the RLD.
Moreover, FDA believes that the

comment's concern about ANDA applicants making SUPAC level 3 changes to
a formulation to avoid submitting failing results is not relevant to
the final rule. As discussed above, the final rule does not use the
SUPAC guidances to interpret the term ``same drug product
formulation.'' Moreover, if a formulation failed to demonstrate
bioequivalence, it is unlikely that manufacturing the same or very
similar formulation at a different site would result in a passing BE
study for submission in an ANDA. (Note that the issue of a change in
manufacturing site is also discussed in the response to comment 15.) In
addition, FDA believes that the intended goals of the rule are best
served by focusing the agency's review on data relevant to the
formulation submitted for approval. Therefore, the agency believes that
the disadvantages of employing such a broad interpretation of ``same
drug product formulation'' outweigh the theoretical benefits. Overall,
FDA believes that its definition of ``same drug product formulation''
strikes an appropriate balance.
    (Comment 10) One comment suggested that FDA's definition of ``same
drug product formulation'' resulted in an inconsistency between how FDA
treats changes pre- and postapproval. Specifically, the comment
suggested that because a BE study will not be required for a SUPAC
level 1 or 2 change postapproval, FDA should not require that BE data
be submitted preapproval for a formulation that differs only by a SUPAC
level 1 or 2 change from the formulation submitted for approval.
    (Response) This comment reflects the confusion created by our
proposal to rely on SUPAC guidance concepts to determine when a drug
has the same formulation for purposes of this rule. The SUPAC guidances
provide recommendations for when FDA will require the conduct of a BE
study to support a formulation or manufacturing change submitted in an
amendment or supplement. In short, they provide guidance for when new
data will be required to support a change to the drug product.
    In contrast, this rule does not address when data are required to
support a product application or product change. It does not require
that a new study be conducted under any circumstances. The rule merely
addresses situations where an applicant has conducted BE studies in
addition to those it seeks to rely on in its ANDA or ANDA amendment or
supplement. It also indicates when the results from those additional
studies must be submitted to FDA, because they were conducted on a drug
product formulation that is the same as, or similar to, that covered by
the application. While SUPAC is focused on determining what product
changes will trigger the need for new data to support the change, this
rule focuses on when existing data must be submitted to FDA, because
they are relevant to the drug product with the same formulation.
    FDA had initially proposed to refer to the SUPAC guidances to
determine when drug products with minor changes are considered to be
the same formulation. Under SUPAC, level 1 or 2 changes to a drug
product formulation do not require a manufacturer to conduct BE testing
or submit BE data in order to market the drug product with those
changes. Level 3 changes are fairly significant and require a
manufacturer to conduct a BE test to demonstrate the equivalence
between the new and old formulations before it may market the new
formulation. However, under this rule, BE test data on a product that
is three SUPAC levels different from the approved or marketed
formulation would not need to be submitted if that formulation is not,
and will not, be marketed. In the proposed rule, we suggested that BE
data on products reflecting modest changes, described as SUPAC level 1
and 2 changes, are relevant to the marketed formulation and would need
to be submitted. As a result, reference to the SUPAC concepts created
confusion, because the instances where SUPAC recommends that
manufacturers conduct and submit BE test data to support product
changes were the exact situations where this rule would not require
submission of existing BE data, because the data are of limited
applicability to the formulation subject to the application.
Accordingly, we are no longer referring to the SUPAC guidances in the
final rule. Instead, we have included a definition of ``same drug
product formulation'' in Sec.  320.1(g) of the final rule, in order to
provide assistance in determining when this rule requires submission of
BE data on a similar formulation.

C. Bioequivalence Studies That Must Be Submitted

    (Comment 11) Several comments requested clarification about the
types of studies that will be required to be submitted under the rule.
In particular, several comments questioned whether ``pilot studies'' or
studies that were designed not to evaluate BE, but to generate BE data,
will have to be submitted under the rule. Such studies could be
performed to: (1) Obtain information related to the performance of
prototype drug formulations, (2) estimate the appropriate number of
subjects necessary for the definitive BE study, (3) determine the
appropriate plasma concentration time curves, or (4) determine whether
a drug entity can be reliably measured in the media chosen. Some
comments suggested that such studies should not be required to be
submitted because they may not be powered to pass BE statistical
criteria and, as a result, are arguably not ``BE studies.''
    (Response) The term ``all other bioequivalence studies'' is used in
the rule without limitation. It is intended to capture all studies
generating BE data, including pilot studies. Therefore, complete or
summary reports of pilot studies conducted with formulations that are
the ``same drug product formulation'' as that submitted in the ANDA
must be submitted under the rule. FDA believes that the submission of
pilot studies is important because they may provide valuable BE
information. For example, they may provide FDA information about the
assay used in the BE study relied on for approval. FDA appreciates the
concern raised in the comments about pilot studies potentially being
underpowered and not designed to evaluate bioequivalence. The agency
will fully consider these issues when reviewing pilot studies. If a
pilot study is not properly powered, FDA will not expect it to
demonstrate bioequivalence.
    (Comment 12) One comment asked if the rule will require submission
of pilot pharmacokinetic studies in animals or in vitro studies.
    (Response) The final rule does not require the submission of animal
studies. In vitro studies must be submitted when in vitro testing is
conducted to demonstrate bioequivalence (Sec.  320.24(b)(5)). Examples
include in vitro testing for nasal sprays and resin binding testing for
bile acid sequestrants. When an in vivo study is submitted to show
bioequivalence of a formulation, all other in vivo and in vitro
bioequivalence data, both passing and nonpassing, for that formulation
must be submitted as well. Similarly, when an in vitro study is
submitted to show bioequivalence of a formulation, all other in vivo
and in vitro bioequivalence data, both passing and nonpassing, for that
formulation must be submitted. The data from in vitro dissolution
studies conducted for purposes other than to show bioequivalence need
not be submitted under this rule, but may be required by other
regulations (for example, Sec.  314.94(a)(9)). In the proposed rule,

FDA cited Sec.  320.24 as the regulatory requirement which ``sets forth
the types of evidence acceptable to establish bioequivalence.''
According to Sec.  320.24(a), bioavailability may be demonstrated by
several in vivo and in vitro methods. Section 320.24 makes it clear
that bioequivalence studies may consist of either in vivo or in vitro
studies.
    Since reviewing the comments to the proposed rule, FDA has become
aware that the language of the proposed rule may cause confusion
regarding the requirement that all in vitro bioequivalence studies must
be submitted. In particular, the section heading of Sec.  320.21,
``Requirements for submission of in vivo bioavailability and
bioequivalence data,'' may lead to this misinterpretation. Thus, in
this final rule, FDA is changing the section heading of Sec.  320.21 so
that it removes the specific reference to in vivo data.
    (Comment 13) One comment asked if prior studies that are not
directly relevant to the assessment of BE by the current criteria must
be submitted. For example, if the current BE recommendation for a
particular product specifies a pharmacokinetic study on the parent drug
in plasma, will the following types of studies have to be submitted: A
pharmacokinetic study on the metabolite only, a pharmacokinetic study
in urine, a pharmacodynamic study, a clinical endpoint BE study or
other clinical study, a sensitization or irritation study for
transdermal patches, etc.?
    (Response) Yes, all studies on the same drug product formulation as
defined in this final rule must be submitted regardless of what FDA's
current criteria for BE testing for the product are. Otherwise, the
agency might not be aware of a study that is relevant to our
determination of whether two products are bioequivalent. For example,
if a firm conducted a pharmacodynamic study that failed to show BE, and
then conducted a pharmacokinetic study that demonstrated BE, we would
want to know about the pharmacodynamic study.
    (Comment 14) One comment noted that the SUPAC guidance states that
for narrow therapeutic index (NTI) drugs, biostudies are required for
all formulation changes except level 1 changes. The comment asked
whether this means that biostudies on any formulations differing by
more than SUPAC level 1 for NTI drugs will not need to be submitted
under the new rule.
    (Response) As discussed in section III of this document, the final
rule does not use the SUPAC guidances to explain what the regulation
means by ``same drug product formulation.'' Instead, the final rule
defines ``same drug product formulation'' as the formulation of the
drug product submitted for approval and any formulations that have
minor differences in composition or method of manufacture from the
formulation submitted for approval, but are similar enough to be
relevant to the agency's determination of bioequivalence. Under the
final rule, all biostudies on the same drug product formulation must be
submitted, regardless of the level of change under SUPAC.
    (Comment 15) One comment asked if a change in manufacturing site
alone (a SUPAC level 3 change) will make the products at the original
and new sites not the same drug product formulation even if the
formulations and manufacturing processes were otherwise identical.
    (Response) No. Manufacturing site changes are not relevant to the
definition of ``same drug product formulation.'' Studies conducted for
products that are considered the ``same drug product formulation'' must
be submitted whether the products are manufactured at the same or
different manufacturing sites.
    (Comment 16) One comment stated that in some cases, it may be
impossible to determine whether a particular older formulation on which
a biostudy had been conducted falls within the scope of a SUPAC level 2
change from the approved or submitted formulation. For example, the
older formulation has only single point dissolution data, precluding an
f2 comparison; or multiple dissolution conditions were used, some of
which yield f2 factors greater than 50 and some less than 50. In such
cases, how is an applicant to decide whether or not a biostudy on an
older formulation needs to be submitted?
    (Response) If a biostudy was conducted on a product that is the
same drug product formulation as defined in the final rule, it must be
submitted. Dissolution testing is not a criterion for submission.
    (Comment 17) One comment stated that the language defining the
``final formulation'' may not capture all relevant bioequivalence data.
For example, formulations containing an active ingredient with a
particle size or morphic form that differs from the drug for which the
ANDA is submitted would not be considered the ``final formulation'' of
the drug. Thus, ANDA sponsors would not be required to submit
bioequivalence data performed on these formulations, although such
differences might affect the drug's pharmacokinetic profile, safety,
and effectiveness.
    (Response) FDA disagrees. The term ``same drug product
formulation,'' as defined in Sec.  320.1(g) of this rule, includes
formulations that differ in particle size and morphic form; thus,
studies on such formulations would need to be submitted to FDA.
    Section 505(j)(2) of the act specifies that an ANDA must contain,
among other things, information to show that the active ingredient in
the generic drug product is the ``same as'' that of the RLD. Section
314.92(a)(1) of FDA regulations provides that the term ``same as''
means, among other things, ``identical in active ingredient(s).'' In
the discussion of ``sameness'' of active ingredient(s) in the preamble
to the final rule adopting the ANDA regulations, FDA specifically
rejected a proposal that would have required an ANDA applicant to show
that the active ingredient in its generic drug product and the active
ingredient in the RLD ``exhibit the same physical and chemical
characteristics, that no additional residues or impurities can result
from the different manufacture or synthesis process and that the
stereochemistry characteristics and solid state forms of the drug have
not been altered'' (57 FR 17950 at 17958, April 28, 1992). Differences
in particle size and polymorphic forms of a drug substance are not
differences in chemical structure, but only in internal solid-state
structure.
    (Comment 18) One comment questioned whether FDA's interpretation of
Sec.  314.81(b)(2)(vi) will require an applicant to submit studies
performed by someone other than the applicant. For example, will the
applicant be required to submit a study performed by a competitor (a
``challenge study'')? The comment noted that a complete or summary
report may not be available to the applicant. Another comment asked if
it will be necessary to conduct literature searches to find BE studies
conducted by third parties.
    (Response) Section 314.81(b)(2)(vi) requires the submission of data
from ``biopharmaceutic, pharmacokinetic, and clinical pharmacology
studies * * * conducted by or otherwise obtained by the applicant.''
This language clearly contemplates that if an applicant obtains the
results of a study conducted by a third party, the results must be
submitted in the annual report. It will not be necessary to conduct
literature searches to find BE studies conducted by third parties.
However, if an applicant obtains a complete or summary report, that
report must be submitted. If the applicant obtains study

results in a form other than a complete or summary report, those
results must be submitted in the annual report.
    (Comment 19) One comment asked whether the rule requires applicants
to contact previous owners of the ANDA to obtain BE studies.
    (Response) Section 314.72 of FDA regulations concerns change in
ownership of an application. Section 314.72(a)(2)(iii) requires the new
owner of an application either to submit to FDA a statement that the
new owner has a complete copy of the approved application, or to
request a copy of the application from FDA. In addition, FDA believes
it is incumbent upon the purchaser of an ANDA to request from the owner
all biostudies conducted on the drug product, even if they were not
submitted to the ANDA.

