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A Discussion of Evolving Benefit/Risk Evaluation Standards Editorial DIA Therapeutic Innovation & Regulatory Science 2018, Vol. 52(5) 531-536 From the Valley of Death to the Crossroads ª DIA 2018 Article reuse guidelines: of Opportunity: A Discussion of Evolving sagepub.com/journals-permissions DOI: 10.1177/2168479018774556 Benefit/Risk Evaluation Standards tirs.sagepub.com Peter J. Pitts, BA1,2 , and Patrick Brady, PharmD3 Abstract A series of recent US Food and Drug Administration (FDA) approvals (such as Sarepta’s Exondys 51, Merck’s Keytruda, and Portola’s Bevyxxa) has generated significant interest within the drug development ecosystem. Facilitated regulatory pathways aimed toward expediting medicines to patients suffering from serious and life-threatening conditions are a good thing, even if it raises curiosity and introduces some degree of uncertainty. Over the last 20 years, two key words in drug development have been speed and innovation. Going forward, the patient voice, data quality, and evidence generation must be added to that list. There is a raging debate over the level of evidence expected to first introduce a treatment to patients. Some argue for less data followed by postapproval follow-up, others for more adaptive clinical trial designs and end-point modification driven by patient-focused drug development and use of real-world evidence. The transition in the regulatory framework is happening in front of our eyes. How are these shifts in regulatory science interpreted within the context of 21st-century drug development—and how can these learnings help advance patient care while placing into context the expected uncertainty we find in benefit-risk data? Keywords expedited review pathways, risk-benefit analysis, adaptive clinical trials, real world evidence, patient-focused drug development A series of recent US Food and Drug Administration (FDA) FDA headquarters in White Oak, MD. According to then FDA approvals (such as Sarepta’s Exondys 51i,Merck’sKeytrudaii, commissioner Robert Califf, “The science is not in dispute and Portola’s Bevyxxaiii) has generated significant interest within beyond the usual types of disagreement that occur when experts the drug development ecosystem. Facilitated regulatory pathways review clinical evidence from different perspectives. ...It is aimed toward expediting medicines to patients suffering from clear that Dr. Woodcock’s decision utilized the flexibility serious and life-threatening conditions are a good thing, even if afforded under the relevant statutory provisions, including con- it raises curiosity and introduces some degree of uncertainty. Over sideration of the life-threatening decisions of the disease and the last 20 years, 2 key words in drug development have been the lack of alternative treatments.”iv The pharmaceutical indus- speed and innovation. Going forward, the patient voice, data try is no stranger to stakeholders rendering different perspec- quality, and evidence generation must be added to that list. There tives over the same data, and this will become increasingly so is a raging debate over the level of evidence expected to first as patients and payers grow their influence in decision making. introduce a treatment to patients. Some argue for less data It is noteworthy that Dr Janet Woodcock, Director of the followed by post-approval follow-up, others for more adaptive FDA’s Center for Drug Evaluation and Research (CDER), clinical trial designs and end-point modification driven by offered these comments at Exondys 51’s Peripheral and Central patient-focused drug development and use of real-world evidence. Nervous System Drugs Advisory Committee meeting, “It’s The transition in the regulatory framework is happening in front of our eyes. How are these shifts in regulatory science interpreted within the context of 21st-century drug development—and how 1 can these learnings help advance patient care while placing into Center for Medicine in the Public Interest, New York, NY, USA 2 E´cole Supe´rieure des Sciences E´conomiques et Commerciales (Paris/Singapore), context the expected uncertainty we find in benefit-risk data? New York, NY, USA 3 Bayer Corporation, Whippany, NJ, USA 21st-Century Regulatory Dimensionality: Submitted 7-Apr-2018; accepted 12-Apr-2018 The Power of the Patient Voice Corresponding Author: Peter J. Pitts, Center for Medicine in the Pubic Interest, 757 Third Avenue, The approval of Exondys 51 (for Duchenne muscular dystro- 20th Floor, New York, NY 10017, USA. phy) struck several chords both inside and outside the walls of Email: [email protected] 532 Therapeutic Innovation & Regulatory Science 52(5) possible to reach different conclusions based on the data pre- As Dr Califf and Deputy Commissioner Rachel Sherman sented today. ...Failing to approve a drug