[Federal Register Volume 68, Number 209 (Wednesday, October 29, 2003)]
[Proposed Rules]
[Pages 61640-61647]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-27187]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 314 and 320

[Docket No. 2003N-0341]


Requirements for Submission of In Vivo Bioequivalence Data; 
Proposed Rule

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
its regulations on submission of bioequivalence data to require an 
abbreviated new drug application (ANDA) applicant to submit data from 
all bioequivalence studies (BE studies) that 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 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 proposing this change 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 formulation performance.

DATES: Submit written or electronic comments by January 27, 2004. 
Submit written comments on the information collection requirements by 
November 28, 2003.

ADDRESSES: Submit written comments to the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
rm. 1061, Rockville, MD 20857. Submit electronic comments to http://www.fda.gov/dockets/ecomments. The Office of Management and Budget 
(OMB) is still experiencing significant delays in the regular mail, 
including first class and express mail, and messenger deliveries are 
not being accepted. To ensure that comments on the information 
collection are received, OMB recommends that written comments be faxed 
to the Office of Information and Regulatory Affairs, OMB, Attn: Fumie 
Yokota, Desk Officer for FDA, FAX: 202-395-6974.

FOR FURTHER INFORMATION CONTACT: Aida L. Sanchez, Center for Drug 
Evaluation and Research (HFD-650), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-5847.

SUPPLEMENTARY INFORMATION:

I. Background

    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 and designated as an RLD. The statutory requirement is 
reflected in FDA's regulations in part 314 (21 CFR part 314) at Sec.  
314.94(a)(7). Part 320 (21 CFR part 320) at Sec.  320.24 sets forth the 
types of evidence acceptable to establish bioequivalence. The most 
common BE studies are those performed on solid oral dosage forms of 
drugs that are absorbed into the systemic circulation. Data from BE 
studies provide an estimate of the rate and extent of drug absorption 
for a test product compared to a reference product. These data are 
examined, using statistical procedures, to determine whether the test 
product meets bioequivalence limits.
    A BE study may fail to show that a test product meets 
bioequivalence 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). Where the relative 
bioavailability of a test 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

[[Page 61641]]

not be as therapeutically effective as the RLD. Where the relative 
bioavailability of a test product is too high, the concern with the 
product generally is not therapeutic efficacy but rather its safety 
relative to the RLD. In some cases, bioequivalence will not be 
demonstrated because of inadequate numbers of subjects in the study 
relative to the magnitude of intrasubject variability rather than 
either significantly high or low relative bioavailability of the 
product.

II. Not All BE Studies Are Currently Being Submitted

    The act and FDA regulations require that an ANDA applicant submit 
information demonstrating bioequivalence of a proposed drug to the RLD, 
but they do not specify the type or quantity of information that must 
be submitted to demonstrate bioequivalence. 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 meets bioequivalence limits. Thus, ANDA applicants that 
have conducted multiple studies on a final formulation producing 
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 only 
infrequently sees data from 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. As discussed in section III of this 
document, information from additional BE studies conducted on a product 
can be important in assessing bioequivalence for that product.

