Federal Register: October 26, 2005 (Volume 70, Number 206)
DOCID: FR Doc 05-21347
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
Docket ID: [Docket No. 2002D-0307] (formerly 02D-0307)
ACTION: Reports and guidance documents; availability, etc.:
DOCUMENT ACTION: Notice.
Guidance for Industry on Potassium Chloride Modified-Release Tablets and Capsules: In Vivo Bioequivalence and In Vitro Dissolution Testing; Availability
DATES: Submit written or electronic comments on agency guidances at any time.
The Food and Drug Administration (FDA) is announcing the availability of a guidance for industry entitled ``Potassium Chloride ModifiedRelease 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 modifiedrelease dosage forms of potassium chloride.
Potassium chloride modified-release tablets and capsules; in vivo bioequivalence and in vitro dissolution testing,
FDA is announcing the availability of a guidance for industry entitled ``Potassium Chloride ModifiedRelease 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 modifiedrelease dosage forms of potassium chloride.
A document entitled ``Guidance for In Vivo Bioequivalence Study for SlowRelease 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requirements for potassium chloride modified release products and was issued in draft on August 7, 2002 (2002 draft guidance) (67 FR 51284).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In the 2002 draft guidance, the agency recommended a threeway crossover design study comparing the reference listed drug (RLD) to both the generic product and a solution of potassium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 The 2002 draft guidance also recommended analysis of covariance (ANCOVA) for the pharmacokinetic parameters.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 twoway 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 twotreatment, twoperiod, singledose, 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 testversusreference 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 baselineuncorrected 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 ProductsGeneral Considerations,'' available on the Internet at 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 modifiedrelease 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.
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
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://www .fda.gov/ohrms/dockets/default.htm.
Dated: October 18, 2005.
Assistant Commissioner for Policy.
[FR Doc. 0521347 Filed 102505; 8:45 am]
BILLING CODE 416001S
FOR FURTHER INFORMATION CONTACT
Lizzie Sanchez, Center for Drug Evaluation and Research (HFD650), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 3018275847.