Requirements for Submission of Bioequivalence Data; Final Rule, 2849-2862 [E9-884]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 74, Number 11 (Friday, January 16, 2009)]
[Rules and Regulations]
[Pages 2849-2862]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E9-884]


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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, 240-276-8782.

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

[[Page 2850]]

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

[[Page 2851]]

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,

[[Page 2852]]

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

[[Page 2853]]

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,

[[Page 2854]]

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

[[Page 2855]]

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 https://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

[[Page 2856]]

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

[[Page 2857]]

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

[[Page 2858]]

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