[Federal Register: October 29, 2003 (Volume 68, Number 209)]
[Proposed Rules]
[Page 61640-61647]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr29oc03-16]
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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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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 http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://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 http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.sba.gov/size/indextableofsize.html
.
4. Balaji, K., ``Generics, The Opportunity Beckons,'' as
reported by Frost and Sullivan (http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://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