U.S. flag An official website of the United States government
  1. Home
  2. Drugs
  3. Guidance, Compliance, & Regulatory Information
  4. Guidances | Drugs
  5. Guidance Recap Podcast | Benefit-Risk Assessment for New Drug and Biologic Products
  1. Guidances | Drugs

Guidance Recap Podcast | Benefit-Risk Assessment for New Drug and Biologic Products


Thank you for joining us for another episode of the Guidance Recap Podcast. My name is Kylie Haskins, and I am today’s host. In this episode, I am excited to be talking with Dr. Jim Smith, the Director of CDER’s Office of New Drug Policy. Dr. Smith will be sharing some thoughts with us on the newly published final guidance titled, “Benefit-Risk Assessment for Human Drug and Biological Products.” Welcome, Dr. Smith! Thank you for speaking with us today.

Can you provide an overview of FDA's approach for benefit-risk assessment in regulatory decision making for medications and provide some of the reasons that FDA issued this guidance?

Sure, I’d be happy to.  For a new medication to be approved in the United States, FDA must, in part, determine that the medication is safe and effective for the reasons that it would be prescribed. Because all medications can have side effects, which can range from mild to severe, FDA concludes that a medication is “safe” if its benefits are expected to outweigh its risks. This weighing of a medication’s benefits with its risks is known as a “benefit-risk assessment.”

Every benefit-risk assessment is unique, and FDA reviewers must consider what is known – as well as what is not yet known – about a medication’s benefits, its risks, and how the known risks would be managed by healthcare providers. There is no set formula because every situation is case-specific; that said, there are some fundamental factors that we always take into account.

First, FDA considers the therapeutic context in which the medication will be used, by which I mean the nature and severity of the condition the medication is intended to be used for, as well as how well patients’ needs are being met by the currently available treatments.  The perspective of patients can be very valuable to us here. For example, we understand that patients with serious conditions are often willing to accept greater risks from their medications, especially if the currently available options are insufficient to treat their condition adequately.  Conversely, there would generally be less tolerance for risk when a medication is intended for use by a large number of healthy people to treat symptoms of a non-serious condition that would be expected to resolve on its own.

Second, FDA reviewers consider the evidence we have about the medicine – both regarding the benefits of use as well as the risks. We do this before a medication is first approved, of course, but we also continue to consider a medication’s benefits and risks after approval as new information becomes available.

Third, we consider what uncertainties remain about the medication’s effects – both the benefits and the potential safety concerns. It’s inevitable that there are things we don’t completely understand about a medication at the time that we need to make a regulatory decision.  We might have uncertainty about all of the ways that a medication may help patients, or how big or little of a help it may be.  Similarly, we may have uncertainty about aspects of a medication’s safety, such as whether – or perhaps how often – a rare but serious side effect may occur. Although it’s certainly preferable to have as much certainty as possible regarding a medication’s benefits and risks – because then healthcare providers and their patients can be that much more informed when making treatment decisions – no matter how much we know about a product, there is always more that we can discover.  In other words, we must be prepared to accept some uncertainty despite having evidence from adequate and well-controlled investigations, especially in certain scenarios, such as when a medication is intended to treat a serious, rare disease and available alternatives are limited or nonexistent.

Finally, FDA considers the options we may have to reduce some of these uncertainties and manage some of the risks. For example, we might only approve a medication for certain subsets of a disease where the benefits outweigh the risks; we require additional clinical studies – either before or after a medication is approved; or we may require certain risk mitigation strategies.

The guidance that we have issued further discusses considerations that factor into this benefit-risk assessment, including how information regarding the patient experience can be used to inform it. It also discusses how drug developers can design and conduct their development programs to collect information that is best suited to inform FDA’s eventual benefit-risk assessment regarding a medication. We are very willing to discuss benefit-risk considerations with drug developers during development, and the guidance addresses opportunities for such interactions. Last, the guidance emphasizes that benefit-risk assessment does not end when a medication is approved by discussing how such an assessment informs regulatory decisions in the postmarket setting.

You mentioned multiple factors that are considered in benefit-risk assessments. Are these decisions usually quite complex?

It’s difficult to describe the “usual” case, since each case is quite unique.  Certainly, some benefit-risk assessments are rather straightforward. For example, if a proposed medicine has clearly been shown to provide important benefits to patients and we also have assurances based on the evidence that the medicine will not cause serious health risks, it would not be difficult to conclude that the benefits outweigh the risks. Other times, the benefit-risk assessment is more complex, particularly when serious risks are involved or when there is more uncertainty in our understanding of the benefits or the risks.