III. Need for Submission of All Studies

    In recent years, there have been certain cases where applicants did 
not submit all of the BE studies conducted on the final formulation of 
an ANDA product prior to approval, and FDA discovered postapproval that 
the submission of such studies could have been important in assessing 
bioequivalence. The agency is not aware of any adverse public health 
consequences associated with products for which studies were not 
submitted. Moreover, the agency is not aware of any information 
regarding any generic product currently on the market that would 
suggest that the product is not bioequivalent to a reference listed 
drug to which it has been designated as therapeutically equivalent. 
However, the agency now believes that it is necessary for the purposes 
of evaluating a drug product submitted for approval under an ANDA to 
have data obtained from all additional BE studies conducted on the 
final formulation. This view was supported by FDA's Advisory Committee 
for Pharmaceutical Science, which recommended in a recent meeting that 
FDA review all BE studies conducted by the applicant on the final 
formulation (Ref. 1). The agency is proposing that ANDA applicants 
submit information from all BE studies for the following reasons:
    1. Data contained in additional passing and nonpassing BE studies 
can be important to FDA's assessment of bioequivalence for a specific 
product.
    2. 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 promotes further development of science-based 
bioequivalence policies.
    The agency's experience with evaluating additional passing and 
nonpassing BE studies has shown that information from such studies can 
be important in assessing whether a formulation is bioequivalent to the 
RLD. For example, in one recent case, the ANDA applicant conducted an 
additional BE study on the final formulation prior to submission of its 
ANDA, but did not submit the results of the study to FDA. The agency 
found out about the results of the additional study after approval of 
the ANDA. The additional study indicated that the bioequivalence of the 
approved product was questionable. Based on the information in the 
additional study, the agency reconsidered its decision to approve the 
drug and requested that the firm voluntarily withdraw the product from 
the market. The firm withdrew the product from the market and withdrew 
its ANDA. Although cases such as this may occur relatively 
infrequently, it is imperative that FDA be aware of the additional BE 
studies and have the information necessary to evaluate their 
significance.
    When FDA receives an ANDA that contains one or more nonpassing BE 
studies for the final formulation, the agency will evaluate the 
significance of both the passing and nonpassing BE studies. As an 
initial matter, for each study submitted in summary report form, FDA 
will consider whether it is necessary to request a full report from the 
applicant. Regardless of the form of the report, however, FDA 
anticipates that a number of factors will be critical in evaluating 
both the passing and nonpassing BE studies. For example, FDA may 
consider: (1) The statistical power of each study, (2) minor 
differences in the formulation used in each study, (3) whether the 
product was administered consistent with the RLD's labeling in every 
study, and/or (4) various other study design issues. In addition, FDA 
may inspect the sites of the different studies to determine whether 
there were technical flaws in how the studies were conducted. For 
example, the reliability of a particular study's results could be 
undermined by flaws in: (1) Its inclusion and exclusion criteria, (2) 
an investigator's compliance with standard operating procedures and/or 
the study protocol, (3) its analytical or assay methodologies, (4) the 
storage of samples, (5) how between treatment washout periods were 
carried out, and/or (6) various other flaws in how the study was 
conducted. The goal of FDA's evaluation will be to determine: (1) The 
importance and reliability of the data collected in the different 
studies and (2) how the studies should be weighed in making a 
bioequivalence determination. Ultimately, however, the responsibility 
to demonstrate that the ANDA product is bioequivalent to the RLD rests 
with the applicant. Therefore, if conflicting BE studies are submitted, 
it will ultimately be the applicant's responsibility to demonstrate why 
the nonpassing study or studies should not undermine a determination 
that the ANDA product is bioequivalent to the RLD.
    Even in cases where information from additional BE studies is not 
critical to the agency's bioequivalence determination for a specific 
product, the data will provide valuable scientific information that 
increases our knowledge and understanding of bioequivalence and generic 
drug development issues. Data from additional BE studies also provide 
FDA with useful and relevant information about drug products submitted 
for approval, including how minor formulation or composition changes, 
or changes in study design, affect the performance of a formulation. 
FDA anticipates that further experience with data from additional 
passing and nonpassing BE studies will facilitate a more focused and 
efficient ANDA review process and enhance FDA's

[[Page 61642]]

ability to ensure sound science-based decisions.

IV. Description of the Proposed Rule

    The proposed rule would amend and clarify current BE study 
submission requirements to specifically require applicants to submit 
data on all BE studies, including studies that do not meet passing 
bioequivalence criteria, performed on a drug product formulation 
submitted for approval under an ANDA or an amendment or supplement to 
an ANDA that contains BE studies. Applicants would 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. In addition to the 
regulatory changes and clarifications described in this rulemaking, the 
agency is planning to issue guidance on this subject to help ensure 
that all affected entities are notified of, and understand, the 
proposed changes.

