An accelerated approval pathway for complex generics, embracing killer apps, publishing CRLs and a swift kick in the leadership at the FDA all figure prominently.
President Trump has made it clear that he’s looking for a revolution at the FDA, which in turn has raised fears that he’ll appoint a revolutionary deregulator as commissioner who will blow up a well established gold standard on drug approvals.
The only name which has surfaced as a serious contender for the top job at the FDA who would also be welcomed by most people in the biopharma industry is Scott Gottlieb, a former deputy commissioner for policy under George W. Bush, conservative commentator and longrunning critic of the agency as it was handled under the Obama administration.
As a leading contender for this job, Gottlieb’s nomination would conform to the tradition of having a trained physician in the commissioner’s office. And he would also be coming in as a reformer with an understanding of the inner workings at the FDA, able to swiftly execute a series of changes that would meet Trump’s stated goal of accelerating approvals and dramatically lowering some drug prices.
Like the rest of the serious prospective candidates for this job, Gottlieb has been keeping a low public profile, declining requests for interviews. Trying to argue over a specific agenda in newspapers or on TV would only threaten his chances for the nomination, which insiders say is still likely weeks away.
But in a review of his public remarks and background discussions with people familiar with Gottlieb’s thinking, I’ve assembled a to-do list that would likely figure prominently in Gottlieb’s first six months at the FDA.
Even if he doesn’t get the tap, Gottlieb has laid out agency reforms that would likely figure prominently at the FDA over the next four years; a middle way between anarchy and a brittle, bureaucratic status quo, revising but not dismantling the agency’s insistence that any new drug that hits the markets has a clear risk/benefit profile for physicians and patients to consider.
Gottlieb does have some low hanging fruit to go after, with a Republican controlled House and Senate that are likely willing to go along.
First task: Reform FDA rules for approving complex generics. While most of the reformers have concentrated on a backlog of thousands of applications for generic drugs, Gottlieb has been saying for a few years now that the agency needs to have more flexibility in approving generic versions of complex therapeutics, a middle ground between the simple small molecule knockoffs that are relatively easy to get through the FDA and biosimilars, which have a specific approval pathway.
These drugs include some of the world’s biggest blockbusters, including Copaxone and Advair, which are only now on the verge of seeing real generic competition long after losing patent protection. But there’s a long list of these complex generics that can be sped along — provided the Commissioner can get the legislation needed to do that.
“Congress should consider legislation to modernize the generic drug framework to allow FDA greater discretion in the kinds of data it relies on for its generic approvals in this narrow category of complex drugs,” Gottlieb told a Senate committee in October 2016, testimony that was highlighted in a note by Jami Rubin at Goldman Sachs a few days ago. “This would require, for example, granting FDA the ability to ask for more than just bioequivalence and bioavailability data in making judgments around sameness.”
“Congress should be tapped to give FDA the latitude to look at the science necessary to make comfortable and reliable determinations,” he wrote in a column for Forbes back in 2015. Commissioner Gottlieb working with the Trump administration and bipartisan supporters in Congress could make short work of this.
Gottlieb has said in the past that legislation is needed, but an aggressive commissioner could go a long way to clearing the path for complex generics. So look for some quick, broad guidance that would give developers a clear regulatory path for the class, tossing aside the more cumbersome case-by-case method that has been in use — often long after these rivals could have made it to the market.
The advantage here is that Gottlieb could have a dramatic impact in a short period, pointing to an accomplishment that would earn a lot of support from the public as well as lawmakers — even as individual drugmakers try to quietly spear any such threat to their own blockbusters. Just picking off the top 10 complex generics would reduce costs by billions, ushering in new competition.
Changing the rules on complex generics to facilitate approvals while going after the backlog in generics in general will require the agency to at least fill its empty positions. That will require an early exception to the president’s hiring freeze.
Get with the BTD program
Gottlieb has been an unabashed admirer of what FDA cancer czar Rick Pazdur has accomplished with the breakthrough therapy designation when it comes to new cancer drug approvals. Oncology R&D has been transformed over the past three years. Development timelines have been streamlined and cut, in some cases by years, as regulators took a more flexible approach to assessing data and medical needs for dying patients.
But he isn’t at all satisfied that the entire agency has gotten with the BTD program. And he’s likely to address that quickly, putting in a team of regulators tasked with ramping up the review process in specific divisions that have lagged behind.
This is not a topic that Gottlieb has addressed extensively in public over the past seven years, since a column of his in the Wall Street Journal castigated the FDA for sticking with burdensome trial requirements to land an approval. Much has changed since then, which he has acknowledged. But much is still left to be done, a subject he brought up last May in a speech he gave at ISPOR titled “Accelerating Cures: Addressing Unmet Patient Need or Putting Patients at Risk.”
