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  5. Panel 2 - Presentations by Academic Research Groups, Prescription Drug User Fee Act Public Meeting November 14, 2005
  1. Prescription Drug User Fee Amendments

Panel 2 - Presentations by Academic Research Groups, Prescription Drug User Fee Act Public Meeting November 14, 2005

Panel I - Presentations by FDA

MS. HENDERSON: Thank you, Jesse. And thanks to our first panel.

I'm going to ask our second panel to come forward an join me at the table to my right. That would be the panel of academic research groups, which includes Doctors Kaitin, Woosley, Berndt and Tilson.

And while they're coming forward, I will introduce the first of the speakers on that panel, who is Dr. Ken Kaitin.

Dr. Kaitin is the Director of the Tufts Center for the Study of Drug Development, an academic drug policy research group providing strategic information to help drug developers, regulators and policy makers improve the quality and efficiency of the drug-development process. Dr. Kaitin is also associate professor of medicine at Tufts University School of Medicine.

And so, without further ado, will let Dr. Kaitin get started.

DR. KAITIN: Good morning. Welcome. It's a pleasure to be here, and I appreciate the opportunity to participate in this hearing.

As you just heard, I am director of the Tufts Center for the Study of Drug Development. And for 30 years we have collected and analyzed drug development data to report on the time, cost and risk to bring new products to market.

What I will talk about here is a series of analyses that we began in 1985 to look at new drug approvals by the FDA, and trends in times and marketing of those products. I believe that these three-year trends give us a good example, or good illustration, of changes that have occurred in the United States as a result of the Prescription Drug User Fee Act.

My talk is going to be divided up into four themes.


The first theme is something that we've already heard about to some degree, and certainly many people are aware of. There are conferences and other workshops that are devoted to the issue of productivity in the industry.

Over the years we have looked at the numbers of products that have been approved. Again, these are in three-year intervals.


If we look at the number of products approved, there was a big jump in 1996 to '98, as the FDA was clearing out the backlog as a result of the mandate of the Prescription Drug User Fee Act. And then that number declined.

Now, what we had looked at and seen over the course of leading up to this last three-year interval, is that although there was--I don't know if you can see this--there was a drop in standard drug approvals, the number of priority approvals remained remarkably consistent over the past decade or so. However, in the most recent time period that we've looked at, we've seen a drop-off also in priority drug approvals, and that drop-off represents a drop of 34 percent.

So the decline in productivity affects not just standard approved products but also priority approved products.

Now, why is there this drop-off in productivity?


One of the main reasons is the increasing time cost and, of course, the riskiness of new drug development times and approval times over two decades, again starting in this first time period, '84 to '86, and looking at the most recent time period, we've seen the well-described reduction in

FDA approval times--these are not review times, but approval times--there was a slight increase, but that's an insignificant increase, in the 2002 to '04 period.

However if we look at clinical development times over that same time period--and this refers to the time from IND filing to NDA submission--we see, after an initial drop-off after the '93 to '99 period, down to 6.4 and then 5.8 years, we've now seen a continuation of the trend that we were seeing prior to PDUFA of seven years to get these products through the clinical testing phase. That's an increase of 21 percent; certainly supporting the notion that it's getting more difficult, and consequently more expensive and difficult to get products through the clinicaldevelopment process.

Very significantly, this affects not just standard drugs but also priority drug approvals. Again, prior to PDUFA we saw this steady increase in the amount of time that priority drugs took to get through the clinical development process. We did see a drop-off post-PDUFA, but now we're almost up to the level of the pre-PDUFA period in the amount of time it takes to get priority drug approvals, the most important drug approvals, through the clinical development process.

This increase from 5.6 to 8.1 years represents a 45 percent increase in clinical development time. And, of course, if you add the increase in overall priority approval times of 33 percent, you end up with a considerably long period of time to get these products through the development process than we've seen in past years. And this is, of course, a cause of concern.


And it's not just the priority versus standard. If we look across different therapeutic categories, we can see that, in fact, the trend is fairly consistent across those categories.

