Over the past year, Congress has engaged in the most far ranging, bipartisan, and thoughtful review of America’s infrastructure for biomedical innovation we’ve seen in a generation – the 21st Century Cures Initiative. Led by Energy and Commerce Chair Fred Upton (R, MI), and his colleague Diana Degette (D,CO), policymakers have heard from patient’s groups, industry, academic medical researchers, Food and Drug Administration regulators, and the National Institute of Health (NIH).
The message to legislators has been loud and clear: our current framework for discovering, developing, and delivering safe and effective medicines and medical devices to patients is too slow, too expensive, and too cumbersome. The resulting legislation, the 21st Century Cures Act, advances many of the precision medicine strategies and initiatives that the scientific, medical, and patient communities (including the FDA) have been advocating for over the last decade. It has been met with nearly universal acclaim from all quarters and both sides of the political aisle.
So it was with some surprise that we read Avorn and Kesselheim’s perspective in the New England Journal of Medicine on June 3 that the bipartisan Cures Act that stated, “instead of catapulting us into the future, could actually bring back some of the problems we thought we had left behind in the 20th Century.” Nothing could be further from the truth.
The Cures Act was developed as a response to a real crisis. As NIH Director Frances Collins has noted, it can still take 14 years and enormous expenditures in preclinical and clinical research to bring a single FDA approved medicine to patients. And the failure rates in this process are in excess of 90 percent.
While the economic costs are substantial, the true burden of this excessively long and unpredictable process falls on patients with Alzheimer’s, severe depression, or hard to treat cancers who are subject to unnecessary suffering and death.
The consensus is simple – we can bring to bear new tools to help evaluate new drugs faster and identify the populations who would benefit the most, without weakening FDA’s regulatory standards for approval. This strategy is commonly called personalized or precision medicine.
With that in mind, we would like to disabuse readers of the Journal of a few misconceptions they may have after reading Avorn and Kesselheim. The first is that rapid means reckless.
This is plainly false. Despite slashing FDA review time from nearly three years to less than a single year, drug withdrawal rates due to adverse events have not increased. And researchers at RAND (Research ANd Development) and the University of Chicago have found that the benefits of faster FDA review of new drug applications nets benefits for patients worth between $7 billion and $20 billion.
Accelerated Approval, which the FDA has used to advance promising new medicines based upon surrogate endpoints that are “reasonably likely” to produce effects on clinical symptoms, has been another astonishing success, particularly for cancer and HIV patients. Although Avorn and Kesselheim point to a single case, Avastin, as a “failure”, because its accelerated approval for breast cancer was withdrawn after clinical trials failed to confirm a survival advantage for those patients, this is a sign of agency success, because the system worked entirely as intended.
The authors correctly point out that the FDA is approving more products with smaller trials; pivotal single arm trials; and quicker studies. They neglect to mention why.
More products than ever before are targeted at smaller cohorts of patients, selected based on genetic or other criteria, that allow manufacturers to demonstrate exceptional efficacy compared to standard of care or placebo, quickly and effectively. Many of these products are for cancer or other rare diseases. Kalydeco, for instance, is a breakthrough treatment for about 6 percent of cystic fibrosis patients with a particular mutation. Xalcori for lung cancer, Zelboraf for metastatic melanoma, and Caldelga for Gaucher’s Disease (Type 1), are just a few of the precision medicines approved by the FDA in recent years.
These products have been designed using tools that help researchers unravel the mechanistic roots of human illness and disease faster than ever before.
Armed with massive computing power and modern analytics, advanced diagnostics like functional MRIs, and electronic medical records, researchers can now compile massive databases containing genomic variants and patient health outcomes that can allow them to rapidly identify, test, and validate hypothesis about effective disease fighting strategies.
With this information in hand, it is unnecessary and perhaps even unethical to demand that we conduct traditional large, blinded and randomized controlled trials for precision medicines supported by a variety of mechanistic and pre-clinical data.
Finally, Avorn and Kesselheim question whether small trials can weed out all the problems associated with drugs “designed to be taken for a lifetime.” This is true. No trial can ever perfectly mimic the real world of widespread and prolonged use. Indeed, the adverse effects of the poster child for drug “scandals” – Vioxx – were only discovered thanks to a powerful electronic health record surveillance system in use by Kaiser Permanente. (Ironically, Vioxx went through a very large pivotal trial with over 8,000 patients.)
However, the answer is not to regress to inaction and inertia but to move forward with modern tools like the FDA’s Sentinel initiative to monitor and track drugs as they are used by real world patients rather than the highly selected subjects in carefully controlled protocols.
The 21st Century Cures legislation makes clear that Congress will continue to demand vigilance and rigor, in addition to efficiency and consistency, from the FDA. In return, a modernized regulatory process can assure every American that they will have access to the medical products they need as rapidly and safely as possible, using the best technology available.
This is not a regression to the past, but a long overdue embrace of the future of medicine.
Paul Howard is a senior fellow and director of the Center for Medical Progress at the Manhattan Institute for Policy Research. Dr. Andrew von Eschenbach is the chairman of the Manhattan Institute’s Project FDA and served as director of the National Cancer Institute and Commissioner of the U.S. Food and Drug Administration from 2005-2009.