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Would you take a drug that could kill you? Understanding benefit-risk assessment in pharmaceutical products


“Would you take a drug that could kill you? We ask questions like this all the time,” noted Bennett Levitan of Janssen Research & Development during a July 29 FasterCures Webinar about understanding the benefit-risk assessment in new pharmaceutical products. “Do I let the wind blow through my hair or do I wear a helmet for safety? Do I text while driving or wait until I pull over?” It is no different for medicine, he noted. Once an individual decides that the benefits exceed the risks for a certain treatment, they want it approved and they want to be able to use it. And that does not always occur because the patient perspective has limited voice right now in the regulatory approval process.

Levitan joined a distinguished panel of experts, including Patricia Furlong of Parent Project Muscular Dystrophy (PPMD) and Robert Meyer of Virginia Center for Translational and Regulatory Sciences, who together shed light on the current assessment process, focusing on how patient perspectives are (and should be) integrated. All three are members of FasterCures’ Benefit-/Risk Advisory Council, which was convened earlier this year to help guide our efforts to expand opportunities for patient input to shape product development and influence regulatory decisions.

There is no such thing as THE patient perspective
“There is no such thing as THE patient perspective, as a static entity,” asserted moderator Kim McCleary, who heads FasterCures’ Benefit/Risk assessment program. “Even for patients with the same condition, needs shift and change in response to dynamic circumstances and the advent of new therapies. What a patient might want or expect is only one of the many pieces of information an FDA reviewer must consider to determine safety and efficacy of a new drug application.”

In reality, the FDA reviewer has a very limited window into patient perspective. In fact, they are exposed to it at just one point during the up-to 15-year drug development timeline, when an external advisory committee is convened to look at a new drug application. And because all the players in the ecosystem evaluate benefits and risks through a different lens – FDA based on an entire population, health care professionals/ prescribers based on a single patient, and individuals based on personal values and other factors (such as cost, impact on family, etc.) – reconciling these views can be challenging.

Patients and patient organizations have begun leveraging the expanded opportunities afforded them through the most recent Food and Drug Administration Safety and Innovation Act (FDASIA) to engage earlier and more often in the regulatory process. The most notable new venue is the Patient-Focused Drug Development Initiative (PFDDI), which is providing patient advocates for 20 selected disease areas to have a direct audience with FDA reviewers to share how the condition affects their lives and what is most important to them about the care and treatments they seek.

Data is king
“Regulators are exposed to huge amounts of data,” noted Levitan. “They love data, especially high quality data like the kind that comes from traditional clinical trials.” And while they generally agree on facts, a benefit risk decision is more than just facts; it involves value judgments based on those facts. “It’s on the issue of values, not facts, around which regulators and patients most often disagree.”

If patients really want to influence the regulatory process, Levitan suggested, data is key. Collection and analysis of patient perspectives must be given the same level of rigor as clinical data, and presented to regulators as such.

Levitan gave the example of a 200-person adult migraine sufferer survey which demonstrated that patients would accept a higher level of risk for heart attack to reduce or eliminate their migraine symptoms as was initially determined by reviewers. These types of studies are becoming more common.  

Accounting for evolving post-approval knowledge of benefits and risks
“Knowledge of benefits and risks as it pertains to drug development and medical practice evolve over time, and that can be for many years post-approval,” said Meyer. “When a drug enters the clinic, typically benefit/efficacy is known by some accepted measure for a relatively defined population, but the understanding of risks is fairly conjectural.” By the time you get to Phase III trials, he went on, patients are carefully chosen and often don’t have other diseases and thus are not necessarily fully representative of patients who will use the drug once it is approved.

So for physicians, who look more at how the body is functioning over lifespan of a patient, not necessarily on how patient is feeling at a given moment, more (and more structured) input from patients on their values is important to strengthening the assessment process. Unlike the population-wide analysis looked at by the FDA, physician assessment of risk/benefit for a particular drug may vary from patient to patient based on the interpretation of efficacy for that individual.

Meyer suggested that in instances where efficacy is still in question after trials, the FDA accept its role as being more an information provider than a determiner of risk/benefit accessibility. Instead of waiting to approve a product until more or better data is available, FDA could instead send the information that is known to doctors and patients, and allow them to make their own determination of appropriateness in partnership with one another.

An intensely personal decision
Furlong closed out the discussion by highlighting the case of Duchenne Muscular Dystrophy (DMD), a rare and fatal pediatric neuromuscular disease that was not one of the 20 included in FDA’s PFDDI hearing schedule. When PPMD originally went to the FDA to talk about the unmet need of DMD and share the stories of parents in their community, they were told that individual anecdotes, no matter how powerful, are not the same thing as quantifiable data and therefore have limited utility in the benefit-risk assessment.

So to add rigor to their data and quantify the case for unmet need, PPMD partnered with Dr. John Bridges at Johns Hopkins University to develop and conduct a DMD caregiver survey that identified a pool of treatment features, including six attributes to cover potential benefits, risks and other features (varying across three levels). The results were illuminating, and, even more important, statistically significant, and FDA has since asked PPMD to expand the survey and work collaboratively with agency to draft guidance for industry. The draft guidance led by PPMD was submitted to the FDA on June 25, 2014. This model is one that is easily replicable across other disease areas, noted Furlong.

Quoting a DMD parent, she said “When it comes to terminal illnesses, the FDA’s job should be to make sure a product is safe and that the risks and benefits presented by the producer are accurate. Our job should be to determine, given all that information, whether to give it to our children. It is an intensely personal decision.”

The July 29 Webinar is just one resource for organizations and individuals interested in learning more about structured benefit-risk assessment and how FasterCures is working to strengthen the consideration of patient perspectives in product development and regulatory decision-making. Here are links to the Webinar archive and other important resources: