The Flexibility Papers, No. 2: Beyond Listening—Making Patient Input Matter

In the first installment of The Flexibility Papers, we outlined several principles that we believe should guide FDA’s new Rare Disease Framework Initiative. Among them was a fundamental shift in the starting point for rare disease drug development: rather than treating conventional development approaches as the default and requiring sponsors to justify departures, FDA and sponsors should begin with the characteristics of the disease, available evidence, unmet medical need, and patient perspectives to identify a fit-for-purpose development pathway.

But what would it take to make patient perspectives a meaningful part of that starting point?

Building a Framework on the Decades-Long Culture Shift to Embrace Patient Voice

On October 16, 2026, FDA’s Rare Disease Innovation Hub, in collaboration with the Reagan-Udall Foundation for the FDA, convened a public meeting on The Patient Voice in Rare Disease Medical Product Development, which emphasized the importance of incorporating patient perspectives early and often throughout product development. FDA and the Foundation also convened an October 28 public meeting focused on the broader Rare Disease Framework Initiative. Together, these meetings provide an opportunity to consider how FDA can translate its commitment to patient engagement into meaningful regulatory practices under the new framework.

The importance of patient engagement is hardly a new concept. Since the establishment of FDA’s Patient-Focused Drug Development (PFDD) initiative under PDUFA V in 2012, a program that HPM’s own James Valentine helped to develop and launch when at FDA, the Agency has made considerable progress in creating opportunities for patients to share their experiences and preferences. The 21st Century Cures Act further advanced these efforts by requiring FDA to report on patient experience data included in certain drug applications (which we blogged about here).

FDA has also increasingly recognized the role of patient experience information in informing benefit-risk assessments. In its October 2023 final guidance, Benefit-Risk Assessment for New Drug and Biological Products, FDA acknowledges that patient experience data, including preference information, “can inform nearly every aspect of FDA’s benefit-risk assessment throughout the drug lifecycle.” And more recently, FDA’s February 2026 draft ICH E22 guidance, General Considerations for Patient Preference Studies, identifies applications of patient preference studies ranging from endpoint selection and the assessment of meaningful change to evaluating benefit-risk tradeoffs. FDA has also released a series of four Patient-Focused Drug Development guidances to “provide detail about how stakeholders can collect and submit patient experience data and other relevant information from patients and caregivers for medical product development and regulatory decision making.”

These initiatives reflect substantial progress in recognizing the importance of patient input and developing methods for collecting it. But, as the October 16 meeting illustrated, a more consequential question remains: What happens after FDA hears from patients?

As FDA develops its Rare Disease Framework, we see multiple opportunities to move beyond collecting patient input toward ensuring that it meaningfully informs regulatory decisions for rare disease drug development.

Patient Perspectives on Uncertainty: A Foundational Component of any Rare Disease Framework

Patient perspectives can inform nearly every stage of rare disease drug development, from understanding disease burden and identifying meaningful treatment benefits to selecting endpoints, designing feasible clinical trials, and evaluating benefit-risk. FDA’s qualitative approaches to patient engagement, including PFDD meetings and patient listening sessions, are particularly valuable because they provide a holistic understanding of the patient experience that extends beyond any single development or regulatory question.

One dimension of patient input, however, deserves greater attention as FDA considers building a fit-for-purpose regulatory approach: patients’ willingness to accept uncertainty regarding treatment benefit.

Discussions of patient preferences for future treatments frequently focus on the benefits patients value and the safety risks they are willing to tolerate. These have been long-recognized “categories” of patient input. But for many rare diseases, particularly those that are severely disabling, progressive, or life-threatening, uncertainty regarding a drug’s effectiveness may be equally consequential.

A patient may be willing to accept not only greater safety risks but also greater uncertainty about whether a treatment will work.

This distinction between risk and uncertainty is particularly important because regulatory flexibility often involves determining how much uncertainty can reasonably be accepted when planning development programs and evaluating evidence of effectiveness. FDA’s own rules already point in this direction. Its regulations for drugs that treat life-threatening and severely debilitating illnesses rest on the recognition that “physicians and patients are generally willing to accept greater risks or side effects” from those drugs, and that a drug’s benefits must be weighed “in light of the severity of the disease being treated” (21 C.F.R. § 312.80). The same reasoning should inform FDA’s assessment of how much uncertainty about a drug’s effectiveness is acceptable in light of the seriousness of the disease and the needs and preferences of the patients it is intended to treat.  This expansion would represent a meaningful update to the regulation.

As we discussed in The Flexibility Papers, No. 1, regulatory flexibility does not require abandoning scientific rigor or lowering statutory standards. Rather, it requires identifying a fit-for-purpose evidentiary approach that accounts for what is “reasonably attainable given the nature of the disease, its onset and progression, target population, patient needs, and the characterizations of the product under investigation” (see FDA’s Rare Disease Framework Initiative announcement).  Patient perspectives on uncertainty can provide important context for identifying a fit-for-purpose development plan.  This should be considered early in development so that the degree of uncertainty that patients will tolerate can prospectively inform the design of a clinical development program (e.g., number of studies, acceptable degree of confidence in surrogate endpoints, choice of control, alpha-level and other statistical considerations).