A. Proposed Requirements for the Submission of Data From All BE Studies 
Conducted on the Same Drug Product Formulation Submitted for Approval 
in ANDAs, Supplements, and Amendments

1. Proposed Requirements for Reporting BE Studies in ANDAs Submitted 
Under Sec.  314.94
    Current Sec.  314.94(a)(7)(i) states that an ANDA applicant must 
submit information that shows a drug product to be bioequivalent to an 
RLD. FDA is proposing to amend Sec.  314.94(a)(7)(i) by adding language 
requiring an applicant to submit information from all BE studies, both 
passing and nonpassing, conducted on the same formulation of the drug 
product submitted for approval. The applicant would continue to be 
required to submit complete reports of the BE studies upon which the 
applicant relies for approval. For all other BE studies on the same 
drug product formulation, the applicant would be required to submit a 
summary report. FDA plans to issue guidance on the format of a summary 
report. If a summary report is submitted and the agency believes that 
there may be bioequivalence issues or concerns with the product, the 
agency may require that a complete report be prepared and submitted to 
FDA.
    Section 320.21(b)(1) and (b)(2) (21 CFR 320.21(b)(1) and (b)(2)) 
requires that any person submitting an ANDA include in the application 
evidence demonstrating that the drug submitted for approval is 
bioequivalent to the RLD or information to permit FDA to waive the 
submission of evidence to demonstrate bioequivalence as provided in 
Sec.  320.21(f). FDA is proposing to amend current Sec.  320.21(b)(1) 
to add language requiring an applicant to submit evidence demonstrating 
bioequivalence that includes information from all BE studies, both 
passing and nonpassing, conducted on the same formulation submitted for 
approval. This change is consistent with the change being proposed in 
Sec.  314.94(a)(7)(i) for ANDA submissions.
2. Proposed Requirements for Reporting BE Studies in ANDA Supplements 
Submitted Under Sec.  314.97 (21 CFR 314.97)
    In addition to modifying the information required in ANDAs, the 
proposed amendment to Sec.  320.21(b)(1) would also modify the 
information required to be included in certain supplements to approved 
ANDAs (which are submitted under Sec.  314.97). Under Sec.  320.21(c), 
any person submitting a supplement to an ANDA must include the evidence 
or information required by Sec.  320.21(b) (i.e., BE studies or 
information permitting waiver) for certain types of changes to the drug 
product or labeling. For example, a change in the manufacturing process 
beyond the variations provided for in the ANDA would require a 
supplement containing BE studies or information permitting waiver of 
such studies. FDA is not proposing to amend the language of Sec.  
320.21(c). However, because Sec.  320.21(c) incorporates the 
requirements of Sec.  320.21(b) by reference, the proposed amendment to 
Sec.  320.21(b)(1) would modify the requirements of Sec.  320.21(c). 
Specifically, for ANDA supplements requiring BE studies under Sec.  
320.21(c), applicants would be required to include the information 
required by proposed Sec.  320.21(b)(1)(i.e., information from all BE 
studies, both passing and nonpassing, conducted on the same formulation 
for which the supplement is being submitted).
3. Proposed Requirements for Reporting BE Studies in Amendments to 
ANDAs Submitted Under Sec.  314.96
    Section 314.96(a)(1) states that an ANDA applicant may amend an 
ANDA that has been submitted but not yet approved to revise existing 
information or provide additional information. FDA is proposing to 
amend current Sec.  314.96(a)(1) to require that, where BE studies are 
submitted in an amendment, the amendment contain information from all 
BE studies, both passing and nonpassing, conducted by the applicant on 
the same drug product formulation, unless the information has 
previously been submitted to FDA in the applicant's ANDA.
4. Proposed Requirements for the Format of the Reports of BE Studies 
Submitted in ANDAs, Supplements, and Amendments
    Under the proposed rule, proposed Sec. Sec.  314.94(a)(7)(i), 
320.21(b)(1), and 314.96(a)(1), as well as Sec.  320.21(c)(which 
incorporates the requirements of Sec.  320.21(b)(1) by reference) would 
require applicants to submit full reports of BE studies upon which the 
applicant relies for approval and either full or summary reports of all 
other BE studies conducted on the same drug product formulation. If a 
summary BE study report is submitted and FDA believes that there may be 
a bioequivalence issue or concern with the product, FDA may require 
that a complete report be prepared and submitted to FDA.

