There is much change happening at FDA. In the wake of the April 1st reduction in force, there has been a great deal of uncertainty about what the impacts will be. This rings particularly true amongst the rare disease patient community, along with many small biotech companies (and their investors) that take on the risk of developing orphan drugs for exceedingly small patient populations.
For nearly a decade, we at HPM along with the rest of the rare disease community have been advocating for greater consistency in application of scientific judgment and regulatory flexibility in the review of applications for rare diseases (see our call to action here). We knew that expertise in the "science of small trials" comes with years of experience of conducting drug reviews, and that certain review teams within CDER and CBER have more experience overcoming the well-known challenges in rare diseases. Last year, FDA heard this message andestablished the Rare Disease Innovation Hub to create a greater teamwork approach to considering rare diseases scientific and regulatory issues. But was this new flagship "hub" retained by the new administration?
Patients and their families and caregivers have long fought to have a seat at the table with decision-makers. This has been a slow culture shift to see patients as having a voice, dating back to the HIV/AIDS crisis in the 1980's, expanded to the cancer advocacy movement in the 1990's, and now with rare disease patients stepping up to have their voices heard to fill the gaps in the medical literature that is so limited in rare disease. Their advocacy has led to long-standing, highly successful programs (i.e., Patient Listening Sessions and Patient-Focused Drug Development meetings) to more systematically involve patients, allowing them to educate all stakeholders about their lived experiences and treatment needs. But are these programs still operating?
And beyond the RIF, where does rare disease and patient engagement sit in the priorities of newly confirmed Commissioner Makary's MAHA (Make American Healthy Again) priorities? In this post, we've summarized what we've learned in the weeks post-RIF, as well as share late-breaking insights from Dr. Makary's first interview as Commissioner published late last night.
Does the MAHA platform have a plan for those suffering from rare diseases?
As for the Rare Disease Innovation Hub, while those who launched the Hub (previous CDER and CBER Directors, Patrizia Cavazzoni and Peter Marks, along with CBER Deputy Julie Tierney) have departed the Agency, the key person hired to operationalize the Hub, Amy Comstock Rick, the Director of Strategic Coalitions, remains. Other key rare disease functions like the CDER Rare Disease Team (led by Kerry Jo Lee) and the CBER Rare Disease Liaison, Julie Vaillancourt, are still boots on the ground too.
Recent remarks from Amy Comstock Rick signal continuity. Speaking to the Biopharma Congress, she shared that the Hub's goals of efficiency, centralization and coordination fit with the Trump Administration's current focus for the FDA (US FDA Rare Disease Innovation Hub's Goals Align With Trump, Leader Says). Her comments should reassure patients and product developers that the progress made with the launch of the Hub is maintained.
When created in 2024, one of the goals of the Hub was collaboration between CDER and CBER. This goal now seems to align with reported plans to merge the various FDA Centers. Although details of the proposed plan to build a unified therapeutic product center are sparse, one could envision enhanced collaboration across orphan drug and biologic review in furtherance of that common goal.
More recently, in his first interview as Commissioner, Dr. Makary took the opportunity to address the need for therapies for those living with rare diseases, calling out ultra rare patient populations in particular. He shared his vision (the full interview is available here):
When you are talking about rare diseases, a genetic issue that affects 52 kids in the world and that's a real thing...or 15 kids..., you can't expect the companies to do a randomized controlled trial. You'll kill innovation. You'll kill investment in those innovative ideas. You've got to say, "Hey, this is a very difficult condition. It's incurable. It's fatal. It's a permanent disability. We're going to customize the approval process to the condition. And, so, we're going to be rolling out a new pathway for drugs, which is a pathway based on a plausible mechanism. If there's a rare condition or a condition that's incurable that affects a small number of people, we may be approving drugs based on a plausible mechanism on sort of a conditional basis.
