PDUFA VI: Do Ask. Do Tell.

Something that bothered me a lot about the Fifth Prescription Drug User Free Act (PDUFA V) was that when you asked people in industry, what does success look like to you, almost unanimously insiders said, “success means getting it done early and having it done clean.” That’s just punting on an amazing opportunity. If success means fast and clean, you miss the rare chance to bargain hard when the agency is really listening.

As we move towards PDUFA VI, people will look hard at what PDUFA V delivered which was, in many respects, a lot of meetings. Today people are saying, “now that we’ve had the meetings we want action, we want movement forward, we want greater predictability in new, more complicated areas.” It’s going to be interesting to see if industry is really willing to step forward and hold the FDA’s feet to the fire, not necessarily hold them hostage but be tenacious negotiators rather than roll-over puppy dogs.

That which gets measured gets done and the FDA will get high marks for, among other things, Patient-Focused Drug Development. There were many disease-specific meetings and they were very worthwhile and respectfully contentious. There was creative tension.

Now, per PDUFA VI, what is going to happen next? How is the FDA going to work with all of the groups they met with to help them help the agency help patients? How can the agency help these organizations draft guidances? What’s the mandated requirement? How quickly can it happen?

Communication is another key issue. PDUFA V spoke to more and more regular communications post-filing but also during the early stages of the process — and that happened. But what hasn’t changed is who is doing the communicating. Has there been more communications at higher levels when there is scientific dissonance between sponsor and agency? I don’t know whether you can write that into PDUFA, but it’s a significant issue. I don’t know how FDA would facilitate since there are only so many senior folks, but it’s an issue that has to move forward – and PDUFA VI presents that opportunity.

What’s interesting, although not strictly speaking a PDUFA issue, is how is the FDA is dealing with the regulation of opioids. One of former Commissioner Hamburg’s big victories was putting her foot down and saying, “Listen, all therapies have risks, and a broader pharmacopeia within any therapeutic categories is important. We have to enhance education.” So where in PDUFA is the FDA’s mandate to do better physician, pharmacist, patient, and caregiver education in a lot of these areas, especially in areas where the medications are of higher risk – and politically sensitive?

Alas, you can’t hold PDUFA negotiations at Yankee Stadium. PDUFA V was the first time patient advocates actually had a seat at the table. But what about smaller biopharmaceutical companies that aren’t dealing in tens of billions of dollars of issues, who have one or no products and aren’t members of PhRMA or BIO? How do you empower companies who aren’t major players by volume to be a valuable part of the regulatory policy conversation? That’s a tough question. You have to bring more senior minds to the table from companies currently at the table as well as those who are on the periphery.

It’ll be curious to see who attends and participates at the July 15th kickoff meeting for PDUFA VI. I’d like to see more patient groups there. I’d like to see more representation of smaller biotech companies too so they can see first-hand about what’s going on. It needn’t be a secret club.

Should there be a discussion within PDUFA VI of the FDA actually putting on paper new, more segmented rules for bioequivalence? It’s been almost three years since the recall of generic bupropion and the FDA is still dealing with bioequivalence on an ad hoc basis for seizure meds, antipsychotics, long-acting release medicines and ADHD products. Industry has said “enough!” Mallinckrodt is suing the FDA for asking them to take their generic methylphenidate off the market because of bioequivalence issues. A judge looking at this case might say, “You know what FDA? I generally want to give you chevron deference on the science issues, but where’s the guidance?” The FDA should drive the issue rather than litigate the process, and maybe PDUFA VI is a way to move the conversation forward in a collegial rather than a confrontational manner.

The issue of what data can you use in approvals, which is within the current draft of 21st-Century Cures, is fascinating and a potential game-changer — but shouldn’t that more appropriately be a PDUFA VI conversation? Similarly the issue of off-label communications. Better to have it dealt with in PDUFA VI than in the courts. A potential legal decision could be a sledgehammer solution that will do nothing other than empower people with ill intentions. The issue of communications isn’t only about who’s presenting it and in what context, it’s also about the intent. And when you begin to try to litigate intent, it’s a blunt instrument. And what about finally getting real in PDUFA VI about FDA’s role – and resources – in accelerating biomarker qualification?

Another thing, relative to PDUFA VI, is recognizing what was done and didn’t work in its previous iterations. Let’s specifically call out early safety signal communications. The theory was the agency was going to, on a quarterly basis, publish a list of products for which it had enough information to require further investigation. All that resulted in were sensational media stories and too many patients going off their medicines. Communications issues notwithstanding, did this program result in one significant label change or product recall? It’s time to examine the risk/benefit ratio.

Should PDUFA VI change the FDA commissionership from a political appointment to a six-year term, like the FBI director? Take it out of the political cycle. It’s an opportunity to have that conversation. The FDA commissioner counts when the commissioner has an aggressive public health agenda. If the commissioner chooses to just be the public face of the agency, it’s a wasted opportunity.

What’s the difference between having a confirmed commissioner and having an acting commissioner? How does it impact the way the agency operates on a day-to-day level? The answer is that it doesn’t really have any impact at all. The agency continues to run. Interesting fact, the FDA has around 16,000 employees. Within that whole 16,000, there are (give-or-take) about ten Schedule Cs (political appointments). That means the director and every employee, every single one, top to bottom of every center without exception is a career public servant. The value of having a confirmed commissioner is having a long-term leader who is engaged AND who doesn’t have a strong learning curve — a guy like Rob Califf, for example, who can actually say, “This is my mission.” A successful commissioner sells his mission to the senior staff and then it becomes organic.

If you think about PDUFA VI, go back to First Principles. Why user fees? Why was the industry willing to pay for something that it previously got for free? The answer is that industry wanted predictability, whether it’s six months, a year, 18 months, two years, getting a PDUFA date is crucial for drug developers for a variety of reasons. Take the concept of predictability one step further and say, “We want not just an action date but predictability on a whole variety of issues — off-label communications, expedited pathways, postmarketing surveillance, biomarker development, over a broad spectrum of regulatory activities”   — that will lay the groundwork for a more creative and fruitful conversation.

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