B. Proposed Requirement for the Submission of Data From All BE Studies 
Conducted on the Same Drug Product Formulation Submitted for Approval 
Under a Petition Approved Under Sec.  314.93

    Section 314.94(a)(7)(ii) states, in relevant part, that if an ANDA 
is submitted under a petition approved under Sec.  314.93, the 
applicant must 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. The agency is proposing to interpret Sec.  
314.94(a)(7)(ii) to require the submission of results from all 
bioavailability and BE studies conducted on the same formulation. FDA 
believes that the language in current Sec.  314.94(a)(7)(ii) is 
sufficient to accomplish this purpose. Therefore, FDA is not amending 
this language, but is clarifying through this rulemaking that it 
intends to require applicants that submit ANDAs under petitions 
approved under Sec.  314.93 to submit information from all BE studies, 
passing and nonpassing, conducted on the same drug product formulation. 
Applicants would be required to submit complete reports of the 
bioavailability or BE studies upon which the applicant relies for 
approval and either a complete or summary report for all other studies 
on the same drug product formulation. If a summary report is submitted 
for an

[[Page 61643]]

additional study and the agency believes that there may be 
bioequivalence issues or concerns with the product, the agency may 
request that a complete study report be submitted to FDA.

C. Proposed Requirement for the Submission of Data From All 
Postmarketing BE Studies Conducted or Otherwise Obtained by the 
Applicant on the Same Drug Product Formulation That Has Been Approved

    Under Sec.  314.81(b)(2)(vi), an ANDA applicant is required 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. All BE studies would fall into one or more of the categories of 
studies (i.e., biopharmaceutic, pharmacokinetic, and clinical 
pharmacology) required to be submitted under this section. As a result, 
the agency is proposing to interpret this section to require ANDA 
applicants with approved ANDAs to submit postmarketing reports of all 
BE studies, both passing and nonpassing, conducted or obtained by the 
applicant during the annual reporting period on the same drug product 
formulation that has been approved. FDA believes that the language in 
current Sec.  314.81(b)(2)(vi) is sufficient to accomplish this 
purpose. Therefore, FDA is not amending this language, but is 
clarifying through this rulemaking that it intends to interpret the 
section to require submission of postmarketing reports of all BE 
studies conducted or otherwise obtained by ANDA applicants. Under this 
section, applicants may submit either complete or summary reports of 
the BE studies conducted or otherwise obtained during the annual 
reporting period. If a summary report is submitted for a BE study and 
FDA believes that there may be bioequivalence issues or concerns with 
the product, the agency may require that a complete study report be 
prepared and submitted to FDA.
    FDA believes that clarifying its interpretation of Sec.  
314.81(b)(2)(vi) is important for ensuring consistency in its 
premarketing and postmarketing requirements regarding the submission of 
BE studies. However, the agency also believes that it would be highly 
unusual for an ANDA applicant to conduct a postmarketing BE study. In 
particular, the agency believes that an applicant would rarely, if 
ever, conduct a postmarketing BE study other than one required for an 
ANDA supplement.

