The benefit-risk assessment is the cornerstone of how all drugs are approved. This assessment captures the scientific evidence, uncertainties, policy, and reasoning used by FDA officials to arrive at their final determination for specific regulatory decisions.
To be approved for marketing, a drug must be safe and efficacious for its intended use. “Safe” is not explicitly defined in the statutes or regulations that govern approval because it is recognized that all drugs have some ability to cause adverse effects. Therefore, the safety of a drug is assessed by determining whether its benefits outweigh its known and potential risks for the intended population.
In the past, some FDA stakeholders have suggested that there is room for improvement in the clarity and transparency of the FDA’s benefit-risk assessment. To address these concerns and enhance FDA’s framework for benefit-risk assessment, the Agency began an initiative in 2009 to develop a structured approach for drug benefit-risk assessments. This structured approach was developed to serve as a template for product reviews, as well as a vehicle for explaining the basis for the FDA’s regulatory decisions in drug approvals.
The FDA assesses the risks and benefits of all drugs in the context of the use indicated in the labeling. However, because of the widespread misuse and abuse of prescription opioid analgesic drugs, the Agency also considers the broader public health effect of these drugs. This involves consideration of the risks related to misuse, abuse, opioid use disorder, accidental exposure, and overdose, for both patients and others. Likewise, the FDA considers any properties of a drug expected to mitigate these risks.
The New Opioid Draft Guidance
In June 2019, the FDA released a draft guidance regarding the benefit-risk assessment framework for opioids. The takeaway from the draft guidance, entitled “Opioid Analgesic Drugs: Considerations for Benefit-Risk Assessment Framework,” is that the concept of risk is being expanded. Under the guidance, there is going to be a large emphasis not just on the risk and benefit to the immediate patient, but also on the broader community.
The purpose of the guidance is to describe the benefit-risk framework that the FDA will use in evaluating whether new drug applications for opioid analgesic drugs meet the standard for approval under section 505 of the Federal Food, Drug, and Cosmetic (FD&C) Act. The draft guidance also summarizes the information that should be included in an application for an opioid analgesic drug to facilitate the Agency’s benefit-risk assessment.
The Benefit-Risk Assessment
Essentially, the draft guidance gives recommendations for information the applicant should provide to assist the Agency in its assessment. The benefit-risk dimensions include analysis of the condition, current treatment options, the benefit, as well as risk and risk management.
Regarding benefits to patients using the drug as labeled, the Agency will consider questions including the following:
- What is the body of evidence supporting a finding of analgesic drug efficacy?
- In what patient population(s) was efficacy demonstrated? How does the population studied reflect the proposed indication (i.e., is the proposed indication broader than the population studied)?
- Does the drug have characteristics that mitigate adverse events associated with opioid analgesic drugs, including respiratory depression, sedation, and constipation? What data support the conclusion that these risks are mitigated?
Regarding risks to the patient using the drug as labeled, the Agency will consider questions including the following:
- Does this particular drug have any novel risks not typically associated with opioid analgesic drugs? How serious are they? Can they be mitigated through monitoring, patient selection characteristics, or limiting duration of use? Are the novel risks reversible?
- Do the formulation and/or excipients pose risks to patients (e.g., tablets that swell in the gastrointestinal tract, tablets that may adhere to moist mucosal surfaces)? For drugs formulated to have abuse-deterrent properties, are there any adverse events associated with the drug product when used as labeled that are attributable to aversive excipients or excipients intended to impart resistance to manipulation?
- Are there characteristics of the drug that increase or decrease the risk for respiratory, sedation, or development of opioid use disorder in patients (e.g., large residual opioid in transdermal systems, high dosage strengths)? Can the risks be mitigated by particular packaging configurations or storage and disposal conditions?
Regarding effectiveness and safety relative to approved analgesic drugs, the Agency will consider questions including the following:
- Do any comparative efficacy data exist for the drug relative to approved opioid or nonopioid analgesic drugs? Does this analgesic drug offer any advantages relative to available approved analgesic drugs for each indication, with regard to effectiveness or duration of response?
- What is the anticipated benefit-risk balance relative to available approved analgesic drugs for each indication? Do any comparative safety data exist for the drug relative to approved opioid or nonopioid analgesic drugs? Does this analgesic drug offer any other safety advantages or disadvantages relative to available approved analgesic for each indication (e.g., less risk of drug-drug interactions)?
- Does the drug have any other advantages over other available approved analgesic drugs (e.g., can be mixed with food)?
Broader Public Health Effects
In the overall benefit-risk assessment of opioid analgesic drugs, the FDA will consider the positive and negative public health effects of the drug, which includes the drug’s potential effect on risks to both patients and nonpatients, such as members of the patient’s household (e.g., children, teenagers, visitors, and others). The risks considered include those related to misuse, abuse, opioid use disorder, accidental exposure, and overdose.
In evaluating ways in which an opioid analgesic drug positively or negatively affects public health, the FDA will consider questions that include:
- Are there characteristics of the drug that increase or decrease the risk of accidental use in children (e.g., tablet size, color, flavor, packaging configuration, appearance of topical systems)?
- Are there characteristics of the drug that increase or decrease the risk of misuse, abuse, opioid use disorder, and related adverse outcomes such as overdose and infectious complications of injection (e.g., abuse-deterrent properties, large residual in transdermal systems, high dosage strengths)? Can the risks be mitigated by particular packaging configurations or storage and disposal conditions?
- Are there increased or decreased risks associated with the indicated method of delivery (i.e. patch, pump, capsule, etc.)? For example, does the delivery method affect an existing risk or introduce a novel risk?
Get the Support You Need
The seriousness of the opioid abuse epidemic has caused the FDA to take positions that can impact the approval of your opioid analgesic drug. When you are ready to submit your new drug application (NDA), turn to ProPharma Group for assistance with giving the Agency all the information they need to assess your drug in the best possible light. ProPharma Group stays up-to-date on the Agency’s current thinking and can help you navigate their risk-benefit analysis.
To learn more about our services and how we can help you achieve successful interactions with the FDA, contact us today.
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