Interview With FDA’s OND Director: Approval Standards, Transparency and More Peter Stein, director of the US Food and Drug Administration’s (FDA) Office of New Drugs (OND) sat down with Focus at FDA’s White Oak campus for an exclusive interview to discuss some of the criticism FDA has received in recent months with regard to the pace of its drug approvals and the possible lowering of its approval standards.
Stein also discussed signing off on Sarepta Therapeutics’ Duchenne’s muscular dystrophy injection Vyondys 53 (golodirsen) in December, and whether FDA can do more to speed confirmatory trials for accelerated approvals, as well as more on FDA transparency and OND’s reorganization. Below is a lightly edited version of that 30-minute conversation.
Focus: A lot has been written in recent months about how the FDA is increasingly approving more drugs based on less clinical evidence, and that more trials without a control arm are being allowed as evidence for new approvals — would you agree with these assessments? Have concerns been raised within FDA about this apparent shift?
Dr. Stein: I think the answer is that you have to consider how we make decisions based upon what’s in front of us, the kinds of drugs that we’re regulating and that are submitted for approval. I mean, the short answer is no, I don’t think our standards have changed, I don’t think the evidence, that when you look at a similar type of application, is different than what we’d required decades ago. Other than there have been some changes to tools. But when you look at what’s required to meet our standards, I don’t think it’s changed. But if you look back 20 years ago and compare to the last several years, we were dealing then with drugs for common chronic diseases, COPD and asthma and diabetes and hypertension and migraine. And if you look in the last couple years, we still see some drugs for chronic diseases, but even there, it tends to be subgroups and populations that were undertreated with drugs previously available, and what we’re seeing is a dramatic increase in drugs for rare diseases.
That’s what’s really changed, and it’s been a remarkable change, the numbers of drugs for cancers, especially for subtypes of cancers and rare cancers where we’ve identified molecular drivers and seen dramatic responses. But do those type of drugs need to be considered differently, you ask, are we using more single-arm, historically controlled trials? Yes, and that’s because we’re dealing with more rare diseases.
If you look at that same type of drug 20 years ago, and look at like vs. like, and ask if it’s different? And I would posit the answer is no. We are accepting smaller programs and more single-arm trials where those type of programs are appropriate. If you compare the apple to the apple and not the apple to the orange, I don’t think you see a meaningful difference when it comes to the packages that we’re basing our approval decisions on.
If you have, for example, a rare cancer with a molecular driver identified, and a drug targeting that molecular driver, we’ve seen some remarkable responses, dramatically different than what was identified in historical controls. A randomized trial isn’t necessary to get a very persuasive and compelling case for that drug to have a meaningful and important benefit for patients.
It’s important to realize we’re always dealing with uncertainty, and with rare diseases, where you’re talking about a progressive, severe and ultimately fatal disease, patients and physicians are willing to accept a bit more uncertainty. We have to regulate within that context. How much uncertainty can we accept in the face of patients who are in marked and desperate need of therapies – that’s always a balancing act. We don’t want to give false hope but we want to try to get to an answer and accept some uncertainty. And certainly in those settings, I think that’s consistent with our regulations and the statute.
Focus: On this idea of uncertainty, there was a little bit of controversy over the approval of Sarepta’s Duchenne muscular dystrophy drug golodirsen and I wanted see if you might be willing to address some of the questions raised in the initial complete release letter?
Stein: I’ll leave the details to the letters that are in the public domain. I think it’s important to point out: We embrace disagreement. Scientists disagree and we think that helps to get to the best possible decisions by allowing and fostering and embracing differences in scientific opinion, but ultimately decisions have to be made. The division came to one decision, Dr. [Ellis] Unger, who I have tremendous respect for as a scientist, came to a different decision, and I reviewed it and came to a different decision.
We all provided our rationale for the decisions. These are challenging datasets when you’re looking at rare diseases and patients in need.
What I would say, it’s important for me that the company was in fact going to be able to progress and do the study, and as I indicated in my letter, the Sarepta study is very much well underway and they’re getting far along in recruitment and to me, part of the whole paradigm is, we’re going to expect that within a reasonable amount of time, as soon as possible, we’re going to have more robust clinical data to validate and confirm that we see that the benefit we hope to see is in fact seen. Knowing that their trial was well underway and that it’s properly powered to assess the issues was an important point to me. It’s one thing to accept the uncertainty, and quite another to allow it in an unlimited way. We accept some uncertainty, but we look to see trials ongoing to allow us to confirm the benefit is there. You may have also seen that I asked Sarepta to confirm that that they understood that the trial would look for benefit and if we can’t find a benefit, the drug should come off the market.
Those are important points, this isn’t an unlimited, endless determination. We’re going to get more information to make more refined decisions as this goes forward.
Focus: What more can FDA do to ensure that companies winning accelerated approvals are completing their confirmatory studies on time? Do you think there will ever been fines for companies that don’t meet their deadlines for confirmatory trials?