D. What Constitutes the ``Same Drug Product Formulation'' for the 
Purposes of Required BE Study Submissions

    FDA is proposing to require ANDA applicants to submit information 
from all BE studies, both passing and nonpassing, conducted on the same 
drug product formulation in conjunction with the submission of ANDAs, 
amendments, and supplements containing BE studies. FDA intends that the 
terminology ``same drug product formulation'' would 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 would consider the original and 
modified products to be similar enough to constitute the same drug 
product formulation for the purposes of the proposed rule. The SUPAC 
guidances include:
    1. ``SUPAC-IR: Immediate-Release Solid Oral Dosage Forms: Scale-Up 
and Postapproval Changes: Chemistry, Manufacturing and Controls, In 
Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation'' 
(November 1995);
    2. ``SUPAC-IR: Questions and Answers about the SUPAC-IR Guidance'' 
(February 1997);
    3. ``SUPAC-MR: Modified Release Solid Oral Dosage Forms: Scale-Up 
and Postapproval Changes: Chemistry, Manufacturing and Controls; In 
Vitro Dissolution Testing and In Vivo Bioequivalence Documentation'' 
(September 1997);
    4. ``SUPAC-IR/MR: Immediate-Release and Modified Release Solid Oral 
Dosage Forms: Manufacturing Equipment Addendum'' (January 1999);
    5. ``SUPAC-SS: Nonsterile Semisolid Dosage Forms: Scale-Up and 
Postapproval Changes: Chemistry, Manufacturing and Controls; In Vitro 
Release Testing and In Vivo Bioequivalence Documentation'' (May 1997); 
and
    6. ``SUPAC-SS: Nonsterile Semisolid Dosage Forms: Manufacturing 
Equipment Addendum'' (Draft Guidance, December 1998).
    Persons interested in a full discussion of level 1 and level 2 
changes should consult the SUPAC guidances listed previously in section 
IV.D of this document. The guidances may be obtained upon request from 
the Center for Drug Evaluation and Research, Office of Training and 
Communications, Division of Drug Information (HFD-240), 5600 Fishers 
Lane, Rockville, MD, 20857, 301-827-4573. The guidances are also 
available on the Internet at http://www.fda.gov/cder/guidance/index.htm 
under the Chemistry heading.

V. Legal Authority

    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 (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. As discussed in section III of this document, 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 formulation of a drug product 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. 
Selective reporting does not consistently contain nonpassing results 
and does not consistently contain a 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. Implementation

    FDA proposes that any final rule that may issue based on this 
proposal become effective 6 months after its date of publication in the 
Federal Register. Proposed Sec. Sec.  314.94(a)(7)(i), 314.96(a)(1), 
and 320.21(b)(1), as well as Sec.  320.21(c)

[[Page 61644]]

(which references the requirements of Sec.  320.21(b)(1)) and Sec.  
314.94(a)(7)(ii) (as interpreted in section IV.B of this document), 
would apply only to ANDAs, amendments, or supplements submitted on or 
after the effective date of the final rule. Thus, applicants who have 
submitted these applications prior to the effective date of the final 
rule would not be required to report additional BE studies that were 
conducted in conjunction with their applications. However, where 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 of the 
final rule, the applicant would be required under proposed 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 
of the final rule, all applicants with approved ANDAs, including ANDAs 
that have been approved or submitted for approval prior to the 
effective date of the final rule, would be required to comply with 
Sec.  314.81(b)(2)(vi), as interpreted by FDA in section IV.C of this 
document. However, the agency is proposing to use its discretion in the 
enforcement of Sec.  314.81(b)(2)(vi) such that it would apply only to 
those additional BE studies conducted after the effective date of the 
final rule. Thus, applicants with approved ANDAs would be required to 
provide information in an annual report on additional passing or 
nonpassing BE studies conducted or obtained by the applicant on the 
approved drug product formulation after the effective date of the final 
rule.

VII. Comments on the Proposed Rule

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments regarding this document. 
Submit a single copy of electronic comments or two paper copies of any 
mailed comments, except that individuals may submit one paper copy. 
Comments are to be identified with the docket number found in brackets 
in the heading of this document. Received comments may be seen in the 
Division of Dockets Management Branch between 9 a.m. and 4 p.m., Monday 
through Friday.