that actually works (now Principal Deputy Commissioner under Commissioner in devastating diseases—these consequences are extreme.”v Scott Gottlieb) commented, “Creating knowledge requires the Exondys 51 was approved under the accelerated approval application of proven analytical methods and techniques to pathway, which provides for the approval of drugs that treat biomedical data in order to produce reliable conclu- serious or life-threatening diseases and generally provide a sions. ...There must be a common approach to how data is meaningful advantage over existing treatments. Approval under presented, reported and analyzed and strict methods for ensur- this pathway can be based on adequate and well-controlled stud- ing patient privacy and data security. ...Rules of engagement ies showing the drug has an effect on a surrogate endpoint that is must be transparent and developed through a process that reasonably likely to predict clinical benefit to patients (eg, how a builds consensus across the relevant ecosystem and its stake- patient feels or functions or whether they survive). holders ...To ensure support across a diverse ecosystem that The FDA also granted Exondys 51 fast track designation, often includes competing priorities and incentives, the system’s which is a designation to facilitate the development and expe- output must be intended for the public good and be readily dite the review of drugs that are intended to treat serious accessible to all stakeholders.”viii conditions and that demonstrate the potential to address an Yes, Serapta’s clinical program was flawed. But there was unmet medical need. It was also granted priority review and undeniable evidence of ...hope. orphan drug designation. Priority review status is granted to Is “hope” now considered a validated biomarker? Certainly applications for drugs that, if approved, would be a significant not—but the FDA’s Patient-Focused Drug Development pro- improvement in safety or effectiveness in the treatment of a gram has begun to shift the agency-advocate relationship from serious condition. Orphan drug designation (fewer than anecdote to ally. How much uncertainty is a patient willing to 200,000 patients) provides incentives such as clinical trial tax accept? How can that tolerance be measurably factored into an credits, user fee waiver, and eligibility for orphan drug exclu- acceptable benefit-risk calculation? sivity to assist and encourage the development of drugs for The tool set for using a more data-driven, regulatory-savvy rare diseases. patient voice is nascent and the tasks are as daunting as the The uniqueness of the debate is that it is not entirely over the opportunities, but it’s a valuable new opportunity to drive a clinical trial design or robustness of the clinical data, or other more patient-centered focus on how we view and interpret traditional criteria—it’s about “failing to approve a drug that data. Such a mindset opens up the opportunity to embrace a actually works.” Is this a new regulatory standard? What does it more complete life-cycle approach to the regulation of health mean? How is it defined and measured? In the past, regulators care technologies. A more dispassionate understanding of have been accused of embracing ambiguity to allow it flexibil- patient engagement in regulatory decision making, combined ity to deny approvals—can we now expect similar regulatory with a more mature expression of how data evolve over time, ambiguity that results in unanticipated approvals? upends the traditional frame of regulatory stasis and intro- While there is increasing disagreement among stakeholders duces the opportunity for a much more dynamic understand- over the extent to which randomized clinical trial data should ing of a medicines benefits and risks that extends far beyond support the approval of a new medicine, the diversity of scien- what is understood at approval. And this is particularly rele- tific viewpoints surrounding the data describing the benefits vant for those innovative medicines approved via new regu- and risks of Exondys 51 underscores a wider debate about the latory pathways. pressures that decision makers face in balancing uncertainty against access for patients who desperately seek treatment. The Beyond Speed: Understanding the Impact of Expedited 21st-century patient voice represents the key variable in a new regulatory dimensionality. Regulatory Pathways In a recent podcast, former FDA Commissioner Dr. Califf In a 2005 In Vivo article, then Acting CDER Director, commented that when there is a life-threatening disease with Dr Steven Galson (now Senior Vice President for Global no effective treatment, “patient groups have been very clear Regulatory Affairs at Amgen) commented that “just because that they are willing to take a high degree
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