A Chat With Janet Woodcock: FDA Exec Discusses Development Obstacles, And FDA’s Efforts To Overcome Them

Janet Woodcock, MD, has served as deputy commissioner for operations at FDA since 2003. Prior to joining the Commissioner's Office, she held a number of positions at the agency, including director of the Center for Drug Evaluation & Research. In her current position, Dr. Woodcock has spearheaded the agency's Critical Path initiative. "The Pink Sheet" recently met with Dr. Woodcock to discuss the agency's accomplishments in 2005, goals for 2006 and role in overcoming industry's productivity slowdown.

"The Pink Sheet": What do you think were FDA's greatest accomplishments in 2005?

Woodcock: On the drug side, the single accomplishment is getting a lot of the drug safety programs - the drug safety oversight board up and running, many of the new safety procedures and the website and everything. That whole orientation around better oversight and also communication about safety issues was a huge accomplishment for the drug center....

We got a tremendous number of comments on the proposed [Drug Watch] guidance and they were all over the map....There were people that were rabidly against the proposal, people who felt it didn't go far enough, people who felt it went way too far. So those comments are being evaluated....We try to get final guidances out as quickly as possible. However, when you get a tremendous number of comments and [the oversight board is] getting ongoing experience on the information they are now posting on the website on some of the safety issues that have occurred and so forth, [it is difficult].

"The Pink Sheet": [Deputy Commissioner for Medical and Scientific Affairs] Scott Gottlieb has mentioned some other routes for disseminating information about emerging risks such as something similar to the CDC's [Morbidity & Mortality Weekly Report]. What is the status of such efforts?

Woodcock: When I was head of [the Center for Drug Evaluation & Research], I long wanted to do something like that. That's partly a matter of staffing and partly a matter of now that these new procedures and programs are in place, which are more centralized in CDER, they may have an opportunity to publish something like that online that would be a different mechanism.

"The Pink Sheet": You have contracted with some new databases to get more information. Is that up and running now or is it going to slowly start producing information?

Woodcock: It is not that different than what has occurred in the past. It's just different databases and different contracts. The center has, since the nineties - perhaps even earlier - had contracts with different groups who had access to drug utilization data to do work and that's how [Office of Drug Safety Associate Director for Science] David Graham did his Vioxx study for example....What's changing is in healthcare there is going to be more linked databases as we move to the electronic health record as managed care organizations and payers have long known what people are taking - what drugs they are taking or what devices are implanted in them because they pay for them. But they have not had links to their outcomes, their medical record, that was not electronic, that was out in physicians' offices.

The contracts that we had in the past had to do with people who were hospitalized or people in Medicare, where there was more access to medical records. Now the healthcare system is gradually becoming electronified, automated and there is going to be much more opportunity in the future. So you will see this growing.

"The Pink Sheet": You mentioned Medicare. There has been talk about using Medicare claims data, both Part B and D, though we've heard that Part B is closer to actually coming into effect. Is this the case?

Woodcock: That is easier because it's been extant for a long time. Certainly, CDER has used Medicare data for a very long time....There are active discussions going on between FDA and CMS about how to construct the databases of the future that will allow better analysis of outcomes. CMS is very interested in this as well. But it is going to take awhile.

"The Pink Sheet": Is there information besides drug safety information that you can get from Medicare data that FDA could use?

Woodcock: There is some. Look at the two studies that were just published about the antidepressants in adults.... They were outcomes studies, or observational studies. That is a different kind of study, you learn different types of information than you would, but basically they took data that was available or looked prospectively at people who were actually taking these drugs and found out what happened to them. You can't learn whether they are effective or not from doing that, okay, but you can learn what happens to the people. Because of all the issues around suicidality - which are real issues - but the way it was reported in the popular press was extremely unfortunate because you seem to think that this would happen to everyone.

These studies give you a sense that the vast majority of people who go on these drugs, a couple months later their status is improved. So that tells you something practical. It doesn't tell you they were effective, it tells you something practical, which is if you are a patient and you are going to take one of these drugs, your odds in a number of months are [you are] going to be better and that is a very good thing to hear. That's something about effectiveness, it's not what the FDA would require for approval, but it's important information nonetheless.

"The Pink Sheet": Can FDA play a role in disseminating that? What's FDA's role in seeing these studies and making doctors aware of them?