VIII. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

IX. Analysis of Economic Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612 (as 
amended by subtitle D of the Small Business Regulatory Fairness Act of 
1996 (Public Law 104-121))), and the Unfunded Mandates Reform Act 
(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 Regulatory Flexibility Act requires agencies to prepare a 
Regulatory Flexibility Analysis for each rule unless the agency 
certifies that the rule will not have a significant economic impact on 
a substantial number of small entities. Section 202(a) of the Unfunded 
Mandates Reform Act requires that agencies prepare a written assessment 
of anticipated costs and benefits before proposing any rule that may 
result in an expenditure by State, local, and tribal governments, in 
the aggregate, or by the private sector, of $100 million in any one 
year (adjusted annually for inflation).
    The agency believes that this proposed rule is consistent with the 
regulatory philosophy and principles identified in Executive Order 
12866. With respect to the Regulatory Flexibility Act, the agency does 
not believe that the proposed rule is likely to have a significant 
economic impact on a substantial number of small entities. 
Nevertheless, because our projections are uncertain, the analysis 
presented below also constitutes the agency's Initial Regulatory 
Flexibility Analysis. Because the rule does not impose mandates on 
State, local, or tribal governments, or the private sector, that will 
result in an expenditure in any one year of $100 million or more, FDA 
is not required to perform a cost-benefit analysis according to the 
Unfunded Mandates Reform Act.

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. As discussed in 
section III of this document, 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, FDA is proposing to require ANDA 
applicants to submit all BE studies, passing and nonpassing, on a drug 
product formulation submitted for approval under an ANDA, amendment or 
supplement.
    As discussed in section IV.C of this document, the agency also 
believes that it is important to clarify that the responsibility to 
submit all BE studies, passing and nonpassing, continues after approval 
under the annual report submission requirements. However, the agency 
believes that it would be highly unusual for an ANDA applicant to 
conduct a postmarketing BE study. In particular, the agency believes 
that an applicant would rarely, if ever, conduct a postmarketing BE 
study other than one required for an ANDA supplement.

B. Affected Entities

    The proposed rule would 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 2000, there were 346 BE studies submitted by 57 applicants 
in 197 ANDAs, amendments, and supplements. FDA estimates that this 
proposed rule would result in a 10 percent increase in the number of BE 
studies submitted annually, or 35 (346 x 0.10) additional studies. 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.

C. Compliance Requirements and Costs

    The main cost of complying with this proposed rule would be staff 
time. This analysis assumes a weighted average wage rate of $40 per 
hour (Ref. 2). FDA estimates it would 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

[[Page 61645]]

each additional BE study summary report. The agency believes that a 
complete report would be required approximately 20 percent of the time, 
while a summary would 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 $2,880 ([120 x $40 x 0.2] + [60 x $40 x 0.8]). Thus, the 
overall impact on the industry of reporting an additional 35 BE studies 
per year would be $100,800 ($2,880 x 35).
    Assuming it is equally likely that each of the 35 additional BE 
studies would be conducted by any of the 57 applicants, a binomial 
distribution can be used to predict how many firms would submit 
additional studies. Based on this distribution, 19 firms would incur 
costs of $2,880 for 1 additional BE study, 6 firms would incur costs of 
$5,760 (2 x $2,880) for two additional studies, and 1 firm would incur 
costs of $8,640 (3 x $2,880) for 3 additional studies (the total number 
of studies in the calculation does not equal 35 because of rounding). 
Thus, the maximum expected annual cost burden for any one firm would be 
$8,640. More than half (31 of 57, or 54 percent) of all firms would be 
expected to incur no additional annual costs under the proposed rule.