Patient acceptance of uncertainty should not be assumed.  It’s possible that for two diseases of similar rarity, given the unique disease manifestations and extent of available therapies, patients would express different levels of uncertainty they are willing to accept.  FDA should explicitly recognize patient acceptance of uncertainty as a dimension of patient experience data, including it in guidance on considerations for designing clinical trials as well as in the evaluation of benefits and risks to meet evidentiary standards. If the new Rare Disease Framework is intended to result in fit-for-purpose approaches, the perspectives of those who will ultimately bear the consequences of that uncertainty should help inform its implementation.

Patient Input on Meaningful Benefits Experienced in Trials

The October 16 meeting also surfaced how patients’ own views of what counts as a meaningful benefit can evolve over the course of a development program, as a once-lofty goal gives way to appreciation for smaller but still significant gains, and as functional changes not captured by the study’s chosen endpoint are experienced by patients. Many rare disease patients have never experienced any effective therapy, and there is often no development experience to know what clinical benefits will materialize.

FDA should remain open to shifts in what patients consider a meaningful benefit as a study or program progresses, and qualitative inputs that can capture unexpected benefits that existing endpoints were not designed to measure, such as through semi-structured exit interviews (see Contesse MG, Valentine JE, Wall TE, and Leffler MG, “The Case for the Use of Patient and Caregiver Perception of Change Assessments in Rare Disease Clinical Trials: A Methodologic Overview,” Adv. Ther. (2019)).  These qualitative findings may guide reviewers to consider effects on certain secondary and exploratory endpoints or post-hoc analyses as contributing to a finding of substantial evidence of effectiveness.

Translating Patient Experience into Regulatory Science & Treating Patient Stakeholders as Partners in Drug Development

FDA has established numerous mechanisms for eliciting patient perspectives, including FDA- and externally-led PFDD meetings, patient listening sessions, and advisory committee participation. But collecting patient experiences is only the first step. The greater challenge is translating those experiences into actionable regulatory science.

For example, patients may identify loss of independence as a particularly burdensome aspect of their disease or stabilization of disease progression as a meaningful treatment goal. Translating those perspectives into clinical trial endpoints requires additional scientific work, including identifying appropriate clinical outcome assessments and patient populations for inclusion in trials, characterizing meaningful change, and determining how those measures should be incorporated into clinical development.

However, patient organizations do not have a practical pathway for engaging FDA on how patient perspectives should inform drug development approaches and tools.

Existing patient engagement mechanisms are principally designed to gather patients’ lived experiences rather than facilitate detailed discussions about their scientific and regulatory implications. Some patient organizations have addressed this gap by convening adjunct scientific workshops with researchers, sponsors, and FDA staff to discuss clinical outcome assessments, natural history studies, and appropriate pivotal study designs (see, e.g., Adjunct Scientific Workshops on Metachromatic Leukodystrophy (2022), Arrhythmogenic Right Ventricular Cardiomyopathy (2023), and Autosomal Recessive Polycystic Kidney Disease (2024)). However, these opportunities remain largely ad hoc and often depend on the willingness and availability of individual FDA review staff.

FDA’s new Rare Disease Framework Initiative presents an opportunity to establish a more formal structure for engagement directly between patient stakeholders and review staff to translate patient experience into drug development tools and strategies. We have identified two key opportunities:

1. Establish science-focused patient engagement meetings or similar meeting mechanism (e.g., the proposed “Type P” meetings discussed at the June 2026 FDA Rare Disease Roundtable) to empower patient stakeholders to facilitate substantive, bidirectional scientific discussions outside of the confines of FDA-sponsor meetings; these would allow the drug development ecosystem to benefit from FDA review staff expertise and input, which we expect would be far earlier than when these same topics are raised by sponsors in the context of individual development programs. Patient organizations are more likely to make the output from these meetings publicly available to ensure that learnings benefit the entire pipeline of products, helping rise all tides.
2. Expand the historical practice of having Patient Representatives serve as Special Government Employees (SGEs) to provide consultation to FDA review divisions. Such representatives provide disease-specific patient perspectives as review teams consider development questions, while providing the protection of confidentiality that allows discussion of specific drug development programs, rather than waiting until an application is taken to an advisory committee (if it ever is). The Agency has the authority to do this and there is precedent for it, e.g., in the early 2000’s, Tiffany House, a person living with Pompe and an advocacy leader, served as an SGE and consulted the CDER review division in considering the meaningfulness results of specific clinical trials supporting marketing applications.