D. Summary and Complete Reports

    (Comment 20) One comment stated that FDA should clarify the
appropriate content of complete and summary reports to ensure that FDA
receives the information necessary to fully evaluate bioequivalence.
    (Response) FDA believes that applicants are aware of the
appropriate content of a complete BE study report, as they are
currently required to submit such a report for the study relied on for
ANDA approval. The draft guidance on the submission of BE data, when
available, will discuss the content of summary reports in greater
detail.
    (Comment 21) One comment suggested that the submission of complete
or summary reports of all other BE studies is unnecessary. Instead, the
comment suggested, the product development report submitted as part of
the ANDA may be the most appropriate place to put a small summary of
the results of all bioequivalence studies performed on the product
prior to ANDA submission.
    (Response) FDA disagrees with this comment. While FDA agrees that
the product development report provides helpful information for the
ANDA review process, a small summary of all bioequivalence studies in
the product development report will be insufficient to satisfy the
objectives of the rule. The agency is requesting complete or summary
reports of the studies in order to be able to evaluate the study design
and the resulting data. A small summary in the product development
report will likely provide insufficient information for the agency to
adequately evaluate why certain studies failed and others passed.
    (Comment 22) One comment stated that in many cases, an applicant
may request only a summary report from a contract research organization
(CRO) when a test product has failed to meet standard BE criteria.
Therefore, if after the applicant submits the summary report, FDA
requests a complete report, the applicant will need additional time and
will incur additional costs for the CRO to generate a complete report.
    (Response) FDA appreciates that industry's current practice may be
to request only summary reports from CROs for failing studies. As noted
in the preamble to the proposed rule, FDA foresees that in the majority
of cases, a summary report will be sufficient to satisfy the rule. For
example, in the case of a pilot study that was not powered to
demonstrate bioequivalence, the agency does not foresee the need for a
complete report. However, in light of the new submission requirements,
the agency encourages applicants to consider whether there is a clear
reason, such as failure to properly power the study, for a study's
failure to demonstrate bioequivalence. In cases where the reason the
study failed is unclear, the applicant may want to consider requesting
a complete report rather than a summary report from the CRO to assist
the applicant in evaluating the study.

E. FDA Criteria for Evaluating Studies

    In the preamble to the proposed rule, FDA listed the following four
factors as examples of criteria it will use to evaluate BE studies when
at least one study failed to demonstrate bioequivalence: (1) The
statistical power of the studies, (2) minor differences in the
formulation used in each study, (3) whether the product was
administered consistently with the RLD's labeling in every study, and/
or (4) various other study design issues (68 FR 61640 at 61641).
    (Comment 23) While recognizing that it is impossible for FDA to
prospectively identify all potential issues, two comments requested
clarification about the criteria FDA plans to use to: (1) Determine
when to require the submission of a complete report of a study when a
summary report has been previously submitted and (2) evaluate
bioequivalence when at least one of the studies submitted by the
applicant failed to demonstrate bioequivalence. In particular, the
comments requested clarification about: (1) What additional data will
be required to demonstrate to FDA that a drug is bioequivalent to the
RLD, (2) whether FDA will be primarily concerned with the conditions
under which the drug was administered or the rationale for the
selection of certain types of study design characteristics, and (3)
whether decisions about bioequivalence will be at the sole discretion
of the reviewer. Another comment asked how conflicting results from two
or more BE studies will be assessed. In particular, the comment asked
if FDA will perform a meta-analysis on pooled studies. One comment
expressed concern that if criteria were not provided, it could increase
the costs associated with compliance with the rule.
    (Response) Generally, the criteria FDA reviewers will use to
evaluate BE studies submitted in response to the rule are the same as
the criteria they currently use to evaluate BE studies relied on for
ANDA approval. Those criteria have been discussed in detail in various
FDA guidances (available on the Internet at http://www.fda.gov/cder/
guidance/index.htm under Biopharmaceutics). When an applicant is
submitting both passing and nonpassing studies, it should include its
own analyses of the data and any potential explanations for nonpassing
results. The decision tree used by the applicant will likely be similar
to that used by FDA. While it is impossible to prospectively state
which issues will be most relevant in any particular case, examples of
likely questions that should be included in that decision tree are:
     Was the study correctly powered?
     Was the assay appropriate?
     Was the formulation inappropriate, and if so, how has the
formulation been changed?
     Was the drug properly administered in the failing study?
     Were there technical flaws in the way the study was
conducted?
    The applicant's explanations for failing results will likely be a
reviewer's first step in evaluating whether to request the submission
of a complete report of any particular study. FDA anticipates that, in
most cases, a summary report will be sufficient. The applicant's
explanations will also likely be a reviewer's first step in evaluating
how to weigh conflicting BE data. However, the reviewer will also
undertake an independent scientific analysis of the study reports
submitted. FDA will not rely on a meta-analysis of pooled studies.
    As the comments recognize, it is difficult to predict what type of
information FDA may request to assure the agency that the drug is
bioequivalent to the RLD. For example, FDA may choose to inspect the
site where a submitted study was conducted, or FDA may request
additional data. As discussed in the proposed rule, the responsibility
to demonstrate that the ANDA product is bioequivalent to the RLD rests
with the applicant. Therefore, it will ultimately be the applicant's