In that speech, Gottlieb focused carefully on how the FDA handles new drugs for rare diseases. As researchers understanding of rare diseases has grown, he writes, it stands to reason that the FDA’s process for reviewing new drugs should speed up. But the reverse happened, as he illustrated with the regulatory history of Aldurazyme, Hurler Syndrome, or MPS 1. There are only about 500 such patients in the US.
As each of the subsequent and different enzyme replacement therapies targeting distinct MPS diseases sought FDA approval, the clinical trial requirements increased substantially. In other words, as FDA got smarter about the mechanism of these treatments, instead of using that knowledge to streamline development, the hurdles grew substantially.
The use of biomarkers as a surrogate endpoint needed for a quick approval is one way that the FDA can advance.
The expertise at the FDA needs to be reorganized, with a new approach to evaluating “trial design, statistical analysis, and the product issues related to new platforms for pursuing biological targets.”
(P)erhaps all drugs for ultra orphan diseases should be reviewed by a separate division just focused on these products – a sort of skunk works for ultra orphan products — where there is more expertise in statistical approaches to clinical trial design that involve open label or single arm studies that are sometimes the only feasible approach in these disease settings. Consultants from the relevant clinical review division could inform the clinical aspects of the review. Right now, it’s the clinical review division that drives the process, with the experts in the product and trial design issues who serve as consultants to the process. This can enable these other considerations to become marginalized, even in cases where they are the more critical and challenging features.
New Bayesian approaches to statistical design may help in certain cases, he said. And Congress could specify where FDA standards could be applied more flexibly, helping regulators abandon a rigid conception that there’s one preeminent standard that has to be applied in all cases.
The FDA also hasn’t just facilitated new drug development over the last few years. It’s also added on new rules related to pre-market development, most noticeably the cardiovascular outcomes studies for some new meds.
Those kinds of add-ons will be rolled back, making it less expensive to get new diabetes drugs to the market — a big issue in that field — with a shift to post-marketing studies.
There’s a variety of ways a new FDA under Gottlieb could adopt new technologies and development designs that would both speed R&D efforts as well as lower the front-end costs biotechs face to get through early-stage research. Modeling and simulation, not a new concept at the FDA, has already been used to scale down the once epic scope of a development program. It’s helped in early dose selection and identifying patient subpopulations most likely to benefit, including often neglected pediatric populations, that can be helped.
PDUFA VI includes a range of features aimed at speeding development, including the better use of biomarkers, adaptive trial designs and better use of all the various FDA programs for accelerating approvals, from BTD to orphan drug designations, which can also be more defined to avoid repeats of deflazacort, the Marathon steroid approved for Duchenne MD and prices anywhere from 50 to 70 times what it’s been sold for outside the US.
Gottlieb’s “killer apps”: get new devices on the market, making the FDA a facilitator rather than an obstacle
Apple’s Tim Cook has been gingerly walking around the FDA when it comes to the new Apple Watch and some of the health applications he’s had in mind.
“We don’t want to put the watch through the Food and Drug Administration process,” Cook told The Telegraph last fall. “I wouldn’t mind putting something adjacent to the watch through it, but not the watch, because it would hold us back from innovating too much, the cycles are too long. But you can begin to envision other things that might be adjacent to it — maybe an app, maybe something else.”
You’ll find Google’s Verily working in the same space, for the same reasons, and with the same regulatory concerns. Drug developers have been increasingly whipped up about the opportunities here. Imagine a device that could alert a patient and physician of heart risks, or a pending episode of major depression or schizophrenia. How well are Parkinson’s symptoms being controlled by a drug?
Apples been playing a slow development game here, knowing that they’re not going to get any help from the FDA. That will have to change. The new FDA will make a point of opening up the regulatory roadway on new med tech, encouraging players like Apple to dive deeper.
And a personal favorite: Publishing CRLs
Gottlieb: “(T)he FDA should be required to disclose its reasons for rejecting a drug.”
In his 2010 column for the Wall Street Journal, Gottlieb signed off on his support for that long-awaited piece of reform. Knowing that the FDA will publish these letters — or provide the contents some other way — would save a lot of time and grief speculating about what’s happening. And it will keep developers on the straight and narrow path as they design trials and map a regulatory pathway most likely to succeed.
The prospect of a public hanging at the FDA would focus developers’ minds wonderfully.
The best place to read Endpoints News? In your inbox.
Comprehensive daily news report for those who discover, develop, and market drugs. Join 25,000+ biopharma pros who read Endpoints News by email every day.Free Subscription