[Federal Register Volume 73, Number 242 (Tuesday, December 16, 2008)]
[Notices]
[Pages 76362-76363]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E8-29692]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2008-D-0626]


Draft Guidance for Industry on Bioequivalence Recommendation for 
Vancomycin HCl; 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availability of a draft guidance for industry entitled ``Bioequivalence 
Recommendation for Vancomycin HCl.'' The recommendation provides 
specific guidance on the design of bioequivalence (BE) studies to 
support abbreviated new drug applications (ANDAs) for vancomycin HCl 
capsules.

DATES:  Although you can comment on any guidance at any time (see 21 
CFR 10.115(g)(5)), to ensure that the agency considers your comment on 
this draft guidance before it begins work on the final version of the 
guidance, submit written or electronic comments on the draft guidance 
by February 17, 2009.

ADDRESSES:  Submit written requests for single copies of the draft 
guidance to the Division of Drug Information, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, rm. 2201, Silver Spring, MD 20993-0002. Send 
one self-addressed adhesive label to assist that office in processing 
your requests. Submit written comments on the draft guidance to the 
Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Submit electronic 
comments to http://www.regulations.gov. See the SUPPLEMENTARY 
INFORMATION section for electronic access to the draft guidance 
document.

FOR FURTHER INFORMATION CONTACT:  Doan T. Nguyen, Center for Drug 
Evaluation and Research (HFD-600), Food and Drug Administration, 7519 
Standish Pl., Rockville, MD 20855, 240-276-9314.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of May 31, 2007 (72 FR 30388), FDA 
announced the availability of a draft guidance for industry, 
``Bioequivalence Recommendations for Specific Products,'' which 
explained the process that would be used to make product-specific BE 
recommendations available to the public on FDA's Web site at http://www.fda.gov/CDER/GUIDANCE/bioequivalence/default.htm. As described in 
that draft guidance, FDA adopted this process as a means to develop and 
disseminate product-specific BE recommendations and provide a 
meaningful opportunity for the public to consider and comment on those 
recommendations. This notice announces the availability of the agency's 
draft BE recommendation for vancomycin HCl capsules.
    Vancocin (vancomycin HCl) oral capsules, approved by FDA in April 
1986, are indicated for the treatment of

[[Page 76363]]

enterocolitis caused by Staphylococcus aureus (including methicillin-
resistant strains) and antibiotic-associated pseudomembranous colitis 
caused by Clostridium difficile. Vancocin oral capsules are designated 
the reference listed drug (RLD) and therefore any ANDA for generic 
vancomycin HCl oral capsules must demonstrate BE to Vancocin prior to 
approval. There are no approved ANDAs for vancomycin HCl capsules.
    Vancomycin acts locally in the lower gastrointestinal (GI) tract. 
After oral administration, a vancomycin capsule releases the drug in 
the stomach and upper GI tract, the released drug is completely 
solubilized in GI fluids, and it is transported along with GI fluids to 
its site of action in the lower GI tract. As set forth in the Clinical 
Pharmacology section of the approved product labeling for Vancocin, 
vancomycin is poorly absorbed after oral administration and does not 
usually enter the systemic circulation. Thus, plasma and urine 
concentrations of vancomycin are generally undetectable following oral 
administration, and traditional BE studies with pharmacokinetic (PK) 
measurements are of limited utility. Accordingly, in 1996, FDA 
recommended an in vivo BE study with clinical endpoints in patients to 
demonstrate BE of generic vancomycin HCl oral capsules.
    In October 2004, FDA asked its Advisory Committee for 
Pharmaceutical Science to consider when dissolution testing could be 
used to establish BE for locally-acting GI drugs. The committee 
concluded that dissolution testing along with PK studies should be 
acceptable to establish BE for such products. In light of the 
committee's conclusions, after obtaining data showing that vancomycin 
HCl is highly soluble at pH conditions encountered in the GI tract and 
expected to be in solution long before it reaches the site of action in 
the lower GI tract, the FDA revised its recommendation in early 2006 to 
include in vitro dissolution studies to demonstrate BE of generic 
vancomycin HCl oral capsules. This approach would provide FDA's Office 
of Generic Drugs with information about drug availability at the site 
of action and would be more sensitive than clinical trials in detecting 
differences in product performance. In accordance with its practice 
prior to publication of the draft guidance ``Bioequivalence 
Recommendations for Specific Products,'' FDA provided its 2006 revised 
BE recommendations to those parties that had requests pending with FDA 
for this information. In March 2006, Viropharma, Inc., the manufacturer 
of the RLD Vancocin, filed a petition for stay of action (PSA) 
challenging FDA's revised recommendation (Docket No. FDA-2006-P-
0007).\1\
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    \1\ This PSA was originally assigned Docket No. 2006P-0124. The 
number was changed to FDA-2006-P-0007 as a result of FDA's 
transition to its new docketing system (Regulations.gov) in January 
2008. This docket also includes a second PSA and numerous 
supplements filed by ViroPharma.
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    In the draft ``Bioequivalence Recommendation for Vancomycin HCl,'' 
FDA further clarifies its recommendations on the design of BE studies 
to support ANDAs for vancomycin HCl capsules. Because generic 
applicants may use different inactive ingredients, which may affect the 
transport, absorption, and/or effectiveness of the drug, FDA is 
currently recommending in vitro dissolution studies only for test 
formulations that are qualitatively (Q1) and quantitatively (Q2) the 
same as the RLD with respect to inactive ingredients. For test 
formulations that are not Q1 and Q2 the same as the RLD with respect to 
inactive ingredients, FDA is recommending in vivo BE studies with 
clinical endpoints. The draft BE recommendation for vancomycin HCl 
capsules is consistent with the 2004 advisory committee's conclusion. 
PK studies are not appropriate in this case, however, because 
vancomycin levels are generally not detectable in the plasma or urine 
due to very limited absorption.
    Comments on this draft guidance will also be considered by FDA as 
it addresses the complicated issues raised in Viropharma, Inc.'s PSAs. 
FDA will carefully consider such comments before responding to the 
petition and finalizing its BE recommendation for vancomycin HCl. 
Because of the lengthy history of FDA's consideration of bioequivalence 
methodologies for vancomycin HCl capsules, the pendency of the PSAs, 
and the complexity of the issues involved, the availability of this 
draft guidance is being announced in a drug product-specific notice, 
and the recommendations include a significant amount of background 
information and explanation of the reasons for the bioequivalence 
recommendations.
    This draft guidance is being issued consistent with FDA's good 
guidance practices regulation (21 CFR 10.115). The draft guidance, when 
finalized, will represent the agency's current thinking on the design 
of BE studies to support ANDAs for vancomycin HCl. 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 statutes and regulations.

II. Comments

    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 between 9 a.m. and 4 p.m., Monday 
through Friday.
    Please note that on January 15, 2008, the FDA Division of Dockets 
Management Web site transitioned to the Federal Dockets Management 
System (FDMS). FDMS is a Government-wide, electronic docket management 
system. Electronic comments or submissions will be accepted by FDA only 
through FDMS at http://www.regulations.gov.

III. Electronic Access

    Persons with access to the Internet may obtain the document at 
either http://www.fda.gov/cder/guidance/index.htm or http://www.regulations.gov.

    Dated: December 8, 2008.
Jeffrey Shuren,
Associate Commissioner for Policy and Planning.
[FR Doc. E8-29692 Filed 12-15-08; 8:45 am]
BILLING CODE 4160-01-S