If patient perspectives are to help establish the starting point for development, FDA needs processes that bring those perspectives into early scientific discussions when they can best inform the development pathway.

Providing Transparency Beyond the Patient Experience Checklist

Perhaps the most consequential gap in FDA’s current approach is the limited transparency regarding how patient input influences regulatory decision-making.

A July 2026 Assessment of the Use of Patient Experience Data in Regulatory Decision-Making provides an important perspective on this issue. The assessment found that patient experience data were referenced in 73% of reviews of original new molecular entity drug applications and biologics license applications, increasing from 69% in 2021 to 85% in 2025. Among approved applications with orphan drug designation, the figure was 91.5%. These findings demonstrate meaningful progress in the availability of patient experience data for FDA’s consideration.

Yet the assessment also acknowledged a persistent transparency problem. FDA reviewers indicated that public-facing review documentation may not fully capture how patient experience data informed discussions and decisions during development. Notably, only approximately 13% of original new molecular entity submissions included references to patient experience data from non-sponsor sources, such as PFDD meetings, Voice of the Patient reports, or published literature. Although these figures do not capture every way patient input may influence development and review, they underscore the difficulty of tracing patient engagement to regulatory decisions.

Another telling example is FDA’s 2026 Request for Information on the impacts of PFDD meetings. After more than a decade of FDA- and externally-led PFDD meetings, FDA sought examples of how those meetings have influenced drug development, research priorities, and other activities. The relatively limited public response to that request, compared with the more than 100 PFDD meetings held to date, raises an important question: Are stakeholders able to identify and document the impact of these substantial patient engagement opportunities?

FDA appears to recognize the need for greater transparency. For example, the proposed PDUFA VIII Commitment Letter for FYs 2028-2032 commits FDA to sharing lessons learned from the use of patient experience data across drug development programs, including publishing case studies on at least two occasions by the end of FY 2032 and hosting a public meeting by the end of FY 2030 to discuss case studies and facilitate broader dialogue about the collection, submission, and use of patient experience data in drug development and regulatory review. These are welcome steps, but periodic case studies and a public meeting are no substitute for routinely explaining how patient perspectives influence regulatory decisions.

Without transparency, stakeholders cannot verify that patient perspectives actually affect regulatory decisions like endpoint selection, the interpretation of clinical benefit, or the Agency’s willingness to accept uncertainty.

FDA should go further, including by building on its existing reporting requirements, by providing substantive explanations in responses to sponsor submissions (e.g., preliminary written comments to sponsor meetings) and in NDA/BLA review memoranda of how relevant patient perspectives informed its recommendations and/or analysis. Where FDA reaches a conclusion that differs from patients’ expressed preferences, it should explain the rationale, as there are other considerations that may legitimately require a deviation. Greater transparency would not only demonstrate the value of patient engagement but also help patient organizations and sponsors understand how to generate patient experience data that meaningfully contributes to regulatory decision-making.

Importantly, greater transparency would advance the broader objective of the Rare Disease Framework: making the exercise of fit-for-purpose regulatory decision-making more consistent and predictable. Guidance and training could delineate methods for collecting patient experience data and employing them in decision-making, much like the current PFDD guidance series does when it comes to clinical outcome assessments and endpoints.  Further, transparency would improve understanding of how FDA weighs patient perspectives in individual decisions. This would help stakeholders anticipate how similar considerations may be applied in future development programs.

From Listening to Action

In the first installment of The Flexibility Papers, we strongly endorsed FDA’s goal to make fit-for-purpose development approaches the norm rather than the exception. Meaningful incorporation of the patient voice is essential to achieving that objective.

FDA’s Rare Disease Framework Initiative presents an opportunity to build on more than a decade of progress since the PFDD initiative. Multiple concrete approaches would help move the Agency from collecting patient perspectives to meaningfully incorporating them into regulatory decision-making: (1) recognizing patient acceptance of uncertainty as a key consideration for fit-for-purpose development and review; (2) incorporating patient input on meaningful benefits experienced in trials, even if not reflected by established endpoints; (3) establishing formal opportunities for early scientific engagement between patient organizations and FDA review staff, including through formal meetings and consultations; and (4) increasing transparency regarding how patient input informs development recommendations and regulatory decisions.  While our thoughts shared in this post primarily focus on the Agency, we equally support the framework creating parallel expectations for industry sponsors.

We were encouraged to hear stakeholders raise many of these same needs, and even some of the specific approaches discussed here, during FDA’s recent public meetings. The challenge now is to translate that input into concrete commitments and practices under the Rare Disease Framework.

Ultimately, the success of FDA’s new framework should not be measured by the number of opportunities created for patients to speak, but by whether their perspectives demonstrably inform the scientific and regulatory decisions that shape the development of treatments.

The next chapter of patient-focused drug development must be about more than listening. It must be about demonstrating what FDA does with what it hears.