Woodcock: Typically the FDA would not necessarily because this is technically not information that would go in labels because it is not rigorous, it doesn't meet the rigorous scientific standards. However, groups like [Agency for Healthcare Quality & Research] and professional societies would use these data to write practice guidelines and everything....When observational data become really compelling, then I believe it should go into the labels as well (see ¹ (Also see "Advisory Committees In 2006: FDA Advisory Cmte. Reviews To Focus More On Lifecycle Of Drugs" - Pink Sheet, 6 Feb, 2006.)).

"The Pink Sheet": What other accomplishments did the agency have in 2005?

Woodcock: It was really a signal year for progress in pharmacogenomics. It's very interesting. The Royal Society...in London has published this very negative assessment, saying that individualized therapies and pharmacogenomics are over a decade away. Well we're doing it here. We didn't read that report. Devices approved - and I regard this as a landmark thing - test kits for drug metabolizing enzymes....On the drug side and the agency side, the voluntary genomic data submission process is up and running and that's a really big deal I think for getting the companies in with their data.

"The Pink Sheet": Are you getting a lot of data from that right now?

Woodcock: Yes....We've had to hire another person. We've had over 20 submissions. Each one of these has a massive amount of data. We have people from all around the agency working on this in the committee, so the agency is learning a tremendous amount about these genomic tests and how they are being used and so forth. It's really very positive. We even had a joint meeting, by videoconference, with the [European Medicines Agency] on one of these submissions because they are interested in this as well.

"The Pink Sheet": There was talk about seeing what avenues there are for sharing some of this information with [academia].

Woodcock: I would say right now much of this is too preliminary to do that sort of thing. It's pretty scattered. We're using this tool that [the National Center for Toxicological Research] has developed called the Array Track to look at the data and analyze it and everything. Eventually we will be able to do things like that. It's very early, in that regard the Royal Society is right, it's early but it is moving so fast.

We've had companies come in with natural history data....They have looked at sick people or drug responders, just looked at their genes and they have data on a disease or something. We have companies come in and look at how you can predict a response. We've had companies come in who are looking at the rare serious side effect from their drug and can they predict that from the genetics and so forth? So it isn't like you can analyze this right now, but we're going to build up to something that is really important. We're extremely positive and excited about this.

"The Pink Sheet": It seems there has been a trend down in NMEs, but last year there was an even more precipitous fall off. Far fewer drugs were approved last year. Do you think that was indicative of the trend you had seen before or was something new in play last year?

Woodcock: No, I think it was indicative of the trend. The [U.K. Centre for Medicines Research] says that 2004 was the lowest number of NMEs introduced worldwide in 20 years. So this isn't something that has to do with the U.S. FDA or the U.S., this is an industry problem. We feel like we brought this to people's attention early by publishing the Critical Path initiative a year and a half ago....Now we weren't the first. Certainly some of the industry observers, consultancy groups....were saying this model was not going to be sustainable, there were going to be problems. They were right. We're in the midst of those now. I think we will see an ongoing trend for a number of years. You can't make anything of one year. They are small numbers and they fluctuate up and down, but certainly it doesn't look like it looked in the nineties.

The issue is less, I think, what the number is, than the fact that the investment has continued to go up. There was something published in [The New England Journal of Medicine] about total R&D investment in the U.S., and industry is 57% of that counting devices, biologicals and drugs together. The majority of R&D in biomedical is industry [funded]. The [National Institutes of Health are] 28% and their's is $30 bil. So it's a lot of money invested.

The point is where is the return on that investment? You would expect it keeps doubling and going up, so where is the increase? Well there isn't an increase. You can argue about whether there is a decrease, there probably has been a slow down. But it's more like why is it going in that direction and not the other way? That's what we think with the Critical Path, that we have some of the explanations.

"The Pink Sheet": Are you seeing the slowdown...at the IND point or is it at the NDA stage? What part of development is it?

Woodcock: We are seeing a decrease in applications. We are not seeing the increase you would expect in INDs or [investigation device exemptions] if all this investment were paying off. They are up a little, but the failure rate is up too. Our approval rate is about the same as usual....If you are talking about drugs, 80% of the applications that we get in are ultimately approved, so it's not there that the change has occurred. There hasn't been the increase in clinical investigations that you would imagine, given this magnitude of investment by the public and private sector and...the failure rate is way up.

