The Future of Drug Regulation: An Interview With Center for Drug Evaluation & Research Director Janet Woodcock

FDA’s top drug regulator sat down for us for an interview about the agency’s efforts to build a higher quality regulatory system in the US—one that focuses on the “content” of regulatory standards rather than just the process. The discussion touched on the need for new and improved standards in classes like weight loss and rheumatology (albeit for very different reasons); the characteristics that make for good drug reviewers (and their managers); and on the drug center’s responsibility for preserving private sector drug development.

Research Director Janet Woodcock

FDA's top drug regulator wants to build a higher quality regulatory system in the US—one that focuses on the "content" of regulatory standards rather than just the process. In a wide-ranging interview, we discuss her vision for a quality regulatory system, touching on the need for new and improved standards in classes like weight loss and rheumatology (albeit for very different reasons); the characteristics that make for good drug reviewers (and their managers); and on the drug center's role in preserving private sector drug development.

The RPM Report: During the Food & Drug Law Institute annual conference in April, you talked about the importance of focusing on the content, rather than just the process, in building a quality regulatory system. What did you mean by that?

Center for Drug Evaluation & Research Director Janet Woodcock: We set standards for regulated entities, and then we check their work against the standards. It is everything from GMPs to what you have to do to get on the market with a new drug or generic. And each one of those is standards-driven. All too often, those standards aren't clear enough. That is what I mean by the "content." I have been trying for a long time to improve the content of the standards.

There are some aspects of current Good Manufacturing Practices that always bothered me. It is kind of like "we know it when we see it." The "current" is "what is everybody else doing?" That is what you have to meet.

We are really talking about quality of a pharmaceutical and what is the bar to show adequate quality. So we've spent six years on the pharmaceutical quality for the 21st Century effort, where we are actually trying to make standards that incentivize companies to use the most modern science. Instead of saying, "GMPs: you check these boxes," you say "What are we trying to achieve?" You can achieve that many different ways, so it is a standard that is becoming clearer—we hope—but is results driven. Hopefully the content of that standard will become clearer.

We are working on clinical trials too, because long ago, we got the Good Clinical Practices harmonized through the International Conference on Harmonization. Through the ICH process, we took a common denominator—maybe the highest common denominator—or whatever people could agree to. And that was a great achievement to get good clinical practices harmonized.

But if you look at it, to a great extent, it is check box driven. That is much better than we had before, which was no harmonized standard, but it was not results-driven.

What are we trying to achieve in doing a clinical trial? We are trying to develop reliable quality data we can use to make regulatory decisions, and we are making sure we protect human subjects at the same time. Those are the two things you are trying to do. There are probably many ways to try to do that, rather than having a rote way of doing things. That is why we are doing the Clinical Trial Transformation Initiative to try to really think through what is the content related to good clinical practices, and how we can innovatively improve that so we do it in an efficient manner.

What about standards for safety and efficacy, for getting onto the market?

What disturbs me about that is that what happens now is that people bring us development programs that may have cost $500 million to complete, and they say: is this good enough? And we might take it to an advisory committee and then everybody scratches their head.

What would really be preferable is to determine with the patients and the treating physicians in a proactive way, before the development programs are done, what are the weights of benefits and how do people count them? What do they look like? How would you evaluate them? How do you do the best possible trial and see if this is going to happen? What are the harms and how do they weigh it against the benefits? Lay that all out in advance and then have people do development programs against what are basically consensus standards.

Right now we put out guidances. Many of them are out of date. We put them out and it is only a small circle who participates. It is announced in the Federal Register. I'm not sure we have real patient input, authentic input from the patient community. Or even from the treating community, outside of a small group of people, like whoever happens to be on an advisory committee at that time.

We have been talking to the industry about this.

We have been having a lot of trouble with obesity drugs lately so we are starting a process with George Washington University. They are going to serve as a neutral convener and they are going to have a series of meetings that include patients, patient societies, bariatricians, ethicists, regulated industry, different regulators and so forth. We are going to talk about obesity and what are potential benefits you could get from reducing weight, and what evidence is there about their benefit. What are the harms that we are considering in these obesity drugs and how do you weigh those two?

Patient-Centered Drug Development

THE RPM REPORT: So the idea is that if this process is useful in weight loss, you would think about applying it in other areas?

A: Exactly. We've done it a few times. I'm a rheumatologist. When I first came to CDER, we developed a new guidance for rheumatoid arthritis. Since then we've had very effective drugs developed. There's been a revolution in rheumatology.

