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By Monica Lee Whitmire, Ruth E. Stevens, and William (Willie) Salminen

Ruth StevensDrugs undergo strenuous testing before they ever enter human bodies. Nonclinical studies are intended to establish that the product will not expose humans to unreasonable risks in relation to the therapeutic benefits of the drug, referred to as the risk:benefit ratio. These guidelines often include Good Laboratory Practice (GLP)-compliant safety pharmacology, general toxicity, toxicokinetic (TK), reproduction and developmental toxicity, and genotoxicity studies.

This GLP safety information is used to establish the initial safe clinical starting dose and dose range, and to identify parameters for clinical monitoring for potential adverse effects that might occur during human clinical trials. These nonclinical data also help assess the risk posed by potential effects that are not easily monitored in the clinic, including carcinogenicity and reproductive and developmental toxicity.

Maybe needless to say, GLPs are integral to safe drug usage. They were established in 1978 after the Food and Drug Administration (FDA) inspections of several research laboratories revealed serious problems with the conduct of nonclinical safety studies in the mid to late 1970s. GLPs regulate all nonclinical laboratory studies that are pivotal determinants of the safety of a drug and will be used to support applications for research or marketing permits for products regulated by the FDA.

Regulation of the conduct of GLP nonclinical studies is important to help ensure data quality and integrity, and is essential for providing pivotal safety pharmacology and toxicology information for the development of FDA-regulated products.

For example, MDS Pharma Services’ 2007 second quarter report details the FDA review of bioanalytical operations. FDA’s Bioresearch Monitoring Program recommended that hundreds of pharmaceutical companies repeat their bioanalytical studies, re-analyze their original study samples at a different bioanalytical facility, or conduct independent data audits of the original study results. This was all due to questions about the validity and accuracy of bioanalytical test results obtained from studies conducted by MDS Pharma Services from 2000 through 2004. The two MDS Pharma Montreal sites were eventually closed because of failure to comply with GLPs.

Another example is when, in 2011, FDA issued an untitled letter to Cetero Research for multiple bioequivalency study data integrity concerns resulting from two inspections. The May 2010 form documented concerns with falsified source records, failure to document procedures for and identify “prep” run injections, and significant concerns relating to the bioanalytical method validations. The December 2010 form also concerned data integrity. The inspections identified significant instances of misconduct and violations of federal regulations, including falsification of documents and manipulation of samples. As a result, on July 26, 2011, FDA notified pharmaceutical companies that bioanalytical studies conducted at Cetero Research between April 2005 and June 2010 in support of marketing applications may need to be repeated or confirmed.

GLP regulations are in the process of being amended to require use of a proactive “GLP Quality System” (i.e., the Proposed Rule) to include standard operating procedure change control and enhanced definitions of roles, responsibilities, accountability, and to reflect current practices for the conduct of nonclinical laboratory studies performed at single and multisite facilities.

The two upcoming AAPS GLP live training events, Summary of Nonclinical Regulatory Requirements and Formulation, Formulation Analysis, and Bioanalytical Perspectives, will delineate the fundamental essential components for regulatory compliance with 21 CFR part 58 and will deliberate upon FDA’s Proposed Rule. The Proposed Rule is intended to build quality into planning, conducting, and reporting a nonclinical laboratory study and to help ensure data quality and integrity of resulting data. The two GLP lectures will include critical points to consider by utilizing case studies of relevant recent impactful GLP related 483s (FDA Inspection Findings) and FDA Warning Letters.

Our fellow members of the CORE team, coauthors, reviewers, and speakers are acknowledged for their many valuable contributions in constructing this diverse, innovative, and broadly applicable ecourse!

Monica Lee Whitmire, M.S., is currently the third shift Supervisor II of the Hematology and Cytology Reference Laboratory Departments at IDEXX Laboratories, Inc. in Memphis, Tenn. Monica was heavily involved in the creation of the introductory AAPS Regulatory Affairs 101 ecourse, Essentials of Regulatory Affairs for Pharmaceutical Scientists, and is the main organizer, one of the three course content developers, a reviewer for the first GLP lecture, and the speaker for the second GLP lecture for this Regulatory Affairs 102 ecourse.
Ruth E. Stevens, Ph.D., M.B.A., has had an integral role in all aspects of drug development for more than 25 years, and brings former FDA team leader experience to her role as Chief Scientific Officer, Executive Vice President and cofounder of Camargo Pharmaceutical Services. Ruth is one of the three course content developers, is the moderator for the introductory overview lecture and all three GCP lectures, and is a reviewer for the second GLP lecture for this Regulatory Affairs 102 ecourse.
William (Willie) Salminen, Ph.D., DABT, PMP, is a Director of Scientific and Regulatory Affairs at Camargo Pharmaceutical Services. He is Board certified in Toxicology with over 19 years of experience. Willie is the moderator for the second GLP lecture, and is a reviewer for both GLP lectures for this Regulatory Affairs 102 ecourse.