responsibility to demonstrate why the nonpassing study or studies
should not affect a determination that the ANDA product is
bioequivalent to the RLD.
    (Comment 24) One comment stated that the four examples provided by
FDA in the preamble to the proposed rule regarding the criteria for
evaluating BE studies submitted (i.e., statistical power, minor
differences in formulations, product administration, and other study
design issues) are so critical that FDA should require the submission
of all BE studies conducted on all formulations of the drug, rather
than only requiring the submission of studies conducted on the ``same
drug product formulation.'' As an example, the comment stated that
requiring the submission of all studies conducted on all formulations
will allow FDA to identify situations where an applicant used
increasingly larger sample sizes in their bioequivalence studies.
Similarly, the comment notes that, by listing ``minor differences in
formulation'' as an evaluation factor, FDA has acknowledged that
formulation changes are relevant to analyzing bioequivalence. The
comment states that this underscores the need to require the submission
of passing and nonpassing studies on all formulations.
    (Response) As discussed in greater detail in response to comment 5,
the decision to require the submission of BE studies conducted on the
``same drug product formulation'' as that submitted for approval was
based on a need to balance competing concerns. Requiring the submission
of all studies conducted on all formulations, regardless of their
relationship to the formulation submitted for approval, will
unnecessarily burden applicants and the review process without a
resulting benefit. Therefore, FDA declines to adopt this suggestion.
    (Comment 25) Several comments requested information about the
dispute resolution procedure that will be used if both passing and
nonpassing studies are submitted. In particular, the comments
highlighted the need for prompt resolution when the applicant and the
agency disagree about how study results should be interpreted. The
comments suggested that the dispute resolution procedure should be
efficient to ensure a timely review process. One comment questioned
whether a new administrative procedure is going to be developed for the
resolution of potential disputes.
    (Response) FDA does not believe that a new procedure will be
necessary to resolve any potential disputes arising from the submission
of additional BE studies. If FDA has questions about an applicant's
explanation as to why a particular study failed or needs additional
information to continue its review of the application, FDA will
communicate with the applicant in the same manner as it does to resolve
any other ANDA issue. FDA also notes there are dispute resolution
procedures available to resolve differences between applicants and FDA.
See 21 CFR 10.75 and 21 CFR 314.103, as well as Center for Drug
Evaluation and Research/Center for Biologic Evaluation and Research
guidance for industry entitled ``Formal Dispute Resolution: Appeals
Above the Division Level.''

F. Enforcement

    (Comment 26) One comment questioned how FDA intends to enforce and
monitor compliance with the rule. In particular, the comment suggested
that FDA should not rely on its preapproval inspection authority to
monitor compliance with the rule. The comment expressed concern that
investigators may not have the opportunity to look for failed studies
during preapproval inspections or, at a minimum, may not be focused on
looking for them. The comment also points out that Compliance Program
Guidance Manual 7346.832 states that preapproval inspections are not
mandated for narrow therapeutic range index drugs or the top 200
prescribed drugs. The comment suggested that rather than relying on
investigators to examine studies, OGD scientists are the most
appropriate personnel for determining whether study results affect
FDA's bioequivalence determination.
    (Response) As discussed in the response to comment 7, Sec.
314.50(d)(3) of FDA regulations already requires NDA applicants to
submit a description of all bioavailability and pharmacokinetic studies
in humans performed by or on behalf of the applicant. That regulation
does not contain a specific enforcement provision, and FDA believes it
is not necessary to provide a specific enforcement mechanism for this
final rule, which imposes similar duties on ANDA applicants. Moreover,
in certain circumstances, noncompliance with this final rule could be
considered a violation of 18 U.S.C. 1001, which prohibits knowingly and
willfully falsifying or concealing a material fact from a branch of the
Federal government.
    FDA agrees that it is not appropriate to rely solely on preapproval
inspections of manufacturing facilities to look for BE studies.
However, the agency has a variety of different enforcement and
oversight mechanisms that we use to ensure compliance with data
submission requirements.
    FDA agrees with the comment's suggestion that OGD's scientists are
the most appropriate personnel to determine how BE study results should
affect a bioequivalence determination. Any studies identified by FDA
will be forwarded to OGD scientists for consideration.
    FDA's initiative ``Pharmaceutical cGMPs for the 21st Century''
promotes a science and risk-based approach to product quality
regulation. Compliance Program Guidance Manual 7346.832 was revised to
reflect the approach described in the 21st Century initiative.
    (Comment 27) In the preamble to the proposed rule, FDA stated that
it may inspect sites where BE studies were conducted to determine
whether there were technical flaws in the way they were performed (68
FR 61640 at 61641). Two comments questioned whether such inspections,
particularly of sites in foreign countries, will slow down the ANDA
review process. One comment focused on pilot studies performed by CROs
in foreign countries and questioned whether the inspection of such
sites could lead to approval delays.
    (Response) FDA appreciates the concern expressed in the comments.
FDA's inspection resources are limited, and the agency does not
anticipate routinely inspecting every site for every BE study
submitted. The agency may, however, inspect any study sites it
determines appropriate in order to assess whether a generic drug is
bioequivalent to its RLD.
    (Comment 28) One comment stated that FDA should not rely on field
investigators to discover the existence of BE studies.
    (Response) FDA expects that most, if not all, applicants will
comply with this final rule and submit the appropriate BE studies of
which they are aware. The agency will not comment on its methods of
investigation with respect to enforcement of the final rule. However,
the agency agrees that field investigators should not be the only
source for discovering the existence of BE studies.

G. Miscellaneous

    (Comment 29) One comment asked what event determines the date the
study was conducted for purposes of deciding whether a biostudy needs
to be submitted.
    (Response) The event that should be considered to determine whether
a BE study must be submitted under this regulation is the date the
first dose in the study was administered. This date should be readily
identifiable by the applicant and FDA.
    (Comment 30) Two comments questioned whether it was necessary for

applicants to retain samples for studies other than the BE study relied
on for approval.
    (Response) It is not necessary to retain such samples. Applicants
are only required to retain samples for the BE study relied on for
approval.
    (Comment 31) Two comments asked whether FDA will apply the Freedom
of Information Act (FOIA) to failed BE studies submitted to FDA under
the rule. The comments expressed concern that if such studies are made
available to the public, confidence in generic drugs could be
undermined, and companies may use this information to disparage other
companies and their products.
    (Response) Information submitted on passing and nonpassing
bioequivalence studies will be available for public release after
approval of the application or supplemental application, consistent
with FDA's disclosure regulations in 21 CFR part 20 and Sec.  314.430,
and with the FOIA. While FDA appreciates the concern expressed in the
comment, the agency notes that in addition to the study results, the
applicant's explanations concerning failed studies and the agency's
determination and the basis for its determination of bioequivalence
will also be publicly available. We believe the availability of this
information should assuage the comments' concerns.

