Bam — FDAMN!

Bam — FDAMN!

July 15, 2015. The pharmacenti were gathered. Policy experts, provider organizations and patient groups, industry, academics and FDA brass. The clock in the White Oak Great Room struck 9AM. The room fell silent. Smart phones were (mostly) on silent mode.

Welcome to PDUFA VI.

The first public meeting on reauthorization of the Prescription Drug User Fee Act (PDUFA) held few surprises but made it clear that this time around there will be more creative tension.

First up was Acting FDA Commissioner Stephen Ostroff. He began with a nod to NASA’s wondrous New Horizons’ space probe. He offered this alliterative flourish, “Just as with the recent success of NASA’s space probe, PDUFA delivers on its promise because of planning, precision, and predictable performance.” He then called on all present to “aim for the stars” in the forthcoming PDUFA process.

Ostroffian p-values aside, whether or not all parties concerned in PDUFA (those noted above as well as legislators and the White House) can embrace such a Plutonic relationship remains to be seen.

Next up was FDA Deputy Commissioner Rob Califf who said, “an increase in predictability creates a better environment for innovators.” This comment set the meeting’s major theme – that PDUFA VI isn’t just about the founding principle of the user fee concept, ensuring predictability in the review process, but must now also help to facilitate the advancement of regulatory science.

Theresa Mullin, the Director of Strategic Programs within the Center for Drug Evaluation and Research (CDER) then made a point to establish a key FDA talking point – that PDUFA isn’t about policy but rather process. And while that is an accurate statement, it belies the fact that process drives policy. That’s more than semantics. Think about it as the power of the pen – another key PDUFA p-value.

The majority of the day was given over to panels representing the consumer, patient, healthcare professional, industry, and academic perspectives on what should matter most in constructing a thoughtful and forward-looking reauthorization package.

Some highlights:

Allan Coukell (Pew Charitable Trusts) urged that PDUFA VI incorporate funding that would help reduce both the time and expense it takes to design 21st century clinical trials – and that a good start would be funding programs that address clinical trial methodologies. All heads nodded – particularly that of Rob Califf.

Sally Greenberg (National Consumers League) suggested that there should be user-fees for marketing material review – particularly television ads. She also wants DTC review to be mandatory. She commented that, on this point, she “sounds like a broken record.” Possibly, but what is for certain is (in the Age of Caronia and Amarin) its her message that’s broken. In any event, that’s policy – not process.

Paul Melmeyer (National Organization for Rare Diseases) stressed the urgency of thoughtful and aggressive next steps per the FDA’s Patient-Focused Drug Development (PFDD) program. Indeed, almost every speaker spoke about PFDD as the Jewel in the Crown of PDUFA V – but that more needs to happen.

Jeff Allen (Friends of Cancer Research) spoke to the need for the FDA to collect and share best practices per various expedited review pathways. He also pointed to the need for the agency to more progressively consider real world evidence in its design of post-marketing commitments.

Cynthia Ben (Alliance for Aging Research) observed that, “PFDD meetings have led to a cultural shift across the FDA elevating the way in which regulators view the value of patient input in the drug development process,” but “there is no one-size-fits-all solution to gathering and employing patient input effectively.” And on the Patient-Reported Outcomes (PRO) front, “We would encourage the dedication of resources in PDUFA VI to support additional workshops aimed at feasibility and reliability of incorporating PROs in trials for complex diseases.” Specifically, “We would support the addition of user fee funds in PDUFA VI to allow for new guidance on performance outcome measures, observer reported outcome measures, and clinician reported outcome measures.” Bravo.

Maureen Japha (Milken Institute/Faster Cures) asked that the patient voice (no longer “an honorary voice”) be heard earlier and more regularly in the review process, not just at the end per benefit/risk considerations. The call for a more comprehensive and integrated patient voice was loud and clear during the entire course of the meeting. Process or policy? Where you stand depends on where you sit.