Just to work you quickly through this slide, this is seven therapeutic categories, across the bottom: anesthetic/analgesic, endocrine, anti-infective, neuropharmacologic, cardiovascular, respiratory, and anti-neoplastic. And this is the clinical development time for the '96 to '98 time period. And then we can put the '99 to 2001. But if now we look at the most recent time period, in five of the seven therapeutic categories there, we see the longest clinical development time in the nine-year period for those categories; most significantly, 11.1 years in the neuropharmacologic area. Coincidentally, it was just about a month ago or three weeks ago that the FDA said that they were going to look into longer clinical development times to get more efficacy and safety data on neuropharmacologic compounds. In fact, the advisory committee that reviewed this voted unanimously not to extend the length of the clinical development times, or clinical trial size, for neuropharmacologics. And I would say this is an example of the process working the way it should.


Drug Safety. Dr. Galson just discussed that. We are one of the groups that have been looking at this since we first looked at the drug-lag issue in the 1970s. At that time, the issue was: are we slower but safer? Now the question is: are we faster but less safe?


And confirming some of the data that the FDA itself has put out, if we look at the total number of approvals going back from 1980 through 2004, these are the total number of approvals over those years. If we look at the withdrawals of products for safety reasons based on the year that the product was approved, we see no consistent trend, despite the increase of six numbers of products that were withdrawn from the 1997 time period. The fact is, there were very few before that, very few in the later years, despite the fact that some of these products may still come off the market, the fact of the matter is: there is no consistent trend in the products that have been taken off the market for safety reasons.


And, in fact, if we look at the pre-PDUFA period of 1981 to 1992, and then the post-PDUFA period of 1993 to 2004, we see the total safety withdrawals of eight and 11, which is 2.8 percent for the first period, pre-PDUFA, and 3.1 percent--a slight increase; these are exactly the same numbers that the FDA put out in their safety report recently--this is an insignificant trend, again reflecting the fact that the overall percentage of products taken off the market for safety has not gone up post-PDUFA.

Significantly, much of the debate is focused on whether there is a relationship between speed and likelihood of a product being withdrawn for safety reasons. Dr. Galson talked about this.


If we look across therapeutic categories, we look at all approvals and then those that have been taken off the market, we see in some therapeutic areas--respiratory, cardiovascular--the time to approve the compounds that were withdrawn was faster than those that were not; but in other therapeutic categories, it's the same or even longer to review the compounds that were eventually taken off the market for safety reasons.

The bottom line is that there is no relationships--no relationship whatsoever--in the time to approval and the likelihood of a product being withdrawn for safety reasons.


The final theme I wanted to discuss is the attractiveness of the U.S. market. I think starting in the early 1990s with the Prescription Drug User Fee Act, as well as many other issues and features of the United States market, the United States market is a very attractive market for manufacturers to bring their products to market first in this country.


In fact, in the most recent analysis, 55 percent of the new drug approvals in the United States were first marketed in the United States. And you can see the numbers for the prior marketing of those compounds.


To get a better sense of how this has changed as a result of the Prescription Drug User Fee Act, in the top line here--the blue line--this is more than one year of foreign marketing. That was already declining somewhat, but I believe that PDUFA hastened that decline rapidly. And although there's been a slight increases, that's a very small increase.

The fact of the matter is: the U.S. as a first market for new products has gone up consistently for this time period, despite the small change there, and now is at 55 percent of new product approvals marketed first in the United States.

So, in conclusion: there is a decline in NME output, and that has declined over the PDUFA era, and that includes not just standard but also priority compounds. There is an increase in clinical times, and that has become somewhat of concern because it's offsetting some of the benefits that we have seen in terms of the reduction in approval time to get these products through the FDA.

Despite this slight rise in percentage of products withdrawn for safety, there is no clear evidence that there is a correlation between speed of approval and the likelihood of a safety withdrawal. So the U.S. remains an attractive market for first launch of prescription drugs.