I've been talking to the rheumatology community and it is time we need to rethink this. The guidance is no longer as relevant because we have all these active treatments. I remember when we developed that guidance, people told me—I remember this vividly in a meeting we had—they said don't even bother developing a definition of remission, because we don't see remission in RA. Now we get about 50% maybe. We still are arguing about the definition of remission, but we can get people down to a very low level of activity. That is the treatment target, to reduce the disease to a minimal level and then we know people won't progress and destroy their joints or anything. But in that milieu, we have to have a different guidance than we did back then.

That's the problem. That is why it is hard for the FDA to keep up.

But I really think we need to have this content. What do patients think? What do the treating clinicians think? What are the tradeoffs between the harms and the benefits? How do the patients weigh them? Lay that out and develop better pathways than we have right now.

THE RPM REPORT: Who in CDER is managing the work on obesity?

A: I am managing it out of my office, because the new drugs folks are so busy with their user fee goals. That is part of the problem. This sort of prospective, proactive thing isn't built into the process as something we are able to do.

THE RPM REPORT: In ideal world, that would be built in to the user fee model?

A: That would be built in, because I think that would benefit the industry.

We are also developing a structured framework for how we describe benefit and risk. We are piloting that. We have gotten pretty far. There was the New York Academy of Science meeting. We have iterated pretty far ahead of that already, and now we are trying out a new version.

It talks about how do you really rate this harm, rate that benefit, what does it really mean to patients. That kind of information is very important.

Structured Risk/Benefit Framework

THE RPM REPORT: A structured framework for risks and benefits would probably be iterative forever, right? You can constantly improve that tool.

A: Exactly.

Ideally at the end of the day this would be our framework for talking about how you make the benefit-risk assessment, because right now it is ad hoc. The first thing we are doing is to pilot putting this in the review process as a kind of a summation. You go through all this data: what is the bottom line? But we need a lot more patient input and treating clinician input about how they weight these things.

The International Foundation for Functional Gastrointestinal Disorders just did a big survey of irritable bowel syndrome patients and how they rank symptoms. They actually asked them the tradeoffs, like how much mortality risk would you tolerate for amelioration of your IBS symptoms. That kind of input is very important for people to understand.

THE RPM REPORT: Is there a way to build in the patient perspective at the end of the process? There is nothing like actually seeing the actual data and looking at the same risk-benefit framework that you had in the abstract and now you have a real thing.

A: I would think that would be the obligation of a sponsor to get a professional society together because we can't do polls. But there might be ways to collect information in that structured way about the results.

THE RPM REPORT: As it stands today, I assume you would be prohibited from sharing the clinical data with outside stakeholders. That would still be considered trade secret?

A: We would probably release that sort of thing at the advisory committee. I hope this is successful, and so far it has been, that we start to structure our presentations and our way of thinking along this framework.

We have done some internally contentious things and we have laid them out this way. Part of this is, it is a way to surface your assumptions and communicate them. Why do you think this is such a high risk? You have some underlying reasons that often are not articulated. Why do you think this is a great benefit? Surface those reasons.

Usually we need to hear patients tell us, otherwise we are just fantasizing about what we think the patient thinks. But that has to be collected long in advance.

We are doing a lot of work on patient reported outcomes, so we will be able to hear from the patient's own voice how they experience the benefits and how they experience some of the harms of a drug in the trials. That would be very helpful to help weigh into the equation.

Input From Sponsors and Society; Regulators "Caught in the Middle"

THE RPM REPORT: Say a drug sponsor is interested in a different class but is convinced you are in the same position you are with weight loss and obesity. If they tried to organize something similar to what you are doing, would you find it credible?

A: I think that it is really hard for an individual developer. They might ask a medical society, but they need to give them an unrestricted grant.

THE RPM REPORT: The process to engage patients and providers is fascinating. Right now, there is a different process that exists where taxpayers can weigh in as well, and that is a member of congress sends you a letter or challenges the commissioner at a hearing. You are getting feedback from taxpayers I think that some type of drugs shouldn't have been approved, or are too expensive or you putting too many resources against this or not against that. Is there a better way? Is there a way FDA can be more proactive in engaging society, distinct from the patients.

A: Society doesn't have an opinion on specific risks and benefits. They react to the facts of the day. Individual members of Congress are reacting to things that happen in their district or individual interests that they or their staffers have. I don't think that they represent society or patients globally on specific diseases. We have to respond to the laws. They set the current standards, so that is what we follow.

THE RPM REPORT: That is a pretty good mechanism now that I think about it. If society really does have an opinion, pass a law.

A: There is a discussion every five years now. PDUFA and the other user fees provide a vehicle for everybody and their brother to get their licks in about what they think should be changed about the system. We observe that and we listen to that.