H. Economics

    (Comment 32) Two comments suggested that FDA's estimate that the
rule will result in a 10 percent increase in the number of BE studies
submitted to the agency was too conservative. One comment stated that,
based on its informal survey of generic drug companies, the number will
be larger. The other comment noted that, because the number of ANDA
applications and correspondence documents has risen in recent years,
the 10-percent estimate is not reflective of recent trends.
    (Response) FDA recognizes that the number of ANDAs and related
submissions has increased in recent years. However we are not able to
accurately predict the number or pattern of future submissions. Due to
this uncertainty, the agency assumed, for the reasons discussed in the
preamble to the proposed rule, that the number of BE studies submitted
annually will increase by approximately 10 percent. This estimate is
based on information suggesting that approximately 20 percent of all BE
studies conducted produce results that do not meet bioequivalence
limits, and that approximately 50 percent of these studies are
conducted on formulations that are not submitted for approval. The
comments appear to acknowledge the uncertainty of trying to predict the
exact increase in the number of studies submitted, because neither
comment suggests an alternative number to FDA's estimate of 10 percent.
Therefore, FDA continues to estimate that the increase in the number of
studies submitted will be approximately 10 percent. The economic
analysis in the proposed rule, however, relied on year 2000 data for
the number of submissions received by the agency. To ensure that the
economic analysis reflects current trends, FDA has revised the economic
analysis (section VIII of this document) to reflect the most current
data available on the number of submissions received by the agency.
    (Comment 33) One comment suggested that the compliance requirements
and cost analysis in the preamble to the proposed rule were flawed
because they failed to consider costs in addition to staff time. The
comment noted that companies often employ CROs to conduct activities
related to the design, initiation, conduct, and report generation of BE
studies. The comment suggested that companies may routinely request
complete reports from CROs, as opposed to summary reports, in the event
FDA requests a complete report. The comment also questioned FDA's
estimate that summary reports will be required approximately 80 percent
of the time and complete reports will be required approximately 20
percent of the time.
    (Response) FDA acknowledges that it is impossible to predict
precisely how often a complete report will be requested in the future.
However, the agency's estimate that a complete report will be required
only 20 percent of the time was based on its belief that, in most
cases, the reason a study failed will be evident from the information
provided in the summary report and the applicant's explanations. FDA
does not believe that the use of a CRO to conduct a study affects its
economic analysis. When a company contracts with a CRO, it may
stipulate the reporting format for the study. FDA does not believe that
stipulating a report format for BE studies in accordance with this rule
will create a significant burden for any affected entity.
    (Comment 34) One comment noted that FDA cited its desire to
increase the agency's knowledge and understanding of bioequivalence as
an objective of the rule. The comment questioned whether the costs
associated with the submission of ``all other bioequivalence studies,''
and the resolution of why various studies failed, were justified by
this objective.
    (Response) As discussed in greater detail in section VIII of this
document, FDA believes the costs of the rule are justified by the
multiple objectives we hope to achieve through this final rule. The
objective cited by the comment is a secondary objective of the rule. In
addition to increasing FDA's knowledge, the submission of all BE
studies is necessary because the data contained in passing and
nonpassing BE studies provide information that can be important to
FDA's assessment of the bioequivalence for a specific product.

V. Legal Authority

    Section 701(a) of the act (21 U.S.C. 371(a)) authorizes FDA to
issue regulations for the efficient enforcement of the act. Under
section 505(j)(2)(A)(iv) of the act, an ANDA applicant must submit
``information to show that the new drug is bioequivalent to the
[reference] listed drug * * *.'' If this requirement is not met because
information submitted in the application is insufficient to show that
the drug is bioequivalent to the listed drug referred to in the
application, FDA may deny approval of an ANDA (section 505(j)(4)(F) of
the act; Sec.  314.127(a)(6)(i) and (a)(6)(ii)). FDA believes that an
application may not be complete if a BE study that is conducted by an
applicant on the same drug product formulation is not submitted for
review, because the agency is being asked to make a bioequivalence
determination based on a review of only part of the available
bioequivalence data. The agency's experience with additional
bioequivalence data on the same drug product formulation has shown that
such data can be important, and even critical, to the agency's
bioequivalence determination.
    Requiring the reporting of all BE studies is consistent with the
act's requirement that applications must not contain untrue statements
of material fact (section 505(j)(4)(K) of the act; Sec.
314.127(a)(13)). FDA believes that failure to report all BE studies
conducted on the same drug product formulation as that submitted for
approval in an ANDA, amendment, or supplement may constitute selective
reporting of a material fact, which can result in withdrawal of
approval of an application under Sec.  314.150(b)(6). Selective
reporting refers to reports that contain certain passing results only.
It may not include nonpassing results and/or the scientific
justification for rejecting the nonpassing data (see FDA's notice
describing selective reporting of

stability tests (60 FR 32982 at 32983, June 26, 1995)).

VI. Effective Date

    Revised Sec. Sec.  314.94(a)(7)(i), 314.96(a)(1), 320.1(g), 320.21
(section heading), and 320.21(b)(1), as well as Sec.  320.21(c) (which
references the requirements of Sec.  320.21(b)(1)) and Sec.
314.94(a)(7)(ii) (as interpreted in section III of this document),
apply to ANDAs, amendments, or supplements submitted on or after the
effective date. Thus, with respect to ANDAs, amendments, or supplements
submitted prior to the effective date, applicants are not required to
report additional BE studies that were conducted in conjunction with
their applications. However, when an ANDA has been approved or
submitted prior to the effective date of the final rule, and a
supplement or amendment to the ANDA containing a BE study or studies is
submitted on or after the effective date, the applicant is required
under Sec. Sec.  314.96(a)(1) and 320.21(b)(1), as well as Sec.
320.21(c) (which refers to the requirements of Sec.  320.21(b)(1)), to
submit all BE studies, both passing and nonpassing, conducted in
conjunction with the supplement or amendment. In addition, on and after
the effective date, all applicants with approved ANDAs, including ANDAs
that were approved or submitted for approval prior to the effective
date, are required to comply with Sec.  314.81(b)(2)(vi), as
interpreted by FDA in section III of this document. As stated in
response to comment 6, in the event that a postmarketing study of an
approved and marketed drug fails to demonstrate bioequivalence, it
would be particularly important for the agency and the applicant to
examine the reason for the failure. Therefore, any annual report
submitted on or after the effective date by an applicant with an
approved ANDA must include reports of all BE studies on the approved
drug product, both passing and nonpassing, conducted or obtained by the
applicant during the annual reporting period, including those studies
conducted before the effective date but within the applicant's annual
reporting period.

VII. 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.

VIII. Analysis of Economic Impacts

    FDA has examined the impacts of the 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 a rule
on small entities. Based on our economic analysis and review of
comments submitted in response to the proposed rule, 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 $130 million, using the most current (2007) 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.

