Opioid alternatives: FDA offers insights on developing non-addictive drugs for acute pain

Regulatory NewsRegulatory News | 09 February 2022 |  By 

The US Food and Drug Administration (FDA) has issued draft guidance to industry on the development of non-opioid analgesics for acute pain in an effort to spur the development of non-addictive pain treatments.
The draft guidance, which is part of a larger Overdose Prevention Strategy from the Department of Health and Human Services (HHS), focuses on generating data for an indication of management of acute pain, labeling claims related to the elimination or reduction of opioid use, and the potential use of expedited programs for regulatory approval.
The guidance defines acute pain as lasting up to 30 days, usually as a result of tissue injury from trauma or surgery. It does not address products for chronic pain, which will be the focus of a future guidance document.
“Opioid misuse and abuse remain a serious public health crisis facing the country. Preventing new addiction through fostering the development of novel non-opioid analgesics is an important priority for the FDA,” Patrizia Cavazzoni, director of the FDA’s Center for Drug Evaluation and Research, said in a statement. “The guidance reinforces the agency’s commitment to confront opioid misuse, abuse and addiction by taking steps to help those with acute pain get access to improved non-opioid treatment alternatives.”
The guidance also fulfills certain legal requirements of the Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment for Patients and Communities Act of 2018 (SUPPORT Act). The draft guidance is the latest step in a multi-year effort by FDA to address overdose deaths from opioids (RELATED: FDA Science Board Addresses US Opioid Epidemic, Regulatory Focus 01 March 2016)
Drug development
The number of well-controlled clinical trials needed 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studied, and the degree to which the information supports efficacy across acute pain settings, according to the draft guidance. Products that have well-established analgesic mechanisms of action could obtain a general indication with at least two clinical trials if each is conducted in a different pain population. However, products with novel mechanisms of action are likely to require trials in more than two different pain populations.
For sponsors seeking a specific acute pain indication that applies to a certain population of patients, evidence from at least two adequate and well-controlled trials is generally required.
Clinical trials for non-opioid analgesics should be randomized, double-blind, superiority trials with a repeat-dose design, the guidance states. The treatment duration should be no less than 24 hours for products that are not limited to a single dose. Trial protocols should prespecify which rescue medications are allowed, along with the frequency, amount, and threshold of pain at which the rescue medication can be administered. “This is particularly 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 a conclusion of ineffectiveness,” FDA wrote in the draft guidance.
FDA recommends that the primary endpoint be based on the change in pain intensity over a suitable time period, rather than on pain relief since pain relief scales may be influenced by concurrent adverse reactions and a patient’s ability to recall prior pain experiences.
Labeling claims on opioid reduction
FDA officials also flagged three ways in which non-opioid analgesics can show benefit in reducing opioid use that could be highlighted in labeling.
  • Eliminating use of opioid analgesics in some or all patients in a care setting where opioids would typically be required to alleviate pain
  • Providing analgesia that allows a patient to be discharged from a health care facility without opioids when they would typically be discharged with opioid analgesics
  • Showing a clinically meaningful reduction in opioid-associated adverse reactions or early functional recovery due to reduced opioid analgesic use
To support these claims, sponsors would need to provide data from at least two adequate and well-controlled trials. The agency does not recommend using an observational study design or the exclusive use of electronic health data, though electronic health data could be useful in assessing opioid analgesics dispensed at discharge or understanding current pain management practices.
Expedited programs
Non-opioid analgesics that are designed to replace or reduce the use of opioid analgesics may be eligible for FDA’s expedited review programs, including fast track, breakthrough therapy, and priority review designations.
The guidance notes that FDA does not have experience with making analgesic approvals 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.
Draft guidance: Development of Non-Opioid Analgesics for Acute Pain 


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