"The Pink Sheet": In regards to the Critical Path, what will be interesting and valuable to look forward to?

Woodcock: Well, we plan to publish our [opportunities list]. I know my credibility is not very high because we haven't published it yet, but we will publish our list in 2006. We will also publish projects we are doing. We are setting up significant consortia to address this problem. The one that has been publicly announced is the C-Path Institute in Arizona. That actually got some congressional funding this year. We are [tackling] some significant problems with them. More consortia we expect will be announced this winter and there will be significant major consortia working on projects that are directly applicable to both drug and biologic and device development issues.

"The Pink Sheet": Are these industry consortia or academic consortia?

Woodcock: All of them involve public/private partnerships. That's how we plan to do the Critical Path. We think that one of the lesions or one of the flaws in the current system is that these sectors have not come together to work on these problems. These are applied science problems. They are not the kind of thing NIH does because NIH is interested in novelty, discovery and everything. These are problems [such as]: What does a biomarker mean, clinically? Can you rely on it?

With bioinformatics right now, we should have computer models of the diseases, have all the natural history data in there, everything we know about the science of that disease. How does it respond to treatment from observed trials? Those models should be built. Then if you are trying to develop a drug for that disease, you plug that drug and its effects into that model and you start running simulations and predictions. This provides an incredible increase in clarity about what's going on, but we don't do it right now because who is going to develop that?

That is a very valuable thing, but we don't have a system that does it and it needs data from a lot of people. One company can't do this, they don't have enough data. The NIH alone, they don't do it, but they couldn't do it, they don't have enough data. So what I see is we will need consortia to do this and also each sector will need to contribute its resources to get this done. It's coming along. Anything that is such a shift in thinking, it takes awhile to get going.

"The Pink Sheet": So you can continue to do these Critical Path projects even if you don't have the list out?

Woodcock: Well yes, that's sort of the point. The fact that we haven't published the list is not related to the fact that we are moving ahead in a lot of areas and there will be a lot of activity in Critical Path in '06.

"The Pink Sheet": There was the biomarker collection project and that was sort of stalled. What is the status of that initiative?

Woodcock: We are doing a survey internally in drugs...[looking at] what are the trial endpoints....We are developing an inventory of what are the criteria for approval, what markers are used. Part of the problem is this has never been organized before intellectually. Some people would think, 'a chest X-ray, oh that's not a marker.' There is a use to it they don't regard as a marker anymore, but of course it's a marker....So we threw up our hands eventually at trying to sort this out and we are actually collecting the data, so we will see what are being used as endpoints. This project is sort of moving along, but it requires a lot of internal introspection.

"The Pink Sheet": Why is identifying biomarkers so important?

Woodcock: What you see is in areas where you don't have a really good outcome measure, what the companies do is they tend to go away from that area and they won't develop devices or drugs in that area because it is too hard, it is too unpredictable. What needs to be done in some areas is develop better outcome measures....

For example, the use of CD4 and then viral load for HIV drugs, that's what made that field explode and be very successful in controlling the epidemic because they knew what they had to do. Industry's job then, they went and developed the molecules and they tested them and they knew how to test them....

Same with RA - when I first went to CDER, we developed the rheumatoid arthritis guidance...and we said what you had to do and what claims you would get. We adopted the ACR 20, 50, and now you see that that is what they have to do and we have many successful RA drugs....So developing more quantitative, objective measures will stimulate a field, and that is why biomarkers are so important for the future of these products.

"The Pink Sheet": So that is how advisory committees could play a role in biomarkers, you could bring a biomarker in and say 'is this a valuable thing?'

Woodcock: Yes and what we need to [do], what hasn't happened, is that there are tens of thousands of biomarkers out there, but people haven't studied the clinical utility of them rigorously enough to use them in regulatory decisions and so we need to do that. We need to do that for all the different products and then once that studying has occurred, we need to take it to an advisory committee and get them to bless it....

The advisory committee role would be to take this mass of data that has been analyzed by the FDA and hopefully performed by a public/private consortium or whatever and say like...we did with RA, 'yes you can use this measure as a marker, a response criterion and here is how you do the trial and then you do these special tests, these biomarkers and you tell whether the drug worked or not.'

"The Pink Sheet": And it is really up to the divisions to decide whether to conduct such meetings?