Representatives from healthcare professional organizations (the American Pharmacists Association, the American Academy of Pediatrics, and the American College of Cardiology) focused their comments on the need for more global collaboration (sharing rather than stipulating best practices), continuing to modernize the agency’s drug safety system, and the importance of advancing regulatory science – the red thread of this early PDUFA dialogue.

Industry association presentations (BIO and PhRMA) tended to applaud the successes of PDUFA V and pointing to the need for all parties concerned to make further progress across the broad spectrum of both predictability and regulatory science. The key phrase from industry is that they, “fully support timely reauthorization.” And there was much sharing of success metrics – particularly the approval of new medicines (NMEs – a love story). But all is not smooth sailing. Kay Holcombe (BIO) addressed the specter of budgetary sequestration as something that must be addressed. Kay also addressed the need for enhanced scientific communications that do not require an “official” FDA meeting. Michael Werner (the Alliance for Regenerative Medicine) called for PDUFA to empower the FDA to work with outside bodies to help develop development and review standards– an idea that has resonance beyond regenerative medicine (biomarkers, functional endpoints, etc.)

The academic panel added robust ideas to the more general discussion of advancing regulatory science.

Greg Daniel (Brookings Institution) called for a PDUFA strategy that would drive agency coordination of pre-competitive biomarker development as well as a common biomarker lexicon.

Daniel Carpenter and Aaron Kesselheim (Harvard University and Harvard Medical School) questioned whether various expedited approval pathways were focused on medicines they considered “non-transformative,” what they referred to as “designation creep.” Policy vs. process.

Ernst Berndt (Massachusetts Institute of Technology) broached the topic of “adaptive licensing,” pointing to EMA programs and their progress under the Innovative Medicines Initiative. To-date, the concept of conditional approvals has found very little support or enthusiasm from either developers or the FDA. Whether or not Dr. Berndt’s suggestion gets traction will depend on how it resonates with any of the various PDUFA constituencies. The last time I spoke with senior members of the FDA, I heard comments like, “What does that even mean?” And, then again, do drug developers really want conditional approval? You invest a lot of time and money to get a conditional approval and then the agency decides to take the product off the market? Is that something to roll the dice on? Unless and until the FDA can ramp up its pharmacovigilance prowess, any kind of provisional approvals will remain problematic. At the moment, the FDA doesn’t have an eye in the sky.

Rena Conti (University of Chicago) raised the topic of drug sourcing. Is there, she asked, an unintended PDUFA incentive to outsource manufacturing – and what are the consequences? She called for greater transparency in who manufactures what – and where.

The final presentation of the day was by Dr. Janet Woodcock (Director, Center for Drug Evaluation and Research). The items on her short list mirrored many of the day’s presentations and themes. Specifically she mentioned the need to advance the agency’s Sentinel program, continue to develop a more advanced view of benefit/risk – and one that includes a more dynamic inclusion of the patient voice, next steps on Patient-Focused Drug Development, better and more regular communications with developers, biomarker development (“still a tremendous amount to be done”), the need for the agency to recruit and retain the best and the brightest, and, of course, advancing regulatory science writ large.

She also warned of getting off the process track – a clear warning shot across the bow to those ready to hang multiple ornaments on the PDUFA Christmas tree.

At the conclusion of the day’s session I was pleased to be able to offer some advice during the open public comment period. Here’s how I concluded my remarks:

“PDUFA VI must continue to provide predictability in the review process and advance regulatory science over a variety of initiatives. But most importantly, PDUFA VI must answer the question of “What next?” for many of the agency’s existing initiatives (biomarkers, risk/benefit evaluation, patient-focused drug development, 21st century clinical trial design). PDUFA VI must redefine what “success” looks like. Dr. Ostroff asked us to aim for the stars, but let’s not settle for an easy, clean, comfortable, and low-altitude orbit.

Per aspera ad astra – Through hardships to the stars. We’ve had FDAMA. We’ve had FDASIA. Now we need FDAMN – FDA Momentum Now.

Nobody said it was going to be easy.


Peter J. Pitts, a former FDA Associate Commissioner, is President of the Center for Medicine in the Public Interest and an Executive Partner at YourEncore.




Morning Consult