By Jim Mittler, PhD
Creating a heightened focus on drug safety early in the drug development process is becoming the new paradigm for pharmaceutical companies. After hearing risk management representatives from several large pharma companies (Biogen Idec, Cephalon, Roche, and sanofi-aventis) speak at the FDAnews Second Annual Risk Management and Drug Safety Summit, titled Building an Effective Global Risk Management and Drug Safety Program, it is clear that pharma is moving towards a “safety first approach and implementing risk management plans much earlier than in the past.
Until recently, risk management was a tool for regulators. After review of a new drug application (or biologic license application), if the FDA determined a drug to have potentially serious safety risks, a complete response letter would require the sponsor to submit a Risk Evaluation and Mitigation Strategy (REMS) for approval. A focus on risk management should not be instituted because of a complete response letter; it must be implemented early. This new approach positions risk management throughout all phases of drug development and is continued through postmarketing pharmacovigilance activities.
As part of the early initiative for risk management, pharma companies are forming a new organizational structure that brings together all the key disciplines (ie, R&D, clinical development, marketing, medical affairs, and regulatory teams) to form cross-functional risk management planning and steering committees. Risk management planning can start at the point of preclinical development if, for example, a potential adverse effect of a new drug can be identified based on the mechanism of action of a drug candidate. Then formal risk management plans for studying the safety of an experimental drug can be instituted and continuously assessed throughout clinical development.
Clearly, the goal of a phase 1 clinical trial is to determine if an experimental drug is safe to be administered to humans. Once phase 2 trials are completed and clinical information about the efficacy and potential risks of an experimental drug are become known, discussions can be opened up to patients and their caregivers to determine their level of acceptance of risk vs the benefit of the drug. Given that the FDA acts on behalf of society to ensure the benefits of a drug outweigh the risks, it is important to include these important stakeholders in the process. Qualitative (focus groups and surveys) and quantitative (conjoint analysis) research on patient perspectives regarding the benefit vs risk of a drug can be performed. In these forums, draft patient communication tools about the potential risks and how they are managed can be set against the benefit of the drug in order to test the willingness of patients to accept the risks. This information can be brought to regulatory advisory committees prior to the NDA submission. In this way, pharma companies and the FDA can work together through phase 3 clinical development to establish the best risk management plan, determine the necessary components of a REMS program, and effectively develop the REMS tools. Once the drug is on the market, pharmacovigilance tools must be implemented and the effect of a REMS program needs to be continuously assessed and modified if necessary (this is a statute in FDA Amendment Act of 2007 [FDAAA]).
Is this new focus on safety a barrier or pathway to drug approval? While it takes a significant human resource and financial commitment, the speakers at the conference seemed to agree that early adoption of risk management planning and development of a REMS program can provide pharma companies with a competitive advantage. Early discussions with the FDA allows an agreed upon long-term process and schedule, and provides time to evaluate and adjust the risk management program if necessary. If a REMS program is developed and ready for implementation when an NDA is submitted, then the new drug could be available to patients sooner than if a complete response letter is issued to a company and approval of a drug is delayed until a REMS program is developed. In the latter case, a new drug would be unavailable to patients who would actually benefit. Even a REMS program that requires restricted access can be advantageous. In this instance, the pharma company typically has a much better understanding of the market and treatment issues related to the disease. Additionally, the relationship between physicians and the company can be enhanced because of the inherent need to work closely with physicians, nurses, and their institutions or practices to ensure safe prescribing and administration.
The REMS program is still a work in progress. Even though FDAAA was passed into law in September 2007, draft guidance on the form and content of REMS programs was just released by the FDA on September 30, 2009. More work is needed to establish validation standards on the effectiveness of REMS communications and education, as well as the elements to assure safe use (ie, restricted prescribing and distribution). It was clear at the FDAnews summit that pharma companies and the FDA are committed to working together to establish the best way to move forward. The new focus on risk management fosters a dialogue between pharma companies and regulatory agencies. This collaboration is refreshing and will certainly serve the patient community well. After all, patients will not receive the benefits of a new drug, in the safest possible way, if it never makes it to market or has to be withdrawn from the market, because of a failed risk management strategy.
