Two years after the Food and Drug Administration Amendments Act of 2007 (FDAAA) gave FDA new powers to require Risk Evaluation and Mitigation Strategies (REMS) for higher risk drugs and biologics, a new report concludes that an optimal future for REMS is possible if the agency adopts a systems approach when designing REMS programs and takes advantage of new technologies -- from electronic medical records to genetic testing -- that are changing the way medicine is practiced.
The result of a September 2009 workshop sponsored by the Society for Women's Health Research and facilitated by the Institute for Alternative Futures, the report -- Optimal Futures for Risk Evaluation and Mitigation Strategies -- concludes that FDA has the greatest potential to improve drug safety if the agency's REMS policies incorporate the real life experiences and insights of all stakeholders: patient advocates, prescribers, pharmacists, academics, payers and sponsors. The report also addresses the potential for unintended consequences that could make future REMS problematic, citing the need for policies to assess differences between patient groups when determining strategies to mitigate risk and for uniform standards to assure both innovator and generic manufacturers are held to the same requirements when implementing restricted distribution programs.
To assess the future for REMS, the workshop used a method called "appreciative inquiry" where separate working groups applied successful experiences with risk evaluation and mitigation to identify changes in policy that will significantly improve REMS programs in four key areas: 1) post-approval studies; 2) restricted distribution programs; 3) monitoring, testing, and special populations; and 4) product quality safety studies. Prepared through a collaborative process involving FDA staff and representatives from academia, the patient community and industry, the resulting report will be distributed widely to health policy makers, clinicians and the pharmaceutical industry with the goal of implementing a series of practical and realizable policy solutions for creating an optimal future for REMS.
"Although REMS provides an avenue to reduce patient risks associated with medicine use, a number of important challenges still need to be addressed," said Phyllis Greenberger, President and CEO of the Society for Women's Health Research. "This report is intended as a nationwide call to action and is provided as a common framework for developing new policies and protocols to assure the safe use of all medicines posing safety risks."
Towards Zero Tolerance in Restricted Distribution Programs
Addressing the need for safe prescribing, dispensing and use of medicines that carry high risks, the appreciative inquiry applied lessons learned from the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.) to identify new policies and procedures that will improve the administration of restricted distribution systems. S.T.E.P.S. was developed by the Celgene Corporation and FDA to strictly regulate the distribution of thalidomide to treat multiple myeloma and a complication of leprosy.
Whereas S.T.E.P.S. tracks every aspect of the drug's distribution to prevent fetal exposure to thalidomide, programs such as the iPLEDGE program for the acne treatment isotretinoin have been less rigorous, resulting in more than 100 pregnancies among users. To reduce these program failures, the report advocates that FDA implement new policies with consistent standards holding all manufacturers responsible for controlling and tracking every prescription and establishing enforcement mechanisms. Moreover, because the number and variety of generic drugs will significantly increase in the years ahead, the report encourages the development of specific guidance for generic drug manufacturers to ensure their risk management programs are equivalent in rigor and scope to those required of innovator companies.
The Optimal Future for Post-Approval Studies
Besides closing potential gaps in policies for restricted distribution programs, the appreciative inquiry focused on the benefits of designing post-approval studies and risk communications that takes into account biological differences between men and women and accounts for the special needs of patients with rare disorders. Here, the assessment began with the success achieved after FDA ordered studies of a widely used contraceptive which led to improved safety for women at risk of cardiovascular events due to high potassium blood levels. Because these studies guided FDA's strategy -- special label warnings and communications targeted directly at women at risk -- the report underscores the benefits of involving all stakeholders in a systems approach to identify important variables the agency may otherwise miss when implementing targeted risk management programs.
The Promise of Personalized Medicine
Focusing on a large-scale trial that used gene testing to determine the optimal dosing of the blood-thinner warfarin, where the ideal dosage varies widely from patient to patient and is often hard to predict, the appreciative inquiry recognized the promise of personalized medicine to identify patients most likely to receive a specific drug at the correct dosing level. Accordingly, the report identified new opportunities for utilizing REMS to assess variations in risk and efficacy in adolescents, older patients, those taking multiple drugs, and patients with variation in genes for drug metabolism. The report also called on stakeholders to learn to use REMS with electronic medical records as another way to personalize medicine use for improved outcomes.
Assuring the Safety of the Drug Supply Chain
Addressing problems such as manufacturing failures or tainted chemicals coming from overseas are not part of FDAAA 2007, yet REMS may be part of the solution. The report recognizes that the legislated new Sentinel System going into effect in 2012 may be used alongside REMS to mitigate new risks. The team assessing this potential used the 2008 recall of contaminated heparin as a case in which FDA worked effectively with the manufacturer to mitigate risks to patients. Now that more than 80 percent of the bulk substances used in drugs comes from foreign sources, the report recommends that FDA integrate REMS with the new Sentinel System to assure the safety of the drug supply chain as globalization brings new threats to the U.S. market.
Study reveals variability in polygenic risk scores for predicting heart disease