So moving forward, I echo what was stated by Dr. von Eschenbach and others from the FDA: the FDA needs to continue working through the critical path to identify better mechanisms for assessing safety and efficacy, moving through the clinical development process; and also the FDA should be looking to identify and address regulation-related causes of lengthening clinical development times.

And, in terms of drug safety--again echoing something stated by Dr. Galson--the FDA should be looking for better systems of identifying safety problems early on, before products move through the clinical development process, but also better systems for identifying and taking action on products that have significant adverse events, once those products are on the market.

Thank you.

MS. HENDERSON: Thank you, Dr. Kaitin, very much.

Our next speaker, well known to this audience, is Dr. Ray Woosley. Dr. Woosley is currently the president and CEO of the Critical Path Institute, also known as C-Path, which is a nonprofit corporation formed by the FDA, SRI International, and the University of Arizona to accelerate the development of safe and innovative medicines.

Since 1999 he has also directed one of seven federally-funded centers of education and research on therapeutics, also known as the CERTs.

Dr. Woosley?

DR. WOOSLEY: Thank you. Thank you for the invitation to say a few words about PDUFA and how important it is. As you can tell, I'm a devotee, a convert, to the critical path. I've been drinking from that lemonade that Janet's been serving, and have a great deal of concern about the drug development process.

In the next few minutes, I'm going to quickly go through some slides, many of which you've already seen, to talk about the impact of PDUFA; talk about how it relates to the Critical Path Initiative; the purpose of the Critical Path Institute that we've created, but only as a model, not as a solution to the problem. I don't think we can take that on--but as a model for new relationships; and then a proposal for a PDUFA initiative.

As you see, the review times have come down.


I'm going to quickly go through this slides. You might say it was already heading down, but it clearly has had an impact, and there's no doubt about that.


There has been a product approval increase transiently, as you've seen. And Ken has more recent data to reinforce that point. Also, the submissions increased transiently, but they've gone down again.


At a time when we as a nation--and I think everybody here knows this diagram from the Critical Path Initiative showing the investment in U.S. pharmaceutical R&D increasing 250 percent, and the NIH budget doubling in recent years, so we've made a tremendous increased investment in science, but the number of new products, new drug applications during that time as decreased. New biological applications have decreased.

So PDUFA has done some very good things. It's given the Agency the resources it needed to get rid of the backlog. But I think it's also unmasked another problem that exists in pharmaceutical or medical problem development.


Part of that is in the success rate. It still remains a very high risk business, with these data in '04 showing 11 percent. That may be a decline from 19 percent success rates 10 years before that. So we still have either a declining, or at best, a very low success rate in a very high-risk business. And the question is: what is happening to the incentives? What's happening to the return on investment of the over $60 billion we spend on pharmaceutical R&D each year?


Again, the Critical Path Initiative called this problem to my attention, and I think all of our attention, in the fact that pre-clinical development and clinical development these delays are the biggest part of the problem. And I think Ken's numbers that he showed today reinforce the increasing development time as the major disincentive to investment in new medical product development.


The response to the Critical Path Initiative has, I think, been overwhelmingly positive. There have been very few negative responses. I think everybody wants new medicines. They want them quickly. They want them to be safe.

In the pharmaceutical industry, several companies have created their own Critical Path Initiative task forces to work and develop their own internal processes for improving the processes.


The NIH collaborations have grown. The FDA has collaborations with NCI, and Human Genome Research Institute, to address the Critical Path Initiative. And academic, as you've heard--well, I also mentioned the Critical Path Institute--we're really not part of academia. We're a nonprofit outside of the University, but partnering with several universities, including our founding partner, the University of Arizona.

But within academia, without even funding available, units have been created at UCSF, the Center for Drug Development Science, that Carl Pack leave, and JETS, have begun to work on the Critical Path Initiative at MIT, I think you'll hear later, the Center for Biomedical Innovation was created; at Indian, ISIS; the ECG Warehouse, at Duke. And now we've just heard last week about 11 universities that are coming together to address the manufacturing challenges that are identified in the Critical Path Initiative.