THE RPM REPORT: Has that become counterproductive? If you are trying to build a better system, you can't be on a zig-zag every five years.

A: You could build a better system through legislative processes, but I don't think it has happened in this particular case.

I think that may reflect the tremendous polarization of our society around issues that are less related to drug regulation than they are to health care: issues about cost of health care and the fact that our health care in this country is for profit. Some people think that is the only way and other people think that is a national disgrace. We are caught in the middle of that even though we didn't generate that system. The drug regulatory system is kind of caught up in that.

In my opinion, people rarely actually look at what we do, except through the lens of some other agenda. Some people are sort of therapeutic nihilists and they believe drug companies shouldn't be selling drugs and most of them are bad for people. Or all the patient groups who have unmet medical needs who realize, which I think is actually true, that the pharmaceutical industry is the only hope for more treatments for their condition, but that their constituents suffer. So they tend to be overtly supportive.

These folks can't get together and talk to one another, and it is unrealistic for us to resolve their differences.

Saving Private R&D

THE RPM REPORT: It appeared to me that you were really struck by some companies' decisions to cut R&D and the fact that they appear to have been rewarded for it in the way that they most care about it, their share price went up. How big an issue is that? Is it part of FDA's mission to make sure that pharmaceutical R&D doesn't die?

A: Our mission is to promote the public health as well as to protect it. What has decreased cardiovascular disease, for example, or cured cancers in some instances, has been mainly drug therapy. But the business model pharma has isn't the only business model. It isn't our role to decide that.

I think that probably the biomedical research enterprise has been overbuilt. I have been saying this for 10 years at least: there is much more pharmaceutical companies can do in the precompetitive space. But instead they decided to build their own soup-to-nuts enterprise and it has become too expensive to sustain.

Even if we approve 50 NMEs every year, is the health care system going to pay massive increases for all of those to sustain the R&D enterprise? Probably not.

They are going to have to change their business models and I think they are very well aware of that.

On the other hand, I'm not in the camp that says that drug development should go away, because I'm not sure what would substitute for that. Because venture capital is drying up, small biotechs are not doing well either. So who is going to develop these drugs? It is not the government.

THE RPM REPORT: Some venture capitalists complain that FDA has become impossible, and that's why they don't invest in biotech anymore. Is there anything you can do to change that perception?

A: McKinsey has published a report and they looked at Phase III failures. 50% of the failures in Phase III were due to the product not having an effect against placebo. I really find it hard to imagine how FDA could cause that.

This year actually we are having a very high first-cycle approval rate of NMEs. That's because many of the drugs sponsors are sending us work really well, against whatever they are comparing them to. Our mantra has always been: if you send us really good drugs we will approve them really fast.

THE RPM REPORT: I saw you were quoted elsewhere saying you thought there would be more new molecules approved this year than last year. I was surprised to read that, first of all because there were so few submissions last year. But I was also surprised that you would invite being judged on that score. I always thought the center would prefer not to be judged on the number of approvals.

A: We would prefer that. The point I was trying to make was not, look we are approving these drugs. Rather, I wanted to make clear that it is not all doom and gloom out there. A lot of these drugs that we have approved in the last five months have been very innovative, or they've been for unmet medical needs, they prolong survival, they have resulted in people apparently having profound response.

The hepatitis C drugs could potentially be curative in a number of the patients. These are results we have not seen before. Melanoma, a survival advantage. We approved a drug for lupus, the first drug in 50 years. We approved an indication, not a new NME, for Wegener's granulomatosis. We've never approved anything for Wegener's granulomatosis before. It goes on and on.

Our staff feel really good about reviewing innovative new therapies. We are promoting the public health. And we didn't take very long to get these out.

As for the numbers, we didn't get them all in last year. Some of them we are approving early, because they provide a benefit. That is really what I was talking about.

We keep telling people we can only approve drugs if they come in the door.

We have always been blamed for every plight of the industry. But take an objective look: biotech has never paid very well, right? The pharmaceutical industry had very high returns in the 90s. I don't know why anyone would think that would continue forever. First we had managed care, now we have catastrophic thinking: I just have trouble imaging how very expensive cancer drugs, unless they have a tremendous effect, how the health care system is going to be able to afford all this.

Did the FDA cause any of these issues? I don't think so.

We do have standards, and we try to make them societal consensus standards, because it's a trade-off between harms and the benefits.

The Best Reviewers; The Best Managers

THE RPM REPORT: To have a quality review system, you have to have quality reviewers. Is there any way to get them, other than to train them yourself?