Woodcock: Well they have to do them obviously, but the management and leadership needs to push in that direction. I wasn't wholly successful in my 11 years as center director. I was somewhat successful.

"The Pink Sheet": Another area on the development side is the follow-on proteins.

Woodcock: I can't talk about them...

"The Pink Sheet": So you are no longer doing follow-on proteins?

Woodcock: Oh no, I am completely doing it. I did it. I didn't say I am not doing it. I said I can't talk about it. I cannot give you timelines or anything like that. What we have said is what we have said. We are under a lawsuit. That's why I can't talk about it.

"The Pink Sheet": Is this like the Critical Path where you can still work on it without actually talking about it publicly?

Woodcock: Absolutely that's right. There was a meeting at the New York Academy of Science on protein characterization that was about a month ago. It was very successful according to our scientists, figuring out how to better use new technologies. This is like a Critical Path type of thing using the latest spectroscopy and all of these other advanced science techniques to see what the proteins are like and characterize them....It made a lot of progress in that particular field, which is actually how do you tell what you've got when you make a protein. That's one of your goals you want to look at it and see what you've got there.

"The Pink Sheet": Prescription Drug User Fee Act reauthorization is starting. What are some of the agency's priorities when you look at the reauthorization? What are some of the things you would like the discussions to focus on?

Woodcock: We feel that the program has been quite successful in improving and supporting the agency review program for processing new human drugs and we would like to sustain that. We had a public meeting where there was a tremendous amount of input about safety from many sectors, that more attention or effort should be put to safety.

So what we are doing [is] we are taking the input from the public meeting and from stakeholders and combining that with the input of our own reviewers and putting together what we feel our position would be on PDUFA.

"The Pink Sheet": There were some discussions about having earlier-stage meetings like Phase IIa. Are these the kind of things that FDA is interested in doing?

Woodcock: We have been doing them on sort of an experimental basis and we have actually found them to be extremely valuable. It turns out that, at least for pharmaceuticals...much is set by the time you are at the end of Phase II and that is traditionally when people would meet with the FDA. Basically they would come in with their position: Here is the dose. Here is what we are going to do and everything. So there isn't much to do with exchange of ideas. It was more like, "Are our endpoints and our trials okay? If we are successful in these trials could the drug be approved?"

The end of Phase IIa meeting is a quite different meeting. How have you studied this drug? How do you propose to study it? What do you know so far?

We've been doing some of these Critical Path activities which are modeling of the data and simulation of the data that have already been generated on the drug to provide a means to discuss with a company what the performance of the drug is so far. These have been extremely illuminating. So this is where the science really comes in - in these early phases of drug development.

"The Pink Sheet": These meetings also create more work. Is this the type of thing you would need more funding to do more broadly?

Woodcock: They absolutely create more work. Probably we would need more funding to do it more broadly, absolutely, because they are actually extremely labor-intensive because they involve a lot of modeling and data handling and everything....

In general though, what we would like to see is that the companies develop more capacity to do this analysis themselves and then come in here and talk.

Obviously we have people who are experts in these analyses so they can evaluate it, but we shouldn't be doing these analyses ourselves. What we would like to do is pool data and natural history data on diseases and then have disease models that can be published and that is something we would like to do for example as part of the Critical Path.

"The Pink Sheet": Are there any other big guidances in the hopper that we should be looking forward to?

Woodcock: Yes. I don't know when though. We've started a [Bio-research monitoring] initiative....We talked about that at the Science Board. We'll have probably an announcement about that soon á la the [good manufacturing practices] initiative as far as all the things we are going to do and produce. There will be a lot of stuff coming out related to that over the next six months.

"The Pink Sheet": Any other goals for the year?

Woodcock: When you are talking to me, I have been focusing on getting Critical Path really made real and getting the research started. People, I recognize, and I don't blame them, are not going to be convinced about this until they see this research happening and they see money being spent and the patients being studied and the results coming out. That is fine, I agree with that - that is how people should feel, but we need to get people over that hump and see this can be done and get engaged in doing this.

My goal this year is really to get this up and running and established. Also to do the BioMo initiative, continue the GMP initiative - which we continue to have ambitious goals in that area for pharmaceuticals. We're working in the commissioner's office to make sure that is well organized and functional and everything. Those are my goals and really what I am focusing on is a handful of mainly regulatory, scientific initiatives.

- Andrew Kasper