So I hope I can say with confidence that everybody believes that this is something who's time has come.


We certainly looked at that and created a nonprofit, publicly funded. We have $10 million from the State of Arizona, and the community, to create neutral ground where scientists from the FDA, academia and pharmaceutical industry can work together to accelerate the development of safe medical products.

Well, you may say: well, that's happening already. I think that's good. And we've heard about the collaborations.

We believe that this "neutral ground" concept is important for some of the things, and some of the discussions that have to take place. C-Path won't develop drugs or medical products. We will work on the process.

As happened with the Food Center--the National Center for Food Safety and Technology--we believe is a proven concept. It was established over 15 years ago as neutral ground. And in their website, the Moffett Center is described as "neutral ground where industry, academia and FDA scientists work together to address food safety. And that was the model that we were aware of and used as we created the Critical Path Institute, or C-Path.

It's neutral territory, publicly funded. Industry consortia can fund projects if it's done with the industry and FDA come together and agree, as they do in the Food Center, that there's important work that needs to be done. And that would be done with transparency and oversight; project-specific funding; oversight board with the FDA, industry and consumer and patient representatives should be present.


We believe that PDUFA, as I said, has uncovered this other problem. And the FDA has issued its White Paper, and it's willingness to work and partner on this. But there are some missing ingredients. A very big one is the lack of funding for the FDA to participate. How can they have the staff to work on these projects and attend these meetings? They need the internal funding.

And then there needs to be a funding for the method development and validation that's part of the call in the Critical Path Initiative.

Most industries invest 5, to 10, up to 15 percent of their annual budgets into changing the process that they use to make their process. So we believe that that kind of funding into developing the process--it's not, as I've said in other audiences--it's not sexy. You won't get an NIH grant for this. You won't get tenure, or you won't get publications for this kind of work. But it is essential in the development of new medical products.

There's also a lack of a process to prioritize and coordinate the Critical Path Initiative activities. That's something that needs to be funded.

There's also at this time a lack of an understanding of a laboratory for testing new methods and biomarkers. Many companies don't want people experimenting with their products as they develop new methods. So we've got to find a way where we can test those new methods in an acceptable environment.

So the proposal that we have--on the next four slides--


--if Critical Path Initiative funding should be made available to the FDA, perhaps a small percent increase in the PDUFA fees, to fund the work at the FDA, with a match from Congressional appropriations, so that the Agency would have the funds to hire the staff to do the work on the process that needs to be changed.


The funding for the methods development and validation also needs to be obtained. And, there again, industry consortia, operating with FDA advisors on, we think, neutral ground is important for that. We think that there needs to be a tie-breaker when the industry and the FDA may disagree about how to go forward with the process. Outside scientists can help generate the consensus for which methods need to be tested, and how.


PDUFA grants and contracts for work mutually agreed upon by a CPI--Critical Path Initiative--steering committee would be one way to do that work.


And how do you develop that process? We suggest using the Moffett Center model, where there's an oversight board, with FDA representatives, industry representatives, consumer/patient reps, and independent scientists and experts who work outside of the environment of the regulators and the regulated.


And the testing environment is perhaps the most difficult area, but I would like to suggest that in life-threatening illnesses, many of the technologies could and should be applied to accelerate the development of safe drugs; orphan drug development. This is an area where Congress mandates the FDA to assist in the development of orphan drugs. Why not have that applied more broadly to all drugs, especially those with life-threatening illness, and for personalized medicine. I would suggest, and perhaps, others be considered as the laboratory for where the process of drug development, or medical product development can be applied.


In summary, the regulators and the regulated, I believe, need neutral ground where they can work together to improve the process of drug development. I think PDUFA could be the catalyst for this change, and a shared investment by government and industry would be the way to do that.

Thank you.

MS. HENDERSON: Thank you, Dr. Woosley.

