Draft guidance contains Nonbinding Recommendations for public consultations

On August 06, 2018, the U.S. Food and Drug Administration issued new scientific recommendations1 aimed at encouraging widespread innovation and development of novel medication-assisted treatment (MAT) drugs for the treatment of opioid use disorder (OUD). The new draft guidance outlines new ways for drug developers to consider measuring and demonstrating the effectiveness and benefits of new or existing MAT products.

About MAT

MAT for opioid dependence relies on prescription drugs, including buprenorphine, methadone and naltrexone, to stabilize brain chemistry, reduce or block the euphoric effects of opioids, relieve physiological cravings, and normalize body functions. Regular adherence to MAT helps patients gain control over their use of opioids, without causing the cycle of highs and lows associated with opioid misuse or abuse. MAT, coupled with relevant social, medical and psychological services, is a highly effective treatment for OUD. Additionally, patients receiving MAT cut their risk of death from all causes in half, according to the Substance Abuse and Mental Health Services Administration.

New scientific recommendations

Clinical trials to evaluate effectiveness of MAT for the purpose of FDA approval have generally used reduction in drug-taking behavior (drug use patterns) as an endpoint. The draft guidance identifies several additional potential clinical endpoints and other outcome measures that drug developers may consider, for example:

  1. Adverse Outcomes of OUD

Reductions in adverse outcomes related to OUD are desirable endpoints for a study. However, to show effects on physical or psychosocial consequences of opioid abuse, trials may need to study a large number of patients for a long period of time. This may make such studies impractical to support initial marketing approval. Nevertheless, FDA encourages sponsors to evaluate the effect of medications in development for OUD on various adverse outcomes like:

  • Mortality (overall mortality or overdose mortality)
  • Need for emergency medical interventions
  • Hepatitis C seroconversion (the period during which antibodies develop and become detectable).
  1. Change in Disease Status Using Diagnostic Criteria for OUD

Efficacy may also be measured by studying the proportion of patients who transition from meeting criteria for being diagnosed with moderate to severe OUD – based on both drug use and its impact on patient wellbeing – at baseline to being considered in remission at the end of the study.

  1. Patient-Reported Outcomes

Improvements in the ability to resume work, school, or other productive activity may also demonstrate clinical benefit. Using input from patients and family members to determine the relevant symptoms/experiences associated with OUD, the sponsor could develop an instrument to evaluate a direct effect on how patients feel or function (e.g., improvement in sleep or mood).

  1. Change in Drug Use Pattern

Change in drug use pattern is the most commonly used endpoint in registration trials for drugs-in-development to treat OUD. Sponsors have used it successfully to provide support of efficacy for all approved products for the treatment of OUD. They use a variety of approaches to evaluate drug use patterns. FDA recommends that sponsors compare percent of responders, rather than group means. One method is to define a responder as a patient who reduces the use of opioids to or below a threshold known to be associated with clinical benefit. A successful trial would show either a higher percent of responders in the treatment arm (for superiority trials) or non-inferiority in the percent of responders (for active-controlled trials).

Other Outcome Measures

FDA is interested in other outcome measures that sponsors might use to demonstrate clinical benefit of medications for the treatment of OUD. There is great societal interest in assessing additional, clinically meaningful, endpoints such as reduction in hospitalizations, emergency department visits, overdose, and death as well as improvements in the ability to resume work, school, or other productive activity.

While understanding that many of these outcomes could be highly valuable, the agency recognizes that evaluating them could require larger trials than those usually conducted for marketing approval. To that end, the FDA is encouraging sponsors to discuss their plans with the agency early in the drug development process. The agency is also committed to providing assistance to sponsors interested in developing a validated measurement of patient-reported experiences, such as "craving" or "urge to use" opioids, which make it difficult for patients with OUD to sustain recovery. Patient-reported experiences could be used to complement other endpoints and help determine how a new treatment's effects on such experiences support the goal of sustained clinical response.

Note- This new draft guidance is part of the FDA's ongoing commitment to promote more widespread development, access to and adoption of MAT. As part of HHS' Five-Point Strategy to Combat the Opioid Crisis, the FDA remains committed to addressing the epidemic on all fronts, with a significant focus on decreasing exposure to opioids and preventing new addiction by taking new steps to encourage appropriate prescribing, supporting the treatment of those with OUD and promoting the development of improved as well as lower cost forms of MAT, fostering the development of novel pain treatment therapies that may not be as addictive as opioids, and opioids more resistant to abuse and misuse.

Footnote

1 https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM615743.pdf

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