A. Background

    Under current regulations, ANDA applicants are required to submit
information demonstrating that a generic product is bioequivalent to an
RLD. In the past, firms have submitted only the results of those BE
studies that demonstrate that the rate and extent of absorption of the
test product meets bioequivalence limits. Firms have not typically
submitted the results of any additional BE studies that were conducted
on the same product formulation submitted for approval. The agency now
believes that data and information from additional BE studies, both
passing and nonpassing, are important for determining whether the
proposed formulation is bioequivalent to the RLD. Therefore, this final
rule requires ANDA applicants to submit the results of all BE studies,
passing and nonpassing, on the same drug product formulation submitted
for approval under an ANDA, amendment or supplement.
    As discussed in response to comment 6, the agency also believes
that it is important to clarify that the responsibility to submit the
results of all BE studies, passing and nonpassing, continues after
approval under the annual report submission requirements. However, the
agency believes that it will be highly unusual for an ANDA applicant to
conduct a postmarketing BE study. In particular, the agency believes
that an applicant will rarely, if ever, conduct a postmarketing BE
study other than one required for an ANDA supplement.

B. Affected Entities

    This final rule will affect establishments that submit ANDAs
containing BE studies. FDA does not know the precise number of
entities, either large or small, that will submit ANDAs in the future.
In the year 2006, there were 511 BE studies submitted by 177 applicants
in 622 original ANDAs, amendments, and supplements. FDA estimates that
this final rule will result in a 10-percent increase in the total
number of BE studies submitted annually, or 51 (511 x 0.10) additional
studies. As stated in the proposed rule, this estimate is based on
information suggesting that approximately 20 percent of all BE studies
conducted produce results that do not meet bioequivalence limits, and
that approximately 50 percent of these studies are conducted on
formulations that are not submitted for approval. Because we did not
receive any comments suggesting specific alternative figures that would
be more appropriate, we continue to rely on these assumptions for the
economic analysis of this final rule.

C. Compliance Requirements and Costs

    The main cost of complying with this final rule will be staff time.
The analysis in the proposed rule assumed a weighted average wage rate
of $40 per hour. The current, comparable figure for 2006 assumed in
this analysis is $47 per hour (Ref. 1). FDA estimates it will require
approximately 120 hours of staff time to prepare and submit each
additional complete BE study report, and approximately 60 hours of
staff time for each additional BE study summary report. The agency
believes that a complete report will be required

approximately 20 percent of the time, while a summary will suffice
approximately 80 percent of the time.
    Based on a weighted-average calculation using the information
presented above, the submission of each additional BE study is expected
to cost $3,384 ([120 x $47 x 0.2] + [60 x $47 x 0.8]). Thus, the
overall impact on the industry of reporting an additional 51 BE studies
per year will be about $173,000 ($3,384 x 51 = $172,584). Assuming it
equally likely that each of the 51 additional BE studies will be
conducted by any of the 177 applicants, a binomial distribution can be
used to predict how many firms will submit additional studies. Based on
this distribution, 38 firms will incur costs of $3,384 for 1 additional
BE study, 6 firms will incur costs of $6,768 (2 x $3,384) for 2
additional studies, and 1 firm will incur costs of $10,152 (3 x $3,384)
for 3 additional studies (the total number of studies in the
calculation does not equal 51 because of rounding). Thus, the maximum
expected annual cost burden associated with this final rule for any one
firm is $10,152. Approximately 75 percent (132 of 177, or 74.6 percent)
of all firms are expected to incur no additional annual costs under the
final rule.

D. Impact on Small Entities

    FDA recognizes that some of the establishments required to submit
additional BE study reports under this final rule will be small
entities with limited resources. In the proposed rule, the agency
acknowledged the uncertainty of its estimates with respect to the
number of additional BE studies that will be submitted, their
distribution among large and small entities, and the number of small
entities affected. We also requested detailed comments on these
important issues. After revising our Initial Regulatory Flexibility
Analysis in response to the public comments received, FDA has
determined that this final rule will not have a significant economic
impact on a substantial number of small entities.
    FDA also recognizes that requiring submission of all BE study
results may result in a longer total application review time if these
additional BE study results suggest that a generic product is not
bioequivalent to the RLD. In these situations, firms will be required
to submit additional data that demonstrate bioequivalence in order to
obtain marketing approval. Marketing approval may be denied if evidence
from the additional BE studies fails to establish bioequivalence. The
agency does not know how frequently these situations might occur.
    According to standards established by the Small Business
Administration, a small pharmaceutical preparation manufacturer (North
American Industry Classification System (NAICS) Code 325412) employs
fewer than 750 employees (Ref. 2). An FDA review of ANDA records
submitted during the 3-year period from October 1996 to September 1999
found that 32 percent of the applications (322 of 1,007) were from
small entities, and that 39 percent of ANDA applicants (64 of 164) were
small entities. (Resource limitations prevented the agency from being
able to perform a similar, labor intensive manual search of similar
records for a more recent time period.) Thus, the majority of ANDAs are
not submitted by small entities. Assuming these proportions continue to
hold, there will be about 69 small entities (0.39 x 177) submitting
ANDAs annually. FDA also assumes that this group of small entities will
submit 16 of the additional 51 BE studies (0.10 x 0.32 x 511) per year.
    Assuming it is equally likely that each of the 16 additional BE
studies will be reported by any of the 69 small entities, a binomial
distribution can be used to predict how many of these firms will submit
additional studies. Based on this distribution, 13 small entities will
incur costs of $3,384 for one additional BE study, and two firms will
incur costs of $6,768 (2 x $3,384) for two additional BE studies. Thus,
the maximum expected burden of this final rule for any one small entity
is $6,768. Nearly 80 percent (55 of 69, or 79.5 percent) of all small
entities are expected to incur no additional annual costs under the
final rule.
    In the proposed rule, FDA relied on information indicating that the
cost of preparing and submitting an ANDA was between $300,000 and $1
million (68 FR 61640 at 61645). Because we were unable to identify any
similar, more recent cost estimates, we have adjusted these earlier
figures for inflation to estimate the economic impact of this final
rule. Our inflation adjustment was made based on percent changes in the
Biomedical Research and Development Price Index (BRDPI) (Ref. 3). Based
on these inflation adjustments, FDA estimates that the cost to prepare
and submit an ANDA is now between $361,500 and $1.24 million. The
details of our inflation adjustment calculations are summarized in
table 1 of this document.