Our next speaker is Dr. Ernst R. Berndt. He is the Louis B. Seley Professor of Applied Economics at the MIT Sloan School of Management, and co-director of the Biomedical Enterprise Program at the Harvard-MIT Division of Sciences and Technology. He's also the director of the National Bureau of Economic Research Program on Technological Progress and Productivity Measurement, and co-director of the Center for Biomedical Innovation at MIT.

Of particular note, much of Professor Berndt's recent research has focused on price, output and outcomes measurement in the health care industries, and on regulatory policies at the U.S. FDA.

Dr. Berndt?

DR. BERNDT: Thank you.

I have more slide material than I have time to discuss, so I'm going to skip through a number of the slides. You should have in your packets, however, a complete set of the slides.

Today I'm going to talk about, briefly summarize, results from two recent research projects.


The first was published this summer in a peer reviewed journal, Nature Reviews: Drug Discovery, and the second is soon to be published, but is publicly available, and if you want a copy, please let me know. [Slide.]

Why PDUFA? Other speakers have discussed this briefly already. FDA, as you know, has two missions: one is to assure safety and efficacy of therapeutics; and the second is to help speed access, or marketplace access, to innovative therapies. And it was this second mission which seemed to be less completely fulfilled. You can see here that if you, depending on what particular two years you choose, you can see quite an increase here in terms of review time, from 22 months in 1970, to over 32 by 1990.

In response to that, Congress addressed the issue by passing a serious of Prescription Drug User Fee Acts, in 1992, 1997 and 2002.


And at least if you look at these rather quickly--this is a study that was published by a Tufts research--there appears to be a decline in the approval time at the FDA.


Now, I should mention that under the PDUFA legislation, all that was mandated is that the FDA review and act on applications. This did not necessarily translate itself into more rapid approvals; simply "act and review on."

And so the issue is: how are these linked? I might add that, as several of the speakers have mentioned, and as a White Paper that was released a few days ago emphasizes, to date the user fee program has been very important for funding at the FDA; roughly about 50 percent of money spent in review of human drug applications--I think it's up to 52 percent this last year--emanate from PDUFA.

And, as Dr. Gottlieb mentioned, user fee programs have long been elsewhere. We've had it in the U.S. patent system for centuries, and we have it elsewhere in the world. The EMEA that about 75 percent of its funding come from industry fees. The U.K. is funded entirely through user fees. Japan has no user fee program.


All right. So, for the first set of issues we wanted to ask is: to what extent have PDUFA I and II been associated with incremental reductions in NDA/BLA review time, controlling for other things that were happening, like patient advocacy groups, change in the composition of therapeutic class applications, and so forth.

Secondly: what is the effect of PDUFA on safety withdrawal rates?

And thirdly: what would the time trend of NME approvals have looked like in a world without PDUFA? Would the R&D slowdown have improved, or would it have been exacerbated?


The research methods we employed in this first study were using the universe actually of 662 NMEs that were approved by the FDA between 1979 and 2004. And we used what's called multivariate regression analysis. And I won't go through the details of that here.


These are just some of the explanatory variables that were employed. You certainly don't want to spend too much time on this, but if you look at the upper right-hand corner, the basic result is that while approval times at the FDA had been declining a bit pre-PDUFA, about 2 percent a year, during PDUFA I this accelerated to about 10 percent decline per year. Then, during PDUFA II, they continued to decline, but at a lower rate of around 5 percent a year; so, clearly, suggest that PDUFA is associated with shorter review times.


You can simulate them using the estimated model: what would the world have looked like without PDUFA? As you see here, if you look at, for example, when PDUFA came in, that was about 24 months review on average. Had PDUFA not been implemented, that probably would have declined, at least the model predicts, to about 20 months. In fact, however, it declined to less than 15 months.


I think is probably one of the most interesting slides of this presentation. What we did is we said: let's assume that the dates on which applications were filed at the FDA was unaffected by PDUFA, but that the previous sort of track record would have continued on. What would have happened instead?