Stein: We’re looking at it now, and it is very important. It was really important with golodirsen and I think that should be the rule, we should do everything we can to ensure we are putting forward a feasible, conductible trial where we will get the information in some reasonable amount of time. Sometimes it’s more challenging and longer than we think.
I will say there’s room for improvement. I think oncology has published their experience and have largely shown a high rate of confirmation in a timeline that’s generally reasonable. Is there more we can do? Yes, and we’re looking at this to optimize our interactions with sponsors and the kinds of trials designed to be feasibly conducted and we’ll be monitoring this, because again, it’s very important we don’t put a drug out there and then not have the subsequent data that we know we need.
I can’t speculate on the fines, but we’ll look at the tools we have, and see how to better cooperate with companies to get their studies off the ground. I think it’s always better to start from a position where you have a study that actually can address the issue, that’s feasible and where we’ve worked closely with the company to ensure the design will answer the questions that we have, that’s the better course, and that we carefully monitor it to make sure companies are doing what they’ve committed to do.
Focus: In what ways do you think FDA could be more transparent? You spoke at the RAPS conference Convergence last fall about how stakeholders looking to retrieve some of the data currently available in FDA-released drug approval packages would need to use the Freedom of Information Act (FOIA) to obtain some of that information under a new plan – how is that new plan progressing?
Stein: I think I misunderstood the question at the conference, and I wasn’t correct, but everything that was in the prior action packages will be available in the new packages. There are still things like supplements that might go through FOIA, as they currently do, but the packages are smaller because we’ve really reduced duplication, but all of the elements of the package are going to be in the action package and available, so there won’t be any meaningful difference in what’s available for anyone who wants to look at the data or our analysis and decision making.
The new integrated review has a second section with a problem-focused discussion of the issues and it provides a comprehensive assessment, but then there’s the appendices with lots of tables and figures that weren’t as critical in the decision as what we put in section two – the things folks are looking for will be available and I think I miscommunicated that. Yes, it’s fewer pages because we’ve eliminated every single review that goes back over the design of the program, design of studies, reviewing things from scratch, presenting efficacy twice, the duplication is eliminated but not the information people were looking for from prior action packages.
We’ve got teams doing the integrated reviews and we’ve completed some and that’s a work in progress, we’re looking at how well they’re achieving our goal, which is greater clarity on what the critical issues are and greater clarity for us, and patients and physicians understanding our thinking about each of the applications. I think we’re more transparent in the integrated review and the issues will be upfront, identified with sections to discuss whether it’s an efficacy or a safety issue. I think it’ll be clearer. The new process includes a lot more team interactions and discussions with management and working groups dealing with the issues. I think people will find that what they’re seeing gives them a greater insight into our thinking and analysis than the individual reviews.
One thing I would emphasize is that we embrace dissent. I think it’s really important in our processes that we have robust scientific disagreements. And this new template in no way stifles that. We have people who disagree with conclusions and say they don’t concur, and then we make sure the team addresses that disagreement. We must come to a decision and an assessment, but we want to embrace differences of opinion.
Focus: Can you talk about how the OND reorganization is helpful for OND?
Stein: I do want to step back and say this modernization is really more than just the restructuring, but we’re looking at a lot of processes, like the application review of NDAs and BLAs (integrated review), that’s an ongoing workstream, we’re looking at how we do 30-day INDs, we’re looking at postmarket workstreams, put more into an IT system, and workstreams on talent and professional development.
The restructuring was really to make OND more therapeutically aligned and to make the divisions more right-sized. So when I came, there were some divisions that were really huge with broad ranges of responsibility, often coming up to a director and deputy director, but really this huge range coming up to small leadership, which was a challenge. So we tried to right-size the divisions, but I think even more importantly, we wanted to get divisions together that were more disease-focused. So the DGIEP [Division of Gastroenterology and Inborn Errors Products] is the best example: that was just a concatenation that didn’t make a lot of sense, so now we’ll have a new division that’s going to be rare disease and medical genetics that will have the inborn error teams, as well as our rare disease group will have a division of gastroenterology and a division of hepatology.
For large divisions, like the division of neurologic products, we split in half so that the leadership ratio to regulatory workload is more rational and the intent of that is to allow our leadership to be able to be more strategic, externally-focused and to lead and contribute to the broader needs in their therapeutic area. Many others offer great examples, look at what we’ve done in oncology [with the Oncology Center of Excellence].
The concept of putting the offices together that are more therapeutically aligned. We’ve got the office of inflammation and immunology where a whole range of drugs actually cross divisions. We have drugs that are for dermatologic conditions, pulmonary and rheumatologic conditions, and all those three divisions in the same office enhances the collaborations and interactions between medical staff and regulatory program management staff in ways I hope will engender more conversations to further enhance drug development and our skills and how we regulate drugs.
Divisions of pharm/tox in each of the offices will foster movement so they can get broader experiences to enhance their understanding and breadth of vision when looking at an IND.
It’s early days, but I think the enhanced collaborations and interactions will allow us to do our job better and I’m excited to see how it plays out over the next couple of years.
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