[Federal Register: October 26, 2005 (Volume 70, Number 206)]
[Notices]               
[Page 61830-61831]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr26oc05-108]                         

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 2002D-0307] (formerly 02D-0307)

 
Guidance for Industry on Potassium Chloride Modified-Release 
Tablets and Capsules: In Vivo Bioequivalence and In Vitro Dissolution 
Testing; 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 guidance for industry entitled ``Potassium Chloride 
Modified-Release Tablets and Capsules: In Vivo Bioequivalence and In 
Vitro Dissolution Testing.'' This guidance document provides 
recommendations to sponsors of abbreviated new drug applications 
(ANDAs) on the design of bioequivalence studies for modified-release 
dosage forms of potassium chloride.

DATES: Submit written or electronic comments on agency guidances at any 
time.

ADDRESSES: Submit written requests for single copies of this guidance 
to the Division of Drug Information (HFD-240), 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 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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/dockets/ecomments.
 See the SUPPLEMENTARY INFORMATION section for electronic 

access to the guidance document.

FOR FURTHER INFORMATION CONTACT: Lizzie 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

    FDA is announcing the availability of a guidance for industry 
entitled ``Potassium Chloride Modified-Release Tablets and Capsules: In 
Vivo Bioequivalence and In Vitro Dissolution Testing.'' This guidance 
is intended to provide information to sponsors of ANDAs on the design 
of bioequivalence studies for modified-release dosage forms of 
potassium chloride.
    A document entitled ``Guidance for In Vivo Bioequivalence Study for 
Slow-Release Potassium Chloride Tablets/Capsules'' was issued on May 
15, 1987 (1987 guidance), and revised on June 6, 1994 (1994 revision). 
The guidance was further revised to incorporate FDA's current thinking 
on the bioequivalence requirements for potassium chloride modified-
release products and was issued in draft on August 7, 2002 (2002 draft 
guidance) (67 FR 51284). Comments were reviewed and incorporated. The 
most substantive changes made are described in the following 
paragraphs. Editorial changes were also made and the final guidance is 
now available.
    In the 2002 draft guidance, the agency recommended a three-way 
crossover design study comparing the reference listed drug (RLD) to 
both the generic product and a solution of potassium chloride. The 2002 
draft guidance also recommended analysis of covariance (ANCOVA) for the 
pharmacokinetic parameters.
    The final guidance provides recommendations for a two-way crossover 
design comparing the generic product to the RLD. This design is 
consistent with the 1994 revision, which stated that the potassium 
chloride solution mentioned in the 1987 guidance was no longer 
necessary and recommended the use of a two-treatment, two-period, 
single-dose, fasting study comparing test product with reference 
product. The FDA determined that the potassium chloride solution arm is 
not necessary because the objective of the bioequivalence study is to 
directly compare the rate and extent of potassium absorption from the 
test product and the reference product. Therefore, the potassium 
chloride solution arm is not necessary for the test-versus-reference 
comparison and adds unnecessary complexity to the statistical 
bioequivalance analysis.
    We also have decided not to recommend the use of ANCOVA in the 
final guidance. Analysis of variance (ANOVA) with baseline correction 
is adequate for bioequivalence analysis of pharmacokinetic data 
obtained following oral administration of potassium chloride drug 
products. The FDA concluded that using ANCOVA with baseline as a 
covariate to analyze baseline-uncorrected data was not as sensitive to 
changes in formulation performance as using ANOVA to analyze baseline-
corrected data.
    The dissolution testing and criteria for waivers on in vivo testing 
for lower strengths are revised to reflect the changes outlined in the 
guidance entitled ``Bioavailability and Bioequivalence Studies for 
Orally Administered Drug Products--General Considerations,'' 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.

    This guidance is being issued consistent with FDA's good guidance 
practices regulation (21 CFR 10.115). The guidance represents the 
agency's current thinking on studies to demonstrate the bioequivalence 
of potassium chloride modified-release tablets and capsules. 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 on the guidance at any 
time. 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

[[Page 61831]]

docket number found in brackets in the heading of this document. The 
guidance and received comments are available for public examination in 
the Division of Dockets Management between 9 a.m. and 4 p.m., Monday 
through Friday.

III. Electronic Access

    Persons with access to the Internet may obtain the document at 
either http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/guidance/index.htm or http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www
.fda.gov/ohrms/dockets/default.htm.

    Dated: October 18, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05-21347 Filed 10-25-05; 8:45 am]

BILLING CODE 4160-01-S