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By Prabu Nambiar and Gary Maier

Prabu NambiarGaryMaierIn 1992, the U.S. Congress passed the Prescription Drug User Fee Act (PDUFA) with the goal of accelerating the New Drug Application (NDA) review process. The major impetus behind this new law was substantial dissatisfaction among all key stakeholders (industry, patients, FDA, and patient advocacy groups) with the NDA review clock. Under the new law, sponsors paid user fees to the agency for each NDA for improved review performance. The user fee also facilitated the agency in expanding internal resources and capabilities (e.g. establishing new Divisions of Pharmacometrics, of Pharmacovigilance, and of Risk Management, as well as initiatives to advance regulatory science). Over the past 20+ years, many novel drugs have come to market, including the increasing number of complex biological products to treat unmet medical needs. Despite these impressive advances in regulatory science and agency capabilities, several reports have appeared in the literature that have suggested FDA may be putting patients at risk because of increased safety concerns and an increase in black box warnings.

A recent study led by Cassie Frank published in Health Affairs concluded that there was a one in three chance that newer drugs (since PDUFA) will end up with a black box warning. The study also found that withdrawals and black box warnings increased from 21% to 26% since 1992. A causal relationship between these increases and the advent of PDUFA could not be shown. The authors, based upon the study results suggest that in essence, the improvement in review times of NDAs has resulted in a “sacrifice of safety.”

However, in our view, the aforementioned analyses do not take into account of the scientific, clinical, and regulatory complexity and challenges associated with the development of truly new chemical or biological entities indicated for unmet medical needs. The authors acknowledge this as part of the limitations of their study.

Since the PDUFA legislation was passed, there has been an increasing level of scientific focus at FDA, which is reflected in the issuance of many industry guidances and in the overall structure of the agency itself. A good example is the Risk Communication Advisory Committee, which is responsible for providing recommendations in the dissemination of the risks and benefits of regulated products. In our view, the risk-benefit trade-off of expedited reviews for breakthrough therapies for truly unmet medical needs is amply justified. Almost by definition, the limited population available for investigation in the case of rare diseases adds to the challenge of identifying all critical safety issues by the time of drug approval. Under the new paradigm, FDA requires Risk Evaluation and Mitigation Strategy (REMS) plans and other postapproval surveillance programs to detect and/or mitigate unexpected safety risks.

Another example of use of regulatory science is the Division of Pharmacometrics’ advocacy of model and simulation as an integral part of drug development. This emerging science evaluates the relationship between drug exposure and its impact upon efficacy and safety. Modeling and simulation have become a key component of drug development and regulatory submissions, and today these constitute an expected standard by the agency. Fully embracing these methodologies with a system pharmacology mindset will play a very significant role in identifying risks early on and helping to manage them properly. We believe that, while it is impossible to predict every safety risk during drug development, in the aggregate proper use of the advanced scientific tools to identify potential risks and instituting proper REMS and postmarketing surveillance programs to mitigate them should go a long way toward appropriately balancing benefit and risk.

Prabu Nambiar, Ph.D., M.B.A., R.A.C., is founder and principal at Syner-G Pharma Consulting, LLC, and provides strategic consulting in the areas of CMC development, Regulatory Affairs Quality, and compliance. His tenure in the industry over 23 years resulted in successful development, filing and approval of several NDAs.
Gary Maier, Ph.D., is founder and president of Maier Metrics and Associates, LLC, engaged in working with clients from discovery to NDA filing, by providing strategically focused pre-clinical and clinical services. He has over 25 years of experience, leading development teams and working closely with regulatory groups, that resulted in successful NDA submissions.