A: We have a multi-discipline team review, with the equal voice, and the way things are set up under the 21st century review process, things are very good with the contribution of different disciplines. As we get further into mechanistic drug development, the role of the clinical pharmacologists and chemistry even and some of the other people is going to become more prominent. Already we've approved some drugs because of our modelers who modeled the appropriate dose or endpoint.

But as far as the medical staff—one of my daughters just finished her first year in medical school. It hasn't changed since I went to medical school. They have more material that they have to memorize, more biochemistry, but it is all memorization. But there is nothing about data. People are not trained in drug development. There are cancer centers everywhere. There are molecular genetics centers. Where is there a center for clinical trials in the US? We should have institutes for clinical trials everywhere. Where is the intellectual firepower and the scholarly programs on what is central not just to drug development but to comparative effectiveness? Where are we going to find these people?

I call it medical evaluation science. How do you evaluate those medical technologies? We have been in this business for a long time, but we have to train them on the job.

THE RPM REPORT: The knowledge is here in a relatively experienced group of people, but you could all leave and who would know how to do it?

A: We have guidelines, but many are process guidelines. Like how do you review an NDA, and we have a whole template, but you can just go through and plug in everything and you have no idea what you have done.

We need people who are data people, who are critical thinkers, who can sit back and say, "What could have gone wrong? How come we got this result? Have we missed something? What could we have missed? This odd side effect here is listed 5 or 7 different ways, but isn't this the same thing?" That is the kind of person who could be a criminal investigator or a financial wizard (with medical training), someone with a very inquiring mind but is good with data, good with numbers and understands randomization.

We have people we hire in who never get randomization. They have to go do something else.

THE RPM REPORT: If you had an open division director position, what would be the most important thing to look for—for someone who is going to sign the letters?

A: The best division directors I have are strong scientists and they also are decent managers. That's what is really hard to find.

By strong scientist, I mean somebody who can think through all these complicated questions. We deal with complicated questions all the time.

On the management side, the question is how do you run a very high level scientific organization that is cranking out scientific decisions all the time and have it decently managed so it can function. We have good people coming up through the ranks.

The way we have it structured that the managers in new drugs sign, we have to have the content experts, but that does create problems for us.

One idea would be to further empower project management staff. But in PDUFA we had to track 33,000 goals in the last five years. So our project managers have to write those down, they have to track our performance and report on how we do against all these goals and actually achieve all the timelines. It is ridiculous.

Under the 21st century review we have the cross-disciplinary team leader position, which is a temporary position. You head up a review team and you are a team leader. It may or may not be a clinician and that is a big shift. It might be the clinical pharmacologist, it might be the statistician, but they are the lead in managing that review.

It isn't the division director. The division director is more like a portfolio manager and also has to make the final decision based on a team recommendation.

How Consistent is FDA in its Decision-making?

THE RPM REPORT: The perception now is that the same application may or may not be approved in some cases based solely on who the division director is. Is that a fair perception? Is that inherent in the fact that you have human beings doing the work and they are different people?

A: I think we try for as much consistency as possible. I don't think we always achieve that. Partly that's because our decisions are a matter of judgment. I would say on all the clear cut ones, we do just fine. Many of them are very clear cut: they met what they intended to do, there weren't any ugly surprises and so forth.

But there are the borderline decisions. And of course what is "borderline" depends on your perspective. If you are a company and your investment has been in the product, you think it's the best thing since CPR or something like that. That is the problem we run into. Maybe more objective people would say this is just another N in a class and it is not providing anything new except some uncertainty about risk.

I believe there are a few true inconsistencies, especially on the margins where it could easily have gone one way or the other, one decision may go and one may say no.

I believe much of this talk on the street though, which has been going for 30 years, is due to the fact that where you sit so much influences your perception. It is amazing how true that is.

THE RPM REPORT: Structurally, you were directed to draw a brighter line between pre-market reviews and post-market, especially safety oversight. Would an ideal regulatory process have a more combined group, where it is all one activity?

A: From my point of view, we have a matrix organization now. It used to be chemists worked for the doctors in each division. I put a stop to that immediately when I came to CDER, because doctors usually don't know anything about chemistry. Talk about inconsistency, each one had its own chemistry standards.

OSE does pharmacovigilance, pharmacoepidemiology, medical errors and risk management. Those involve specialized expertise. To me they all fit within the idea of a matrix. At the time we review a drug for approval those disciplines get involved and once it is on the market, we utilize those disciplines to look at the outcomes and perhaps influence the outcomes with risk management. So I don't see it as inconsistent with how we use statistics or medical knowledge or anything. So I wouldn't see putting pharmacoepidemiology, for example, back into every division. I don't think we would have a core expertise.