D. Impact on Small Entities

    FDA recognizes that some of the establishments that would be 
required to submit additional BE study reports would be small entities 
with limited resources. As shown in the following paragraphs, the 
agency estimates that the maximum expected cost of the proposed rule 
for any one small entity would be between 0.58 percent and 1.9 percent 
of the total cost of preparing and submitting an ANDA, and that the 
maximum expected burden for any one of these small entities would be 
0.005 percent of average revenues. Although FDA does not believe it 
likely that the proposed rule would have a significant economic impact 
on a substantial number of small entities, the agency acknowledges the 
uncertainty of its estimates with respect to the number of additional 
BE studies that would be submitted, their distribution among large and 
small entities, and the number of small entities affected. As a result, 
the agency has prepared this Initial Regulatory Flexibility Analysis 
and requests detailed public comment regarding the number of small 
entities affected by the proposed rule as well as its economic impact.
    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 would 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 (SBA), a small pharmaceutical preparation manufacturer 
(NAICS Code 325412) employs fewer than 750 employees (Ref. 3). An FDA 
review of ANDAs 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 sponsors (64 of 
164) were small entities. Thus, the majority of ANDAs are neither 
submitted nor sponsored by small entities. Assuming these proportions 
continue to hold, there would be 22 small entities (0.39 x 57) 
submitting ANDAs annually. FDA also assumes that this group of small 
entities would submit 11 of the additional 35 BE studies (0.10 x 0.32 x 
346) per year.
    Assuming it equally likely that each of the 11 additional BE 
studies would be reported by any of the 22 small entities, a binomial 
distribution can be used to predict how many firms would submit 
additional studies. Based on this distribution, seven small entities 
would incur costs of $2,880 for one additional BE study, and two firms 
would incur costs of $5,760 (2 x $2,880) for two additional BE studies. 
Thus, the maximum expected burden for any one small entity would be 
$5,760. More than half (13 of 22, or 59 percent) of all small entities 
would be expected to incur no additional annual costs under the 
proposed rule.
    The cost of preparing and submitting an ANDA is believed to be 
between $300,000 (Ref. 4) and $1 million (Ref. 5). Based on this 
information, the maximum expected cost burden of the proposed rule on 
any one firm would be between 0.86 percent and 2.9 percent of the total 
cost of preparing and submitting an ANDA. The maximum expected cost 
burden for any one small entity would be between 0.58 percent and 1.9 
percent 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 (Ref. 5). These 15 small entities 
had an average of 331 employees and average annual revenues of $115 
million. The maximum expected burden of this proposed rule for any one 
of these small entities therefore would be only 0.005 percent of 
average 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 would suffice 80 percent of the time provided that complete 
results are available to FDA upon request. The agency believes that a 
summary report would 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 proposed 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 would incur no additional reporting costs, 
although some firms might experience significant costs if their product 
were 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 
proposed rule would require reporting of all BE studies, but would 
permit summary reports for nonpivotal BE studies except where full 
reports are specifically requested by the agency. The agency believes 
that the proposed rule therefore addresses the perceived regulatory 
need in the least intrusive and most cost effective way. FDA 
specifically requests public comment regarding any other viable 
alternatives to this proposed rule.

[[Page 61646]]

E. Benefits of the Proposed Rule

    The proposed rule would generate economic benefits both for 
individuals and for society as a whole to the extent that the reporting 
of data from all BE studies would prevent product discontinuation and 
adverse health effects. Also, the data from additional BE studies could 
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 
proposed rule would permit FDA to make more informed BE determinations 
in the future.