Let's say there's a condition that affects 75 people in the world and there's a treatment that makes sense physiologically. The mechanism is scientifically plausible that this treatment would help these individuals. No one's forcing these medications on these individuals. If they want to try these new medications even though we don't have a randomized controlled trial because it's not feasible, we will allow that and at the same time monitor everybody who gets it so that we can make inferences as soon as the data speaks with a signal in the data.
The approach to development and regulatory pathway to approval for orphan drugs has been ever-evolving since the Orphan Drug Act was passed in 1983. While FDA has a long-standing history of exercising reasonable judgment when considering drugs for rare diseases (see our previous analysis here), asking FDA officials to "color outside of the lines" can only go so far. Dr. Makary's proposal for a mechanism-based conditional approval approach to ultra-rare disease holds great promise.
We have seen firsthand the dire consequences of trying to apply regulatory standards that date back to the 1960's (when the "substantial evidence" requirement was first established) to rare disease settings. We have seen development programs be halted despite great promise, and scientists' life's work, patients' sacrifice from participating in trials, and difficult-to-obtain investment dollars be washed away when impractical study designs were expected. As a result of our cumulative experience across many dozens of ultrarare products in development, we at HPM have been advocating for a similar change to the standard of approval of drugs for ultra rare diseases. We want to give FDA review officials the tools they need to be able to reduce barriers and "customize" what development looks like for ultra rare products (see, e.g., coverage of Frank Sasinowski's remarks at the May 21, 2024 EveryLife Foundation for Rare Diseases Scientific Workshop, Debating a new pathway for ultrarare).
Where does Commissioner Makary see a place for patients and their loved ones?
Based on our experiences working with patient organizations, it appears that both the patient affairs team responsible for Patient Listening Sessions within the Office of the Commissioner, as well as the Patient-Focused Drug Development (PFDD) staff across CDER and CBER are intact and operational. These programs have been successful in systematically eliciting the patient perspective on specific diseases and their treatments. The program helps FDA understand the context in which regulatory decisions are made for new drugs.
The flagship PFDD program, which consists predominantly of patient group-organized Externally-led Patient-Focused Drug Developments meetings (EL-PFDD) has been active. The current webpage for EL-PFDD lists at least 6 upcoming meetings, primarily focused on rare disease populations (Upcoming EL-PFDD Meetings | FDA). We know that at other EL-PFDD meetings have been granted in the last couple of weeks too. Continuation of these meetings in the face of other programmatic cuts is significant and gives us hope that the patient voice will continue to be heard.
Beyond existing programs, yesterday, Dr. Makary announced a new policy on individuals serving on FDA Advisory Committees, which includes an important commitment to include and perhaps expand of patient and caregiver participation. The announcement states, "As part of this effort, the agency will prioritize and elevate the role of patients and caregivers, strengthening the voices of their communities." FDA has long-included patients and caregivers as voting members on advisory committees for drugs and biologics, as Patient Representatives, however the program staff have often not been given enough time or resources to recruit individuals with direct disease experience to participate on a particular committee. We hope the Commissioner's prioritization of the patient voice will lead to a better-resourced Patient Representative program.
What should rare disease and patient stakeholders look for from here?
With every new administration comes change. Experience tells us that top-down policy priorities take time to have an impact on the day-to-day review work, if they do at all, as FDA leadership have many competing priorities and there will necessarily be public health emergencies that pull their attention. Ultimately, predictability and continuity of the drug and biologic review work at FDA are what drive investment and, therefore, innovation in medical research. The maintenance of rare disease and patient-focused personnel at FDA, in addition to the scientific and clinical reviewers themselves, many who have been staunch advocates for patients and their families, offers promise that innovation will not slow down.
However, the proof is in the pudding, so the community should keep an eye on the level of engagement review staff are able to maintain (including in-person sponsor meetings with FDA to provide expert guidance) and how well the Agency is able to meet its review timeframes (e.g., PDUFA dates for NDAs and BLAs being reviewed). We can be excited for new policies while also expecting accountability.
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