THE RPM REPORT: The perception, though, is that you do have the review group has a stake in their decision about approval being right, and then there are a group of people who may feel that their motivation would be to find problems.

A: That is a fair reflection of perceptions on the outside.

I believe sometimes there may be people who may be biased by their role in making a decision. Sometimes there may be people who may be motivated by finding a problem. We see that externally. You could say companies are biased to see no harm, and there are other people who are sort of professionally going to find harm, on the outside.

To some extent that is reflected internally. We are trying to make certain that our systems and processes are set up to minimize any of that type of bias. We are charged by the public with doing an unbiased assessment both pre-market and post-market. We take that very seriously.

I am very opposed to drama. I think it is extremely bad. Science is not drama.

People on the outside have a very, very exaggerated view of the different parties' positions. We have certainly seen situations where the new drugs people feel there is a problem and OSE looks at it objectively and says no there is nothing there. Most of the new drugs staff I do not think have a bias one way or the other. They reviewed all the harm data and they are well aware there might be harms. They inserted all this information in the drug label. I'm just allowing that occasionally you could have a personality who is attached to his or her own point of view, but you see that everywhere.

Our job is to set up a structure and processes so that we can have an unbiased evaluation. That is what we owe the public and the companies, is an unbiased scientific evaluation of whatever the data are.

Our problem is that we work in a situation of uncertainty and that provides a lot of opening for opinion and emotional biases and so forth, because there isn't a clear answer.

FDA Review Pathways—And Future Role in CER

THE RPM REPORT: Over the years there have been a lot of review pathways created: accelerated approval, priority versus standard, fast track, expedited approval is probably still on the books. Is getting to be time to say that the review standard is that we prioritize based on the metrics you laid out earlier, rather than end up in debates over which pathway and whether we are following the right pathway?

A: That would require Congress. Basically right now what we have is accelerated approval on a non-validated but reasonably likely surrogate. We have priority review, which only speaks to the speed of a review clock. Then we have the general safe and effective standard. Those are the three that we are operating. Sometimes we give people a rolling review under fast track.

People have talked for a long time about other structures. Generally if you step back and look at the situation, it is the patent life that is the issue and that is going to be included in the discussion.

There is a whole group of people out there who would like more information on a drug before it is approved, maybe outcomes data which might take years. So people such as Alastair Wood have suggested a tiered approach where you get on the market and then have additional incentives if you demonstrate more substantive and maybe clinically relevant data about your drug.

Say you said we are really altruistic and we are going to prevent osteoarthritis or we are going to prevent Alzheimer's. It is going to take 20 years, they set up a trial, they get everything done, they show they can prevent Alzheimer's disease and they have no patent life.

It is not an economically viable proposition. That is why people are saying there should be some more incentive structure put in place.

There are other people who, I think, misunderstand what the approval process is for. The approval process is about does a drug work or not, not about what its place in the entire armamentarium is. If you want to determine that you have to do a lot of comparative trials. A lot.

To get that done, they set up PCORI, that is going to be government funded. And maybe you can provide incentives. Incentivize people to do those trials and give them some reward for doing it.

There are others who think we should raise these standards or we shouldn't have so many drugs on the market.

So I think it is formidable to think about opening up the statute. You would think the senators and representatives have some other things on their minds with wars and tornadoes, tsunamis, nuclear meltdowns, and the debt ceiling. Do we really want to take on this one now?

THE RPM REPORT: You mentioned PCORI. As it stands today, how much of your time if any is involved in that activity; broadly speaking, should that become part of what FDA is doing over time?

A: I don't think we are involved in PCORI specifically at all. They are still trying to figure out the scope of questions they need to tackle.

But we review comparative trials all the time.

The difference with us is we are a lot more rigorous than people are going to want to be in the comparative effectiveness world. We require non-inferiority studies or superiority studies. We just approved a sartan on the basis of superiority and they did those comparative studies pre-market, probably strictly for marketing reasons—

THE RPM REPORT: It probably made it easier to approve too?

A: It makes it real easy. As you long as you don't have any major side effects and you are better than the competition it is not really an issue.

THE RPM REPORT: Thinking longer term, as you develop a risk/benefit tool, is that something that should align with what is happening on PCORI?

A: I just don't know what is going to happen. They have such a broad mandate, and they are looking a lot at health delivery and comparative models. Even if they get a very large budget, one very large trial comparing two drugs costs a lot. I don't know whether I could see them spending the budget on a drug comparative trial.

And there are philosophical, epistemological or scientific differences—whatever you want to call them—that we will have to straighten out. They want to do real world trials, but then can you do non-randomized trials and get reliable comparative data. We are very skeptical about that.