                Table 1.--Details of Inflation Adjustment
------------------------------------------------------------------------
                                       Percent Change       Inflation
    ANDA Cost          Base Year        in the BRDPI      Adjusted ANDA
     Estimate                          from Base Year     Cost Estimate
------------------------------------------------------------------------
$300,000           2001               20.5%             $361,500
------------------------------------------------------------------------
$1 million         2000               24.4%             $1.24 million
------------------------------------------------------------------------

    Based on this information, the maximum expected cost burden of this
final rule on any one firm will be between 0.8 percent ($10,152 for
three additional BE studies / $1.24 million) and 2.8 percent ($10,152 /
$361,500) of the total cost of preparing and submitting an ANDA. The
maximum expected cost burden for any one small entity will be between
0.6 percent ($6,768 for two additional BE studies / $1.24 million) and
1.9 percent ($6,768 / $361,500) of the total cost of preparing and
submitting an ANDA.
    A year 2000 survey of 26 public generic drug companies revealed 15
firms with fewer than 750 employees (as described in the proposed rule,
68 FR 61640 at 61645). Because FDA was unable to identify a similar,
more recent survey available in the public domain, we have relied on
this information to estimate the impact of the final rule on small
entities. The 15 small entities identified in the survey had an average
of 331 employees and average annual revenues of $115 million. The
maximum expected burden of this final rule for any one of these small
entities is therefore expected to be only 0.006 percent ($6,768 / $115
million) of average annual revenues. The agency believes this cost
could be recovered through drug sales after marketing approval.
    In recognition of the potential economic impact on small entities,
the agency has structured the rule to minimize the reporting burden.
For example, the agency believes that summary reports of additional BE
studies will suffice 80 percent of the

time, provided that complete results are available to FDA upon request.
The agency believes that a summary report will require only 60 hours of
staff time per BE study, or half the time and expense required to
prepare and submit a complete report. This provision should prove
particularly beneficial for small entities.
    Furthermore, no specific educational or technical skills are
required to complete and submit the additional BE study reports.
Trained and qualified employees of an establishment who are involved in
normal operations generally complete similar activities. Also, FDA has
reviewed related Federal rules and has not identified any rules that
duplicate, overlap, or conflict with the final rule.
    FDA has evaluated only two regulatory options: (1) Continuing the
current practice of requiring the submission of only pivotal BE study
results, or (2) requiring the submission of results from all BE studies
conducted by an applicant on a final drug product formulation. Under
the first option, firms will incur no additional reporting costs,
although some firms might experience significant costs if their product
was initially approved and subsequently recalled, or had approval
withdrawn because the product is found not to be bioequivalent to the
RLD. The agency believes that the second option, requiring that results
from all BE studies conducted on the final drug product formulation be
submitted for approval, is important for assessing bioequivalence. The
final rule requires reporting of all BE studies, but also permits
summary reports for BE studies other than those the applicant relies on
for approval, except where full reports are specifically requested by
the agency. The agency believes that the final rule therefore addresses
the perceived regulatory need in the least intrusive and most cost
effective way.

E. Benefits of the Final Rule

    The final rule will generate economic benefits both for individuals
and for society as a whole, to the extent that the reporting of data
from all BE studies on the same drug product formulation as that
submitted for approval prevents product discontinuation and adverse
health effects. Also, the data from additional BE studies may provide
valuable scientific information, thereby increasing the agency's
understanding of bioequivalence and generic drug development issues,
and improving the drug approval process. Therefore, this final rule
will permit FDA to make more informed BE determinations in the future.

IX. Paperwork Reduction Act of 1995

    This final rule contains 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). The
title, description, and respondent description of the information
collection requirements are shown below with an estimate of the annual
reporting burden. Included in this estimate is the time for reviewing
instructions, searching existing data sources, gathering and
maintaining the data needed, and completing and reviewing each
collection of information.
    Title: Requirements for Submission of Bioequivalence Data; Final
Rule
    Description: FDA is amending the requirements for certain ANDAs,
ANDA amendments, and ANDA supplements submitted under Sec. Sec.
314.94, 314.96, and 314.97. Specifically, FDA is amending Sec. Sec.
314.94(a)(7)(i), 314.96(a)(1), and 320.21(b)(1), as well as modifying
the requirements of Sec.  320.21(c) (which refers to Sec.
320.21(b)(1)), to require an ANDA applicant to submit information from
all BE studies, both passing and nonpassing, conducted by the applicant
on the same drug product formulation as that submitted for approval
under an ANDA, amendment, or supplement.
    In addition, FDA is announcing its intention to interpret Sec.
314.94(a)(7)(ii) as requiring that ANDA applicants who submit ANDAs
under a petition approved under Sec.  314.93 submit information on all
bioavailability or BE studies conducted on the same drug product
formulation submitted for approval.
    FDA is also clarifying through this rulemaking that it intends to
interpret Sec.  314.81(b)(2)(vi) as requiring the submission of
postmarketing reports of all BE studies conducted or otherwise obtained
by ANDA applicants in the applicant's annual report. However, FDA
believes an applicant will rarely, if ever, conduct a postmarketing BE
study, other than one required for an ANDA supplement.
    Description of Respondents: Persons and businesses, including small
businesses and manufacturers.
    Burden Estimate: Table 2 of this document provides an estimate of
the annual reporting burden under the rule.
    The rule will affect establishments that submit ANDAs. FDA does not
know the precise number of entities, either large or small, that will
submit ANDAs in the future. In the year 2006, 177 applicants submitted
511 BE studies in 622 original ANDAs, amendments, and supplements. FDA
estimates that this rule will result in a 10-percent increase in the
number of BE studies submitted annually, or 51 (511 x 0.10) additional
studies. This estimate is based on the assumptions that approximately
20 percent of all BE studies conducted produce results that do not meet
bioequivalence limits, and that about half of these studies are
conducted on formulations that are not submitted for approval.
    FDA estimates it will require approximately 120 hours of staff time
to prepare and submit each additional complete BE study report, and
approximately 60 hours of staff time for each additional BE summary
report. The agency believes that a complete report will be required
approximately 20 percent of the time, while a summary will suffice
approximately 80 percent of the time. Based on a weighted-average
calculation using the information presented above, the submission of
each additional BE study is expected to take 72 hours of staff time
([120 x 0.2] + [60 x 0.8]).
    In table 2 of this document, FDA has estimated the reporting burden
associated with each section of the rule. FDA believes that the vast
majority of additional BE studies will be reported in ANDAs (submitted
under Sec.  314.94) rather than supplements (submitted under Sec.
314.97), because it is unlikely that an ANDA holder will conduct BE
studies with a drug after the drug has been approved. Moreover, drugs
approved under an ANDA prior to the effective date of the final rule
will only be required to report additional BE studies conducted after
the effective date, which should not result in the submission of many
BE study reports in supplements. With respect to the reporting of
additional BE studies in amendments (submitted under Sec.  314.96),
this should also account for a small number of reports, because most BE
studies will be conducted on a drug prior to the submission of the ANDA
and will be reported in the ANDA itself.