X. Paperwork Requirements

    This proposed rule contains information collection requirements 
that are subject to review by OMB under the Paperwork Reduction Act of 
1995 (44 U.S.C. 3501-3520). A description of these requirements is 
given 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.
    With respect to the following collection of information, FDA 
invites comments on: (1) Whether the proposed collection of information 
is necessary for proper performance of FDA's functions, including 
whether the information will have practical utility; (2) the accuracy 
of FDA's estimate of the burden of the proposed collection of 
information, including the validity of the methodology and assumptions 
used; (3) ways to enhance the quality, utility, and clarity of the 
information to be collected; and (4) ways to minimize the burden of the 
collection of information on respondents, including through the use of 
automated collection techniques, when appropriate, and other forms of 
information technology.
    Title: Requirements for Submission of In Vivo Bioequivalence Data; 
Proposed Rule.
    Description: FDA is proposing to alter the requirements for certain 
ANDAs, ANDA amendments, and ANDA supplements submitted under Sec. Sec.  
314.94, 314.96, and 314.97. Specifically, FDA is proposing to amend 
Sec. Sec.  314.94(a)(7)(i), 314.96(a)(1), and 320.21(b)(1), as well as 
modify 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 formulation of the drug product submitted for approval 
under an ANDA, amendment, or supplement.
    In addition, FDA is proposing through this rulemaking 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 proposing to clarify 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, 
as discussed in section IV.C of this document, FDA believes it would be 
highly unusual that an applicant would conduct a postmarketing BE 
study. In particular, the agency believes that an applicant would 
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 1 of this document provides an estimate of 
the annual reporting burden under the proposed rule.
    The proposed rule would 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 2000, 57 
applicants submitted 346 BE studies in 197 ANDAs, amendments, and 
supplements. FDA estimates that this proposed rule would result in a 10 
percent increase in the number of BE studies submitted annually, or 35 
(346 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 would 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 would be required 
approximately 20 percent of the time, while a summary would 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 1, FDA has estimated the reporting burden associated with 
each section of the proposed rule. FDA believes that the vast majority 
of additional BE studies would be reported in ANDAs (submitted under 
Sec.  314.94) rather than supplements (submitted under Sec.  314.97) 
because it is unlikely that a sponsor 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 would 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 would be 
conducted on a drug prior to the submission of the ANDA and would be 
reported in the ANDA itself.

             Table 1.--Estimated Annual Reporting Burden\1\
------------------------------------------------------------------------
                                Annual
    21 CFR         No. of      Frequency     Total    Hours per   Total
   Section      Respondents       of        Annual     Response   Hours
                               Response    Responses
------------------------------------------------------------------------
314.94(a)(7)   33             1           33          72         2,376
------------------------------------------------------------------------
314.96(a)(1)   1              1           1           72         72
------------------------------------------------------------------------
314.97         1              1           1           72         72
------------------------------------------------------------------------
Total                                                            2,520
------------------------------------------------------------------------
\1\There are no capital costs or operating and maintenance costs
  associated with this collection of information.


[[Page 61647]]

    In compliance with section 3507(d) of the Paperwork Reduction Act 
of 1995 (44 U.S.C. 3507(d)), the agency has submitted the information 
collection provisions of this proposed rule to OMB for review. 
Interested persons are requested to send comments regarding this 
information collection to the Office of Information and Regulatory 
Affairs, OMB (see ADDRESSES).

XI. Federalism

    FDA has analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the proposed 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 proposed 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.

XII. References

    The following references have been placed on display in the 
Division of Dockets Management (see ADDRESSES) and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
    1. Minutes, Pharmaceutical Sciences Advisory Committee, November 
16, 2000.
    2. U. S. Department of Labor, Bureau of Labor Statistics, Table 
20: Private Industry, Health Services, Employer Costs per Hour 
Worked for Employee Compensation, Professional Specialty and 
Technical Occupations, available online at www.bls.gov/ncs/ect/sp/ecechist.pdf.
    3. U. S. Small Business Administration, Office of Size 
Standards, Table of Size Standards, available online at www.sba.gov/size/indextableofsize.html.
    4. Balaji, K., ``Generics, The Opportunity Beckons,'' as 
reported by Frost and Sullivan (www.frost.com), 4 July 2001.
    5. Humphreys, A., ``Generics: Gaining Momentum, Special 
Report,'' Med Ad News, vol. 19, p. 42, October 2000.

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.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR parts 314 and 320 be amended as follows:

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

    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, 355a, 356, 
356a, 356b, 356c, 371, 374, 379e.
    2. Section 314.94 is amended 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, 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
* * * * *
    3. Section 314.96 is amended 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, 
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

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

    Authority: 21 U.S.C. 321, 351, 352, 355, 371.
    5. Section 320.21 is amended by revising paragraph (b)(1) to read 
as follows:


Sec.  320.21  Requirements for submission of in vivo 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)). 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: October 7, 2003.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 03-27187 Filed 10-28-03; 8:45 am]
BILLING CODE 4160-01-S