This is the number of new drug, or NME approvals, that actually occurred, in blue, versus what would have happened had PDUFA not been implemented, in orange. And what you see basically is that whole curve is shifted to the left. By 1997, for example, in the bottom of this figure, we say what's the cumulative number of NMEs that were approved, by 1997, at the end of PDUFA I, had PDUFA not been implemented, the model predicts that only 187 drugs would have been approved, whereas, in actuality, 220 were. So that's a 15 percent acceleration.

By 2002, 389 drugs were actually approved. What would have happened in the absence of PDUFA is about 376, about 3 or 4 percent less. So you see this backlog that was basically filled out and much more rapidly acted upon in response to PDUFA.

And the bottom line, then, is that effectively what PDUFA did is it meant that many patients now had more rapid access to innovative medical treatments.

Now, what about safety?


We can compute safety withdrawal rates, and there are only three problems that I can think of with safety withdrawal-rate calculations. One is the numerator; two is the denominator; and three is the time span. Other than that, they're just straightforward.

So--numerator. What constitutes a safety withdrawn, when a drug is withdrawn and then reintroduced later on under more strict conditions, is that a withdrawal or not?

Denominator--what sample of drugs should be included? Biologics? Vaccines? Radiologicals? Annual vaccines? There's some ambiguity there.

Third, the time period definition--what defines "pre-PDUFA" and "post-PDUFA?" Is it when drugs were approved? Or when drug applications were submitted?

You can move these numbers around a fair bit. Because withdrawals are so relatively rare, you can move these numbers around quite a bit just by using calendar year versus fiscal year, and a variety of things like that. And one should bear that in mind.

With that caveat, let me just mention three studies.


One was a study published by the GAO, and focused only on chemical entities, not biologics. And although they didn't actually do the calculation, we used their numbers and calculated that there was no significant difference between those calendar years '86 to '92, versus '93 to 2000.

There was an internal FDA analysis that was also put out. And, again, you can do a test on whether there was a significant difference in terms of approval dates pre- and post- PDUFA; withdrawal rates based on approval. Again, no significant difference.

And we did a study of that, as well.

Now, all these studies suffer from theproblem that there's differential time on themarket. Drugs approved before PDUFA have been on the market much longer, have had greater opportunity, if you will, to experience safety issues. And so what we did was do a survival analysis, which folks, I'm sure, in this audience, know very well, a Kaplan Meier curve.

And I'd like you to look at two things here. Basically, the dark blue is the cumulative survival rate pre-PDUFA, and the more purple one is the post-PDUFA.

Notice two things: the first thing is they tend to converge after about 12 years on the market. And, secondly, notice how--I mean, this graph kind of accentuates the difference because it starts at 97 percent, not zero percent--notice that drugs, at least in terms of calendar time, are now being withdrawn from the market more rapidly. Whether they're being more rapidly withdrawn in terms of exposure to patients is not clear, and is worthy of some examination.


This slide just simply points out that drugs that were withdrawn from the market are now withdrawn much more rapidly; the mean of 2.4 months post-PDUFA, compared with 5.19 pre-PDUFA.


Okay, let me switch to the second paper. As Dr. Kaitin and others have mentioned, while there's been an admirable success in reducing review times and approval times at the FDA, we can't say the thing about what's happened to clinical development times. These things haven't budged for 25 years; still about six years.

And so what I did with some of my students at MIT is we decided to interview 50 senior R&D folks at a variety of biotech and pharma companies, as well as a few CROs, and we also interviewed eight senior staff members at the FDA. This was all done in the first half of last year, prior to Vioxx withdrawal and the anti-depressant hearings.

It was pretty evenly divided between biotech and big pharma. And we asked them what can be done to make the clinical development time more efficient? Is the FDA a problem? Is the industry a problem?

And basically we've written up these results at some length. Let me just talk about a few of the questions we asked.

One was that we asked industry whether they thought FDA was doing a good job in terms of preventing unsafe drugs from coming to the market. There was general feeling by industry that the FDA was doing a good job of that. I would say the industry had "guarded respect" is probably the right choice of word to use.