Furthermore, our benefit-risk assessment can change over time as new information becomes available. For example, the medication natalizumab – the trade name is Tysabri – was originally approved for relapsing forms of multiple sclerosis, a progressively debilitating neurological disease. During the approval process, the clinical trial results for Tysabri were very promising, and the safety profile was acceptable given the available data. FDA approved the medication, but a few months later, two cases of a life-threatening brain infection that had not yet been observed in clinical trials occurred in patients receiving Tysabri. In response, the sponsor voluntarily withdrew the medication from the market, suspended all clinical trials, and conducted an extensive safety assessment. After reviewing additional information about the medication’s benefits, risks, and the remaining uncertainties – and after holding a public Advisory Committee meeting to obtain additional input from experts, patients and their families, and healthcare providers – FDA ultimately determined that the benefits did continue to outweigh the risks, despite this new safety information, allowing Tysabri back onto the market with a risk mitigation strategy that includes requiring that patients be regularly evaluated while taking the treatment and setting up a post-marketing safety study to gather more information about the risk of brain infections. This case is certainly one example of a complex benefit-risk assessment.

The guidance discusses a Benefit-Risk Framework. Can you explain what the Benefit-Risk Framework is, and describe how it is used during regulatory review?

The Benefit-Risk Framework is a structured, organizational tool that we use to help us conduct the benefit-risk assessment, document the information under consideration for each assessment, and communicate our regulatory decisions. The Benefit-Risk Framework outlines the important areas necessary to make the benefit-risk assessment and organizes the information under consideration for each area, including both the evidence as well as the uncertainties that remain at the time. The Benefit-Risk Framework provides a structured approach that helps us systematically think through and talk about each of the fundamental factors that impact our decision making from a benefit-risk perspective. At the end of our review, all of the information is integrated to inform our conclusions regarding a medication’s benefits, risks, and uncertainties, taking the therapeutic context for patients into consideration as well. The Benefit-Risk Framework has become an important tool and is now included in FDA’s review documentation that supports our regulatory decisions for medications.

The guidance talks a lot about sponsors’ roles in informing FDA’s benefit-risk assessment, can you talk more about that?

FDA’s benefit-risk assessment depends on the information available to inform the assessment. Sponsors generate this information through their product development programs. The decisions they make about designing clinical trials require careful thought to ensure the trials produce the information needed to inform FDA’s benefit-risk assessment adequately. This guidance notes that benefit-risk planning is a very purposeful activity; sponsors should keep benefit-risk considerations in mind throughout the development process, particularly if challenging benefit-risk considerations are anticipated.

Does the benefit-risk assessment end with the medication’s approval?

Not at all.  As I mentioned a moment ago, we learn more about medications once they are on the market, and ideally, we learn more about both the benefits and risks and, with this information, hopefully reduce some of the uncertainties that we had at the time of approval. Occasionally, new information arises that makes us reconsider the benefit-risk balance, including whether we may need to take additional action, such as informing the public, revising the prescribing information for a medication, taking additional steps to investigate new safety information further, among other things. If the new information results in a situation in which the benefits no longer outweigh the risks despite various risk mitigation strategies that we have available, the medication may need to be removed from the market entirely.

How can patient experience inform the benefit-risk assessment?

The patient perspective can certainly influence FDA’s benefit-risk assessment for a medication, as it should, since patients are the ultimate stakeholders of our regulatory decisions. During the past 10 years, FDA – and really the whole community involved in the development of medical products – has sought to increase opportunities for patients to contribute their perspectives. This guidance reiterates FDA’s support for the use of patient experience data in the benefit-risk assessment, encourages sponsors to obtain feedback during the design of studies to collect such information systematically, and outlines current related initiatives, such as Patient-Focused Drug Development and Science of Patient Input.

The guidance contains an incredible amount of useful and important information.  What are a couple of key items that you especially want listeners to remember?

Thank you, that is a great question. I would hope that listeners remember that FDA’s benefit-risk assessment is shaped by the amount of information available to us, and this is only possible if the information is collected. For those developing medications, the most important potential benefits and risks should be identified as early as possible so that they can be carefully evaluated as the development program proceeds. Although there will always be some degree of uncertainty with respect to a medication’s benefits and risks, it is often possible to reduce this uncertainty with deliberate planning. If a challenging benefit-risk assessment is anticipated – perhaps because of a known serious risk of concern – collecting as much data as possible to provide clarity regarding the nature of the medication’s benefits should greatly facilitate FDA’s benefit-risk assessment. The needs and perspectives of patients can be very informative here. Finally, I would also like listeners to remember that the benefit-risk assessment is not a static judgment, but rather has the ability to evolve over time as we learn more about the medication. 

Dr. Smith, thank you for speaking with us today about the final guidance on Benefit-Risk Assessment. We have learned so much from your insights on this document. We would also like to thank the guidance working group for writing and publishing this final guidance.

To the listeners, we hope you found this podcast useful. We encourage you to take a look at the snapshot and to read the guidance.




Back to Top