To herald the new year and as part of the last efforts of an outgoing administration, the FDA released a number of draft and final guidance documents as well as finalized several pending amendments to the regulations. In early January, FDA released draft and final guidance documents on topics ranging from Good Reprint Practices for the distribution of medical journal articles and medical or scientific reference publications on unapproved new uses of approved drugs and approved or cleared medical devices to Good Importer Practices to guidance for clinical investigators, sponsors, and institutional review boards on adverse event reporting for the protection of human subjects. In addition, the Agency finalized rules regarding registration requirements for institutional review boards and requirements for submission of bioequivalence data.

While contract manufacturers should familiarize themselves with many of the published draft and final guidance documents and rules, two are highlighted below. First, the final rule on the submission of bioequivalence data is presented. Following this discussion is an overview of the draft guidance document regarding the submission of laboratory packages to the Agency by accredited laboratories for FDA-regulated products presented for import into the U.S.

Final Rule on Submission of Bioequivalence Data

FDA recently amended its regulations regarding the submission of bioequivalence data (BE) needed to support an abbreviated new drug application (ANDA). As revised, the final rule requires submission of all data from BE studies that an applicant conducts on a drug product. The revised regulations require that an applicant submitting BE studies in an ANDA, ANDA amendment, or ANDA supplement submit full reports of BE studies that the application relies upon for approval and either full or summary reports of all other BE studies conducted on the same drug product formulation.

Historically, ANDA applicants have only been required to submit certain BE studies, including those demonstrating that a generic product meets the bioequivalence standards established by FDA needed support approval. For ANDA approval, the Federal Food, Drug, and Cosmetic Act (FDCA) requires, among other things, that applicants submit information showing that the ANDA drug is bioequivalent to a drug previously approved by the FDA, which is identified by FDA as the “reference listed drug” or RLD. The acceptable types of evidence to establish bioequivalence is provided in the regulations. BE studies are routinely performed on solid oral dosage form of drugs absorbed systemically, and estimate the rate and extent of drug absorption for the test as compared to reference product. The results derived therefrom are statistically assessed to evaluate whether the test product falls with prescribed BE limits as compared to the RLD.

In October 2003, FDA proposed the amendment to Parts 314 and 320 of Title 21 to the U.S. Code of Federal Regulations. In the 2003 proposed rule, FDA opined that both passing and non-passing bioequivalence studies were necessary in order to comprehensively evaluate the drug product that was the subject of the application, and proposed amending requirements related to the contents of an ANDA, the amendment of an ANDA, and the submission of in vivo bioavailability and bioequivalence data. In addition, the Agency detailed how it anticipated interpreting other provisions affected by the proposed rule, including its position regarding how the Agency would interpret the regulation on ANDAs submitted pursuant to an approved suitability petition and the post-marketing reporting requirements. It is the Agency’s position that theses types of submissions also require submitting both passing and non-passing BE studies to FDA for review.

Effective July 15, 2009, applicants will be required to submit data on all BE studies performed on a drug product formulation as part of the ANDA or in an amendment or supplement to an ANDA that contains BE studies, including studies that do not meet passing bioequivalence criteria. The new rule also requires applicants to submit all post-marketing BE studies conducted or obtained on the approved drug formulation on an annual basis. The regulation requires that BE studies on the “same drug product formulation” be submitted to the Agency. While FDA did not originally define this term, it adopted a formal definition as part of the final rule, explaining that the “same drug product formulation” means the formulation of the drug product submitted for approval and any formulations that have minor differences in composition or method of manufacture from the formulation submitted for approval, but are similar enough to be relevant to the agency’s determination of bioequivalence. Initially, FDA intended to rely on the use of the phrase in several scale up and post-approval changes (SUPAC) guidance documents. However, the Agency received numerous negative comments on this topic, pointing out that the SUPAC guidance documents were not sufficiently clear.

Submission of Laboratory Packages from Accredited Laboratories

In January, the FDA Office of Regulatory Affairs (ORA) released a draft guidance document entitled, “Guidance for Industry: Submission of Laboratory Packages by Accredited Labora-tories,” intended to provide information and recommendations regarding laboratory accreditation standards and the quality and type of data generated by accredited laboratories to support testing results submitted to the Agency, particularly in reference to detained articles offered for import. The draft guidance document was published in response to a recommendation made to ORA by the President’s Interagency Working Group on Import Safety, which was established in July 2007 under an Executive Order to conduct a comprehensive review of the U.S. import system and to ascertain ways by which to further increase the safety of products entering the country.

At the time of import of an FDA-regulated product, FDA considers whether the articles comport with the FDCA, and determines whether to refuse to admit the product, subject to the importer’s right to introduce evidence of admissibility. If FDA has sufficient evidence to refuse future shipments of an imported article, it may act to detain shipments without physical examination. In this instance, the importer can submit evidence demonstrating that the articles meet FDA standards, a tactic that may include sampling and testing in private laboratories. The Agency reviews “laboratory packages” of data and information from the private laboratories submitted by the article’s importer to assess whether product should be admitted to the U.S.

Given the amount of products imported, FDA is presented with the ongoing challenge of how best to ensure the validity of the laboratory packages. Due in part to rigorous, contemporary accreditation standards, FDA has determined that abbreviated laboratory packages from accredited laboratories can provide FDA with assurance comparable to those available in full laboratory packages from non-accredited laboratories, when developed in conjunction with FDA guidance on the subject. The draft guidance document outlines the process by which FDA expects an abbreviated laboratory package to be acceptable for submission to FDA for review. According to the draft guidance document, the importer should:

utilize an accredited private laboratory for sampling and testing;

provide FDA with advance notice that it will use a particular accredited laboratory; and

direct the accredited laboratory to submit all test results directly to FDA.

Accreditation, under the draft guidance document, refers to a rigorous assessment conducted by an independent science-based organization, or “accreditation body,” to assure the overall capability and competency of a laboratory and its Quality Management Systems. At a minimum, an accredited lab should have established standard operating procedures that are routinely followed and have quality systems in place for identifying and correcting deviations from those procedures. A lab should receive accreditation from an accreditation body operating according to the International Organization for Standardiza-tion (ISO) standard ISO/IEC 17011, General requirements for accreditation bodies accrediting conformity assessment bodies, that participates in the International Laboratory Accreditation Cooperation (ILAC) Mutual Recognition Arrangement.

FDA anticipates that accredited laboratories will be competent to conduct tests for which they have been accredited and that their analyses will generally conform to established standards. In addition, the Agency believes the accreditation body’s ongoing role of surveillance relative to the accredited laboratory would provide the Agency sufficient confidence in reviewing abbreviated laboratory packages from accredited laboratories. Such abbreviated laboratory packages should consist of documents identifying the entry from the importer of record, a Summary of Analysis, and an affirmation by the laboratory director.

The Agency believes that the confidence afforded through the use of accredited laboratories will facilitate a quicker review of submitted abbreviated laboratory packages and the related decision to admit or deny admittance of the product into the U.S. FDA feels the scheme supports an overall efficient use of resources by permitting the Agency to focus its laboratory and field staff on assessing full laboratory packages submitted by non-accredited laboratories.

Gary C. Messplay is a partner in the Washington, D.C. office of Hunton & Williams LLP, where he is co-chair of the law firm’s Food and Drug Practice. Colleen Heisey is an attorney in the firm’s Food and Drug Practice.