FDA Releases White Paper on the Speed of Drug Discovery and Development

July 22, 2015

By Alexander J. Varond

In a recent FDA Voice blog post, titled “More Collaboration, Research Needed to Develop Cures,” FDA discusses the speed of drug discovery and development.  The blog post also references a white paper released the same day, titled “Targeted Drug Development:  Why Are Many Diseases Lagging Behind?”  The white paper briefly describes “the state of scientific knowledge and its effect on drug development in four key disease areas other than cancer and HIV/AIDS.”  These disease areas are:  (1) Alzheimer’s disease, (2) diabetes, (3) rare diseases, and (4) hepatitis C.  We provide snippets from the white paper on each of the disease areas below.  For the anxious reader, FDA’s topline answer to the question it presents in the title of its white paper is: there is “inadequate scientific understanding of specific diseases.”

Before getting to the particular disease areas, we note that, when taken in the context of the current legislation before Congress (e.g., 21st Century Cures Act), the blog post and white paper seem to indicate a degree of defensiveness on the part of FDA.  The blog post, in particular, begins by stating that FDA’s drug approval process “is the fastest in the world.”  It then relates that “[w]hen research does not offer answers to important scientific questions, cures cannot be developed.  And when viable cures are not in the pipeline, focusing on regulation will not improve the situation . . . .”

While it is true that basic science and research is necessary to advance the understanding of diseases and develop cures, the conclusion that “focusing on regulation will not improve the situation” is too dismissive.  Even a cursory review of the 21st Century Cures Act reveals myriad examples of new regulation that will help therapies already in the pipeline by, for example, helping to calibrate benefit-risk profiles from patient input.  There have also been countless examples in the past, including providing new incentives to drug sponsors and expressly allowing the approval of drugs on the basis of a single study with confirmatory evidence.

The blog post and white paper also confound unvalidated surrogate endpoints with validated surrogate endpoints and conflict with a recent analysis that shows that FDA has not, in fact, used the accelerated approval pathway and unvalidated surrogates widely or to its full potential.  While the white paper states that “between 50% and 60% of rare disease therapies were approved on the basis of surrogate endpoints,” this number likely includes approvals using validated surrogates (drugs approved on the basis of validated surrogates are granted “full” approval rather than accelerated approval) and therapies for cancer and HIV/AIDS.  In reality, fewer than 20 therapies for non-cancer, non-HIV/AIDS indications have been approved on the basis of unvalidated surrogates via the accelerated approval pathway.  In fact, both the 2012 President’s Council of Advisors on Science and Technology report, entitled “Report to the President on Propelling Innovation in Drug Discovery, Development, and Evaluation,” and FDASIA have exhorted FDA to increase its use of unvalidated surrogates to approve therapies via the accelerated approval pathway.

FDA’s effort to take stock of these four disease areas is admirable—after all, each of the disease areas represents a very clear opportunity to broadly improve public health.  However, the conclusion that everyone must “continue to work together to improve our understanding of disease and the tools to translate scientific discovery into cures” (which could be seen as supporting the 21st Century Cures’ proposal for increases in funding to NIH) should be expanded.  New legislation and regulatory tools for FDA would be an important step toward developing new cures.

Below, we provide an overview of FDA’s discussion on each of the four disease areas:

Alzheimer’s disease

“For all but rare genetic forms of the disease . . . scientists have not yet confirmed that any potential biomarkers can accurately identify individuals who have Alzheimer’s, predict its clinical progression in specific patients, identify successful drug targets, or identify subsets of patients who might respond differently to different treatments.  Thus far, promising biomarkers, when tested, have all failed to predict clinical improvement. . . .  FDA is helping to facilitate development of potential treatments for the disease by allowing surrogate endpoints to support product approvals, encouraging the use of enrichment designs in clinical trials, and collaborating with the healthcare community on the development of biomarkers.”


“Although the major factors associated with the development of diabetes are generally understood, the exact genetic, molecular, and environmental causes of both type 1 and type 2 diabetes remain to be discovered. . . .  Without this information, it is not yet possible to develop drugs targeted to prevent or treat diabetes in particular patients.  And it remains necessary to test new diabetes drugs in a broader patient population. . . .  Despite scientists’ incomplete understanding of diabetes and its causes, FDA has long allowed manufacturers to show that a diabetes drug works by using a simple surrogate endpoint: lowered blood sugar.”

Rare diseases

“Scientific understanding about the causes of rare diseases—those affecting fewer than 200,000 patients–varies by disease.  For many . . . rare diseases . . . basic research is lacking, which limits scientists’ understanding of their causes or how to intervene in their progression.  As a result, we lack drug targets and biomarkers that can be used to help make clinical trials more efficient and successful.  Nevertheless, FDA is actively engaged in helping companies speed development of potential treatments for rare diseases by designing trials that address the challenges of small patient populations and novel endpoints.”

Hepatitis C

“For decades, hepatitis C infection was poorly understood . . . however, the knowledge and technology developed in the massive research effort on the HIV/AIDS virus helped unravel the genetic and molecular bases for other viral infections.  Since 2011, FDA has been approving targeted treatments for hepatitis C, and in December 2013, FDA approved the most dramatic improvement in therapy to date.  The targeted drug Sovaldi provides a greater than 90% virologic cure rate in the hepatitis C genotypes for which it is approved, has manageable side effects, and does not require co-administration of interferon for most patients.”

Each of the four disease states discussed in FDA’s white paper points out that FDA has, in fact, been able to make at least incremental progress despite imperfect understanding of the diseases.  Thus, legislation that gives FDA additional ways to do what it has already done (i.e., approve important drugs for these critical disease areas despite limited understandings of the underlying disease processes) should be encouraged.