                                 Table 2.--Estimated Annual Reporting Burden\1\
----------------------------------------------------------------------------------------------------------------
    21 CFR            No. of         Annual Frequency       Total Annual        Hours per
    Section        Respondents         per Response          Responses           Response         Total Hours
----------------------------------------------------------------------------------------------------------------
314.94(a)(7)                   49                     1                 49                 72              3,528
----------------------------------------------------------------------------------------------------------------
314.96(a)(1)                    1                     1                  1                 72                 72
----------------------------------------------------------------------------------------------------------------
314.97                          1                     1                  1                 72                 72
----------------------------------------------------------------------------------------------------------------
Total                                                                                3,672
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

    The information provisions of this final rule have been submitted
to the Office of Management and Budget (OMB) for review, as required by
section 3507(d) of the Paperwork Reduction Act of 1995. The
requirements were approved and assigned OMB control number 0910-0630.
This approval expires November 30, 2011. An agency may not conduct or
sponsor, and a person is not required to respond to, a collection of
information unless it displays a currently valid OMB control number.

X. 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.

XI. References

    The following references have been placed on display in the
Division of Dockets Management (HFA-305), Food and Drug Administration,
5630 Fishers Lane, rm. 1061, Rockville, MD 20857, 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 FDA is not responsible
for any subsequent changes to the Web sites after this document
publishes in the Federal Register.)

    1. U.S. Department of Labor, Bureau of Labor Statistics, Table
11. Employer costs per hour worked for employee compensation and
costs as a percent of total compensation: Private industry workers,
by occupational group and full-time and part-time status, December
2006, Management, professional, and related series.
    2. U.S. Small Business Administration, Office of Size Standards,
Table of Size Standards, available online at http://www.sba.gov/idc/
groups/public/documents/sba_homepage/serv_sstd_tablepdf.pdf.
    3. National Institutes of Health, Office of Science Policy
Analysis, Biomedical Research and Development Price Index (BRDPI),
available online at http://officeofbudget.od.nih.gov/PDF/BRDPI_2_
5_07.pdf (viewed April 20, 2007).

List of Subjects

21 CFR Part 314

    Administrative practice and procedure, Confidential business
information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 320

    Drugs, Reporting and recordkeeping requirements.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts
314 and 320 are amended as follows:

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG

0
1. The authority citation for 21 CFR part 314 continues to read as
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 356a,
356b, 356c, 371, 374, 379e.

0
2. Amend Sec.  314.94 by revising paragraph (a)(7)(i) to read as
follows:

Sec.  314.94  Content and format of an abbreviated application.

    (a) * * *
    (7) Bioequivalence. (i) Information that shows that the drug
product is bioequivalent to the reference listed drug upon which the
applicant relies. A complete study report must be submitted for the
bioequivalence study upon which the applicant relies for approval. For
all other bioequivalence studies conducted on the same drug product
formulation as defined in Sec.  320.1(g) of this chapter, the applicant
must submit either a complete or summary report. If a summary report of
a bioequivalence study is submitted and FDA determines that there may
be bioequivalence issues or concerns with the product, FDA may require
that the applicant submit a complete report of the bioequivalence study
to FDA; or
* * * * *

0
3. Amend Sec.  314.96 by adding four sentences at the end of paragraph
(a)(1) to read as follows:

Sec.  314.96  Amendments to an unapproved abbreviated application.

    (a) * * *
    (1) * * * Amendments containing bioequivalence studies must contain
reports of all bioequivalence studies conducted by the applicant on the
same drug product formulation, unless the information has previously
been submitted to FDA in the abbreviated new drug application. A
complete study report must be submitted for any bioequivalence study
upon which the applicant relies for approval. For all other
bioequivalence studies conducted on the same drug product formulation
as defined in Sec.  320.1(g) of this chapter, the applicant must submit
either a complete or summary report. If a summary report of a
bioequivalence study is submitted and FDA determines that there may be
bioequivalence issues or concerns with the product, FDA may require
that the applicant submit a complete report of the bioequivalence study
to FDA.
* * * * *

PART 320--BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS

0
4. The authority citation for 21 CFR part 320 continues to read as
follows:

    Authority: 21 U.S.C. 321, 351, 352, 355, 371.

0
5. Amend Sec.  320.1 by adding paragraph (g) to read as follows:

Sec.  320.1  Definitions.

* * * * *
    (g) Same drug product formulation means the formulation of the drug
product submitted for approval and any formulations that have minor
differences in composition or method of

manufacture from the formulation submitted for approval, but are
similar enough to be relevant to the agency's determination of
bioequivalence.

0
6. Amend Sec.  320.21 by revising the section heading and paragraph
(b)(1) to read as follows:

Sec.  320.21  Requirements for submission of bioavailability and
bioequivalence data.

* * * * *
    (b) * * *
    (1) Evidence demonstrating that the drug product that is the
subject of the abbreviated new drug application is bioequivalent to the
reference listed drug (defined in Sec.  314.3(b) of this chapter). A
complete study report must be submitted for the bioequivalence study
upon which the applicant relies for approval. For all other
bioequivalence studies conducted on the same drug product formulation,
the applicant must submit either a complete or summary report. If a
summary report of a bioequivalence study is submitted and FDA
determines that there may be bioequivalence issues or concerns with the
product, FDA may require that the applicant submit a complete report of
the bioequivalence study to FDA; or
* * * * *

    Dated: January 13, 2009.
Jeffrey Shuren,
Associate Commissioner for Policy and Planning.
[FR Doc. E9-884 Filed 1-15-09; 8:45 am]

BILLING CODE 4160-01-S