FDA to Address Opioid Trial Challenges

March 3, 2016

Clinical trials are challenging because pain is subjective, making it hard to define objective endpoints or to compare one drug to another.

FDA is under tremendous pressure from Congress, state officials and the public health community to do more to address the national epidemic of opioid abuse that is causing thousands of deaths and medical emergencies. But while patients and providers demand effective treatments for chronic and acute pain, the public wants safeguards to prevent overdosing and misuse of these products. Drug labels, boxed warnings, prescriber education and postapproval monitoring have not deterred abusers. Now FDA Commissioner Robert Califf and agency leaders are implementing a new Action Plan to address the problem more forcefully, and hopefully to quell critics on Capitol Hill and in the medical community.

One important element of the plan is to encourage development of new, more effective pain medications with abuse deterrent (AD) properties, an issue addressed at the March 1 meeting of the FDA Science Board. FDA is reassessing how it weighs risks and benefits in approving opoid medications, and expanded use of its advisory committees is part of this process.

A main FDA strategy in recent years has been to encourage development of abuse-deterrent formulations (ADFs) of opioids. Five products with AD claims in labeling have been approved by the agency, supported by guidance finalized in 2015 on what studies and data is needed to support AD product development and approval. The Office of New  Drugs (OND) in the Center for Drug Evaluation and Research (CDER) is evaluating some 30 active INDs for these products and other new technologies.

Despite these efforts, many development programs for new pain medicines fail, said Sharon Hertz, director of the Division of Anesthesia, Analgesia and Addiction Products in OND. There are many sources of variability in clinical analgesic trials, which makes it very difficult to measure treatment effect, Hertz explained at the Science Board meeting. Nonclinical models are limited, and clinical trials are “very challenging,” she noted, because pain is very subjective, making it hard to define objective endpoints or to compare one drug to another. It also is difficult for a study to enroll a population of pain patients that are able to respond to the test drug. Inadequate bioavailability of the test drug creates problems, as does study blinding when the test drug has specific adverse events. And there are limits on how long patients can remain in pain before administering a rescue medication, and that action can reduce study effect size and confound adverse events.

Consequently, just two out of 100 trials get past Phase II, Hertz pointed out. Sponsors have to ask, “how many failed studies can you survive before you have to give up on the drug program.”

FDA seeks to address such R&D issues through collaboration with academics, health professionals, advocacy groups and industry. The aim is to gain consensus on standards for measuring pain intensity and on different outcomes in clinical studies and to optimize clinical trial methods to increase study efficiency. FDA officials also will be seeking more advice on these and related issues from advisory committees, as part of its plan to have these expert panels consider the approval of new opioid formulations, particularly treatments for children. The agency’s action plan also calls for further guidance and recommendations for developing and approval of generic ADFs, which aims to increase prescriber uptake of these safer products. A main goal is to provide a broader range of treatment options for patients and prescribers, particularly therapies that are less attractive to abusers and addicts.