[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Draft Guidance for Industry on Waiver of In Vivo Bioavailability 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availability of a draft guidance for industry entitled ``Waiver of In 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DATES: Written comments on the draft guidance document may be submitted 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ADDRESSES: Copies of this draft guidance for industry are available on 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written requests for single copy of the draft guidance for industry 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on the draft guidance to the Dockets Management Branch (HFA-305), Food 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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