Consider a variety of endpoints for OUD treatments: FDA guidance

Regulatory NewsRegulatory News | 02 October 2020 |  By 

Consider a variety of endpoints for OUD treatments: FDA guidance
A new final guidance document from the US Food and Drug Administration (FDA) gives drugmakers considerations for choosing endpoints for new medications to treat opioid use disorder (OUD).
“We recognize that there’s great interest in developing new treatment options that result in meaningful outcomes, said FDA Commissioner Stephen Hahn, MD, in announcing the final guidance, which has only minor changes from an earlier draft version. “We know from research that treatment for OUD with both prescription drugs – including buprenorphine, methadone and naltrexone – and relevant social, medical and psychological services is a highly effective treatment,” said Hahn.
The guidance offers some general considerations in selecting study populations, including considering whether patients who still have problematic opioid use are appropriate for a trial; in some cases, said the agency, patients who have already stopped problematic use may be appropriate for consideration for trials of maintenance therapy.
“Reductions in adverse outcomes related to OUD are desirable endpoints for study,” said FDA, giving the examples of mortality, needing emergency medical interventions, and becoming infected or reinfected with hepatitis C. “Data on background rates of the adverse outcomes in specific target populations would be useful in determining needed sample size and trial duration,” said FDA in the guidance.
Another endpoint could be built on the diagnostic criteria for OUD contained in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (DSM-5), said the guidance. Here, drug developers can look to the DSM criteria for OUD and track the number of patients who meet criteria for OUD remission by the trial’s end. This could be either a primary or a secondary endpoint, said FDA.
Changes in the patterns of drug use by those with OUD are generally accepted by FDA as a surrogate endpoint for the benefits of abstention or the “presumed benefits” of a reduction in drug use. 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 treating OUD,” according to FDA.

However, it is impossible to have complete assurance that a participant has been completely abstinent of drug use, so investigators should specify how change in drug use will be measured and ensure the trial includes a testing scheme that comes as close as possible to supporting a determination of complete abstinence. Additionally, a trial that includes a drug use pattern to define clinical response to a drug candidate should support that endpoint with data from such sources as clinical trials and prospective observational studies showing the change in drug use equates with clinical benefit.
 In addition to the traditional endpoint of changes in drug-taking behavior, the guidance offers suggestions about developing novel, patient-centered ways to measure the benefit of OUD treatments.
As an example, the guidance suggests that sponsors gather input from patients and their family or household members to ascertain the “most concerning” symptoms of OUD, and what experiences are most troublesome for the patient and those close to the patient. From this information, says FDA, sponsors can consider developing a patient-reported outcome (PRO) instrument “to evaluate a direct effect on how patients feel or function,” looking to see if such measures as sleep or mood improve with the OUD treatment medication.  
An important consideration in designing trials with PROs as secondary endpoints, said FDA, is to pre-specify the degree of improvement, and the duration in sustained improvement, that will constitute a clinical benefit.
Other outcomes of interest to FDA may be difficult to include in the type of trial usually used to seek marketing approval, the agency acknowledged in the guidance. Still, tracking such outcomes as reduced hospitalizations or increased ability to work or attend school “would be highly valuable,” said the agency, encouraging sponsors to collect data on such clinically meaningful outcomes even if they will not be used to support regulatory decisions.

Ultimately, said FDA, “the demonstrated benefit of a product will be weighed against the risk under FDA’s drug approval standard.” The more serious the adverse events seen with an OUD treatment candidate, the more compelling the demonstration of clinical benefit will need to be.


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Tags: FDA, opioids, US

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