FDA considers a benefit-risk assessment for opioid analgesics

The FDA issued a draft guidance for the pharmaceutical industry when providing information in a new drug application (NDA) for opioid analgesic drugs. The FDA assesses risks and benefits of all drugs in the context of their labeled uses when reviewing NDAs. However, because of the widespread abuse of opioids the FDA will also consider the broader public health effect, including the risks related to misuse, abuse, opioid use disorders, accidental exposure, and overdoses for patients and others. The guidance details what data is required for the FDA to complete their benefit-risk analysis after receiving an NDA (Notice, 84 FR 29211, June 21, 2019).

Patient benefits. For the FDA to analyze patient benefits, pharmaceutical companies submitting opioid NDAs should show the efficacy and safety of the drug when used for its proposed indication. The NDA should provide a body of evidence supporting a finding of drug efficacy, what patient population was used and why, and a proposed duration of use for each proposed indication. In addition to efficacy, the companies should show the safety of the drug when used for its proposed use. The NDA should show drug safety by submitting supporting data of drug characteristics that mitigate adverse events associated with opioids, such as respiratory depression, sedation, and constipation. The FDA would also need data supporting any drug characteristics that mitigate risks of opioid use disorder.

Patient risks. In addition to the already known risks of opioids, the FDA will also consider questions about the risks to patients who are prescribed the drug and use it as labeled and directed by their physicians. The NDAs should provide data to support the answers to the following questions:

  • Does the drug have any risks not normally associated with opioid use? How serious are these risks, and can they be mitigated? Are the risks reversible?
  • Does the drug formulation cause any risks such as tablets that swell in the GI tract or stick to mucous membranes? For drugs formulated with abuse-deterrent properties, are there any risks associated with formulation?
  • Does the drug have characteristics that increase or decrease the risks of respiratory depression, sedation, or development of opioid dependence? Can packaging particulars or storage and disposal conditions mitigate the risks?
  • Is there evidence that typical adverse events associated with opioids occur at a higher rate?

Effectiveness and safety. The FDA considers the benefits and risks relative to other available treatment options for the prescribed condition. The comparative data of the drug to other treatment options is valuable, but the FDA notes, it is not required to be found superior to other options, to be approved for an ANDA. The FDA will consider the following questions when determining the effectiveness and safety of drugs in ANDAs:

  • Does efficacy data exist comparing the drug with other opioids or nonopioids for the condition? Does the drug have any advantages compared to other treatment options?
  • Does comparative safety data exist with other treatment options? Are there any safety advantages or disadvantages compared to other options?
  • What is the anticipated benefit-risk balance compared to other treatment options?
  • Does the drug have any other safety advantages over other treatment options?

Public health effects. The FDA proposed in the guidance that it would consider the greater public health effects of new opioids including patients and nonpatients. Nonpatients can be members of patient’s households, visitors to patient’s households and others. The risks are those related to misuse, abuse, opioid use disorder, accidental exposure, and overdose. The FDA will consider the following when analyzing public health effects:

  • Are there characteristics of the drug that increase or decrease risk of accidental exposure to children?
  • Are there characteristics of the drug that increase risk of misuse, abuse, and related adverse outcomes? Can the risks be mitigated?
  • Are there risks with the method of delivery?
  • Are there any potential unintended adverse consequences?
  • Safety of unintended routes of administration such as intravenous, intranasal, or inhalation
  • Discussion of anticipated use-specific subpopulations such as teens or patients with mental health disorders and how to mitigate such risks

Risk management. The FDA determined that there is a risk evaluation and mitigation strategy necessary for all opioid drugs intended for outpatient use to make sure the benefits outweigh the risks. The mitigation strategy requires training for all health care providers involved in the treatment of pain. To meet this requirement drug companies with approved opioid NDAs must provide grants to continuing education providers for development of these training courses. Any NDA must include any risk evaluation and mitigation strategies thought to be necessary to make sure the benefits outweigh the risks of the opioid drug.