USA – In order to combat the opioid crisis even further, the Food and Drug Administration (FDA) has issued draft guidance on the development of novel analgesic drugs with the potential to reduce opioid use and prevent addiction.

The FDA defines acute pain in the draft guidance as pain that lasts up to 30 days and is typically caused by some type of tissue injury, such as trauma or surgery.

Clinical trials that support a finding of efficacy for a nonopioid analgesic for the management of acute pain, according to the Agency, should be randomized, double-blind, superiority studies with pain intensity as the primary outcome measure.

Furthermore, the labeling should include information indicating that using the product would eliminate or reduce patient exposure to opioid analgesics.

Nonopioid analgesic development programs aimed at replacing or reducing opioid analgesic use may also be eligible for expedited review through one or more of the FDA’s expedited programs.

Preventing new addiction through fostering the development of novel nonopioid analgesics is an important priority for the FDA.”

Patrizia Cavazzoni, MD, director of the FDA’s Center for Drug Evaluation and Research.


Drug development

According to the draft guidance, the number of well-controlled clinical trials required to support a general acute pain indication will depend on the drug’s mechanism of action, the populations studied, and the degree to which the information supports efficacy across acute pain settings.

Products with well-established analgesic mechanisms of action may be granted a broad indication after at least two clinical trials, each conducted in a different pain population.

Products with novel mechanisms of action, on the other hand, are likely to necessitate trials in more than two different pain populations.

Evidence from at least two adequate and well-controlled trials is generally required for sponsors seeking a specific acute pain indication that applies to a specific population of patients.

The guidance states that clinical trials for non-opioid analgesics should be randomized, double-blind, superiority trials with a repeat-dose design.

For products that are not limited to a single dose, the treatment duration should be no less than 24 hours.

The trial protocols should specify which rescue medications are permitted, as well as the frequency, amount, and pain threshold at which the rescue medication can be administered.

This is especially important in placebo-controlled trials, where increased use of rescue medication in the control group may diminish the study drug’s treatment effect, leading to an ineffective conclusion,” FDA wrote in the draft guidance.

Because pain relief scales can be influenced by concurrent adverse reactions and a patient’s ability to recall prior pain experiences, the FDA recommends that the primary endpoint be based on the change in pain intensity over a suitable time period rather than pain relief.

Accelerated programs

Non-opioid analgesics intended to replace or reduce the use of opioid analgesics may be eligible for the FDA’s expedited review programs, such as fast track, breakthrough therapy, and priority review.

According to the guidance, the FDA has no experience approving analgesics based on a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit, which is the standard considered for accelerated approval.

Given that pain intensity is a subjective experience that can only be directly reported by the patient, it is difficult to envision how surrogate or intermediate endpoints could be used to predict analgesic effect,” FDA wrote.

Prior to issuing final guidance documents, the FDA will be accepting public comments on the draft guidance until April 11, 2022.

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