[Federal Register Volume 64, Number 31 (Wednesday, February 17, 1999)]
[Notices]
[Pages 7897-7898]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-3777]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 99D-0121]
Draft Guidance for Industry on Waiver of In Vivo Bioavailability
and Bioequivalence Studies for Immediate Release Solid Oral Dosage
Forms Containing Certain Active Moieties/Active Ingredients Based on a
Biopharmaceutics Classification System; Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is announcing the
availability of a draft guidance for industry entitled ``Waiver of In
Vivo Bioavailability and Bioequivalence Studies for Immediate Release
Solid Oral Dosage Forms Containing Certain Active Moieties/Active
Ingredients Based on a Biopharmaceutics Classification System.'' When
final, the guidance will provide recommendations to sponsors of
investigational new drug applications (IND's) and applicants submitting
new drug applications (NDA's), and abbreviated new drug applications
(ANDA's) who intend to perform bioavailability and bioequivalence (BA/
BE) studies for immediate release solid oral products during either the
preapproval or postapproval periods.
DATES: Written comments on the draft guidance document may be submitted
by April 19, 1999. General comments on the agency guidance documents
are welcome at any time.
ADDRESSES: Copies of this draft guidance for industry are available on
the Internet at http://www.fda.gov/cder/guidance/index.htm. Submit
written requests for single copy of the draft guidance for industry
entitled ``Waiver of In Vivo Bioavailability and Bioequivalence Studies
for Immediate Release Solid Oral Dosage Forms Containing Certain Active
Moieties/Active Ingredients Based on a Biopharmaceutics Classification
System'' to the Drug Information Branch (HFD-210), Center for Drug
Evaluation and Research, Food and Drug Administration, 5600 Fishers
Lane, Rockville, MD 20857. Send one self-addressed adhesive label to
assist that office in processing your requests. Submit written comments
on the draft guidance to the Dockets Management Branch (HFA-305), Food
and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD
20852.
FOR FURTHER INFORMATION CONTACT: Ajaz S. Hussain, Center for Drug
Evaluation and Research (HFD-940), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-827-5927.
SUPPLEMENTARY INFORMATION: FDA is announcing the availability of a
draft guidance for industry entitled ``Waiver of In Vivo
Bioavailability and Bioequivalence Studies for Immediate Release Solid
Oral Dosage Forms Containing Certain Active Moieties/Active Ingredients
Based on a Biopharmaceutics Classification System.'' When it becomes
final, this guidance for industry will provide recommendations on when
in vivo BA/BE studies may be waived for NDA's and ANDA's submitted to
the Center for Drug Evaluation and Research during either the
preapproval or postapproval period.
In 1974, the Office of Technology Assessment's Drug Bioequivalence
Study Panel made eleven recommendations, one of which stated:
It is neither feasible nor desirable that studies of
bioavailability be conducted for all drugs or drug products. Certain
classes of drugs for which evidence of bioequivalence is critical
should be identified. Selection of these classes of drugs should be
based on clinical importance, ratios of therapeutic to toxic
concentrations in blood, and certain pharmaceutical characteristics.
Based on this and other recommendations of the panel, FDA proposed and
finalized regulations in 1977 entitled ``Bioequivalence Requirements
and In Vivo Bioavailability Procedures'' (42 FR 1624, January 7, 1977).
In these regulations, now at 21 CFR 320.33, under the title ``Criteria
and Evidence to
[[Page 7898]]
Assess Actual or Potential Bioequivalence Problems,'' FDA provided
criteria to assess actual or potential BE problems. Drug products
meeting these criteria were deemed ``bioproblem'' drug products, with
the understanding that other drug products would be able to document
BA/BE through in vitro studies. FDA applied these criteria to decide
whether a Drug Efficacy Study Implementation (DESI) effective drug
could demonstrate bioequivalence through in vitro studies alone, or
whether a combination of in vivo and in vitro approaches were required.
The list of DESI effective bioproblem drug products appeared in
Sec. 320.22 (21 CFR 320.22) (1992). Beginning in 1979, DESI effective
oral immediate release drug products that were not considered to
contain bioproblem drugs were allowed to document BE via in vitro
studies and achieved an AA rating in FDA's ``Approved Drug Products
with Therapeutic Equivalence Ratings'' (the Orange Book). In a 1981
document (46 FR 27396, May 19, 1981), FDA instituted a policy termed
the ``paper NDA policy,'' which provided for approval of some duplicate
versions of post-1962 drugs. As part of this policy, FDA required
demonstration of in vivo BE for all duplicate post-1962 nonsolution
drug products, including locally acting drug products, prior to
approval for marketing. With the passage of the Drug Price Competition
and Patent Term Restoration Act of 1984 (Waxman-Hatch), this general
approach was recommended for all post-1962 nonsolution drug products
(54 FR 28872 at 28882 through 28883, July 10, 1989).
Although the approach to require in vivo documentation of BA/BE
for many drug products, both pre- and post-1962, has been generally
followed, FDA has in some cases allowed in vitro methods for
documenting BA/BE even for post-1962 drug products. Furthermore, as
noted both at Sec. 320.22 ``Criteria for Waiver of Evidence of In Vivo
Bioavailability or Bioequivalence'' and at 21 CFR 320.24 ``Types of
Evidence to Establish Bioavailability or Bioequivalence,'' many options
exist to allow waivers of in vivo documentation of BA/BE and to
demonstrate BA/BE through in vitro methodology. The draft guidance
describes when waivers of in vivo BA/BE studies will be allowed under
specified circumstances depending on the solubility, intestinal
permeability, and dissolution characteristics of the drug substance and
the drug product and based on the biopharmaceutic classification
system.
To further justify the objective of reducing regulatory burden
while maintaining adequate documentation of BA/BE, FDA encourages the
submission of data that support or refute the recommendations in the
guidance, specifically the submission of in vivo and in vitro data that
document bioinequivalence of pharmaceutically equivalent immediate
release products that are rapidly dissolving, and contain a highly
permeable, and highly soluble drug.
Following receipt of public comments on this draft guidance, FDA
intends to discuss the draft guidance before a meeting of the Advisory
Committee for Pharmaceutical Science. After receipt of the public
comments, the advisory committee deliberation, and further discussion
within the agency, the guidance document will be finalized. FDA does
not recommend that any provisions of the draft guidance be implemented
at this time.
This draft level 1 guidance document is being issued consistent
with FDA's good guidance practices (62 FR 8961, February 27, 1997). It
represents the agency's current thinking on BA/BE approaches for
immediate release solid oral products. It does not create or confer any
rights for or on any person and does not operate to bind FDA or the
public. An alternative approach may be used if such approach satisfies
the requirements of the applicable statute, regulations, or both.
Interested persons may submit written comments on the draft
guidance to the Dockets Management Branch (address above). Two copies
of any comments are to be submitted, except that individuals may submit
one copy. Comments are to be identified with the docket number found in
brackets in the heading of this document. The draft guidance and
received comments are available for public examination in the Dockets
Management Branch between 9 a.m. and 4 p.m., Monday through Friday.
Dated: February 10, 1999.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 99-3777 Filed 2-16-99; 8:45 am]
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