By Mark Camercon
Safety liabilities are a major cause of attrition during drug development. Adverse drug reactions resulting in post-approval withdrawal of a medicine cost the pharmaceutical industry millions of dollars and affect thousands of people every year. Developing biomarker assays and processes to eliminate adverse compounds earlier in the drug development process should provide safer drugs more efficiently.
A biological marker or “biomarker” is defined as a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or biological responses to a therapeutic intervention. According to the 2010 FDA Guidance for Industry, Qualification Process for Drug Development Tools, “changes in biomarkers following treatment may predict or identify safety problems related to a drug candidate or reveal pharmacological activity that would be expected to predict an eventual benefit from treatment.”
The Critical Path Institute (C-Path) is an independent, nonprofit organization that coordinates collaborative efforts among scientists from government, academia, and the private sector to support the regulatory science initiatives of the FDA. Its goal is to use the recent advances in science to create faster, safer, and more predictive pathways for innovative drugs, devices, and diagnostics that improve human health.
Led by C-Path, the Predictive Safety Testing Consortium (PSTC) is a public-private partnership that brings pharmaceutical companies together to share and validate common safety testing methods. The PSTC, which operates under advisement of the FDA and the European Medicines Agency (EMA), has 18 corporate members (Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, ClinXus, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Hoffman-LaRoche, Johnson and Johnson, Merck, Millennium, Mitsubishi Tanabe, Novartis, Pfizer, Sanofi, and most recently, Celgene) that share internal experiences with preclinical and clinical safety biomarkers. Members are divided into six working groups: kidney, liver, muscle, vascular injury, cardiac hypertrophy, and carcinogenicity. This biomarker research has a strong translational focus, which is to select new safety tools that include the identification and development of new biomarker assays. The aim of the PSTC is to qualify preclinical biomarkers to reduce the cost and time of preclinical safety studies. The PSTC uses combined resources and expertise to generate a biomarker assay panel that the FDA/EMA deems suitable in screening for potential safety issues.
The kidney working group has recommended, and the FDA has qualified, seven biomarkers of kidney injury. The kidney injury biomarkers are KIM-1, Albumin, 2-microglobulin, Total Protein, Cystatin C, Trefoil Factor-3, and Clusterin. These seven kidney injury biomarkers are now considered qualified for voluntary use in nonclinical safety studies that support regulatory agency decision making to complement the traditional creatinine and blood urea nitrogen (BUN) clinical pathology indicators of renal impairment. Studies reporting the levels of these biomarkers will result in greater confidence in the safety of drug candidates that enter human testing. This achievement represents a significant advance not just for FDA, but also for the pharmaceutical industry in total and for public health in general. These kidney toxicity biomarker assays, developed by members of the PSTC, are tools to enhance the safety evaluation of promising new drugs and are now available for drug development use.
New biomarkers of safety and efficacy are becoming powerful and valuable tools in drug development. The FDA has been aggressive in publishing industry guidance and has encouraged the formation of consortia that generate the data for biomarker review and qualification. The new and evolving qualification procedure is aimed at enhancing the utility of a qualified biomarker across the industry. Previously, a biomarker may have been identified and used as part of an IND (investigational new drug), BLA (biologics license application), or NDA (new drug application). The new process is designed to publicize a list of those biomarkers that satisfy the qualification so that future drug development programs benefit from this knowledge.
Mark Cameron, M.S., is the associate director of biomarkers and assay development at MPI Research. After earning his M.S. in biology from Eastern Michigan University, he has acquired nearly 25 years of experience in academia, clinical research, biotech, and contract research and is recognized as an expert in flow cytometry, cell therapy, and immunoassay design.