Draft Guidance for Industry on Bioequivalence Recommendation for Vancomycin HCl; Availability, 76362-76363 [E8-29692]

Download as PDF sroberts on PROD1PC70 with NOTICES 76362 Federal Register / Vol. 73, No. 242 / Tuesday, December 16, 2008 / Notices and to provide recommendations on how to evaluate the safety of these impurities. Genotoxic compounds, because of their ability to induce genetic mutations, chromosomal breaks, and/or chromosomal rearrangements, have the potential for being carcinogenic to humans. Regulatory issues related to the presence of genotoxic or carcinogenic impurities have arisen with greater frequency because of enhanced technological capability in identifying impurities and an increased focus on their potential for negatively affecting human health. FDA guidance documents that address issues related to impurities and residual solvents include the following International Conference on Harmonisation (ICH) guidances for industry: ‘‘Q3A(R2) Impurities in New Drug Substances,’’ ‘‘Q3B(R2) Impurities in New Drug Products,’’ and ‘‘Q3C(R3) Impurities: Guideline for Residual Solvents.’’ However, these ICH guidances do not fully address situations in which genotoxic or carcinogenic impurities are present. This draft guidance describes acceptable approaches for initially evaluating the genotoxic potential of impurities as well as approaches for handling impurities with known genotoxic or carcinogenic potential. These approaches include prevention of the impurity formation, reduction of the impurity level to an acceptable threshold, or additional characterization of the genotoxic and carcinogenic risk. The draft guidance also discusses various factors that should be considered in the overall risk assessment based on the drug indication, duration of use, and the clinical development stage. FDA has developed this draft guidance because these types of impurities are being identified more frequently and because FDA has received a number of questions from industry regarding acceptable approaches. This draft guidance is being issued consistent with FDA’s good guidance practices regulation (21 CFR 10.115). The draft guidance, when finalized, will represent the agency’s current thinking on recommended approaches for genotoxic and carcinogenic impurities in drug substances and 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 statutes and regulations. VerDate Aug<31>2005 17:09 Dec 15, 2008 Jkt 217001 II. The Paperwork Reduction Act of 1995 This guidance refers to previously approved collections of information that are subject to review by the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501–3520). The collections of information in 21 CFR parts 312 and 314 have been approved under OMB Control Numbers 0910–0014 and 0910– 0001, respectively. III. 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. IV. 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. E8–29674 Filed 12–15–08; 8:45 am] BILLING CODE 4160–01–S 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. SUMMARY: The Food and Drug Administration (FDA) is announcing the PO 00000 Frm 00033 Fmt 4703 Sfmt 4703 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 productspecific 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 productspecific 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 E:\FR\FM\16DEN1.SGM 16DEN1 sroberts on PROD1PC70 with NOTICES Federal Register / Vol. 73, No. 242 / Tuesday, December 16, 2008 / Notices 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 VerDate Aug<31>2005 17:09 Dec 15, 2008 Jkt 217001 a petition for stay of action (PSA) challenging FDA’s revised recommendation (Docket No. FDA– 2006–P–0007).1 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 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. PO 00000 Frm 00034 Fmt 4703 Sfmt 4703 76363 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 DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA–2008–D–0614] Draft Guidance for Industry on Changes to Approved New Animal Drug Applications—New Animal Drug Applications Versus Category II Supplemental New Animal Drug Applications; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration (FDA) is announcing the availability of a draft guidance for industry #191 entitled ‘‘Changes to Approved NADAs—New NADAs vs. Category II Supplemental NADAs’’. This guidance is intended to assist sponsors who wish to apply for approval of changes to approved new animal drugs E:\FR\FM\16DEN1.SGM 16DEN1

Agencies

[Federal Register Volume 73, Number 242 (Tuesday, December 16, 2008)]
[Notices]
[Pages 76362-76363]
From the Federal Register Online via the Government Printing 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.

-----------------------------------------------------------------------

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\
---------------------------------------------------------------------------

    \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.
---------------------------------------------------------------------------

    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