However industry also believed that in a number of cases there were significantly delayed review times that ultimately had a substantially negative impact on the public health.

I might add that in this thing we didn't interview legal counsel or CEOs, or CFOs. This was senior R&D folks, who might have a different view than others.


Now, more germane to this particular hearing, we also asked questions to both industry and the FDA: where would additional communications with the FDA be most valuable? And what was sort of interesting: industry believes that additional communications and interactions with the FDA would be very valuable across all phases of the development process, from pre-clinical IND to Phase I, Phase II, Phase III, and the actual NDA.

By contrast, in four of these five stages, the FDA rated the value of additional interaction much lower--significantly lower--than industry. In one case, however--and I think it's a very notable case--the FDA and industry agreed that additional communication would be very valuable: that was early on in Phase II, particularly with respect to dosing issues.


And much to our surprise, industry seemed to be willing to put their money where their mouth was, at least the R&D directors were. And industry interviews indicated that 'Our company would be willing to pay PDUFA type fees" particularly in Phase II. If you look at that, 80 percent--or 990 percent all together--were willing to pay more than $100,000 for additional contact with the FDA.

The FDA working paper issued over the weekend indicated that, in fact, there have been a more meetings--I think they're called Class B meetings, in particular. And that suggests to us at least, on this project, that there might be some very fruitful discussions with industry and the FDA in terms of using additional user fee program to fund Phase II meetings.


We had a number of recommendations that came out of that, as I just mentioned. Two of them were to institute better metrics and goals for development in exchange for PDUFA-like fees; increase interactions prior to Phase III, funded by user fees. I have a friend at Harvard University, Dan Carpenter, who's also just written recently suggesting that user fees might be tied to post-launch surveillance issues. We did not ask those questions in this survey, nor did we link user fees to DDMAC approvals of advertising content. But those are issues that might very fruitfully be discussed.


Finally, we've done some additional work in this area that tries to monotize some of these benefits and costs of PDUFA. That's now in the peer-review process. If you want a copy of that paper, you can download it from te National Bureau of Economic Research.

Thank you.

MS. HENDERSON: Thank you very much, Dr. Berndt.

Finally on this panel we have Dr. High Tilson.

After retiring from GlaxoWellcome in 1996, Dr. Tilson joined the full time faculty of UNC School of Public Health in Chapel Hill where is a clinical professor of public health leadership, adjunct professor of epidemiology and health policy, and senior advisor to the dean.

In addition, he is adjunct processor of social medicine at UNC; medicine at Duke; and pharmacy at UNC.

He is an advisor to government andindustry in health outcomes, drug safety, and evidence-based health policy, including most recently public health preparedness.

Of importance to the topic at hand today, Dr. Tilson chairs the National Steering Committee for the Centers for Education and Research on Therapeutics--the CERTs program.

Dr. Tilson.

DR. TILSON: Thanks, Madam Moderator. And, in fact, thank you for actually giving my talk. My reason for being here is to let you know that the Centers for Education and Research and Therapeutics--the CERTs--are here to help you.

In fact, I have three very simple messages. The first is: the CERTs belong to the FDA, and the FDA needs to use them.

The second is: the CERTs belong to the FDA, and the FDA needs to build them.

And the third is: PDUFA provides an extraordinary opportunity for the FDA to leverage its work with the CERTs even more than it has up til now.

It's wonderful that I get to be the last member of this panel, because I get to bring you a terrific success story. I'm very optimistic about what the CERTs have already been able to achieve, and the promise here, particularly in the face of renegotiating PDUFA, is quite extraordinary.

The CERTs were part of the second regulatory revolution. If PDUFA was the first, then certainly the FDA Modernization Act--or FDAMA--was the second. And the CERTs were created by the FDA Modernization Act in 1997, specifically by act of Congress, to extend the public health role of the Food and Drug Administration through education and research, beyond simply the regulatory stick.

While directed to the Food and Drug Administration, it is administered by AHRQ, through an extraordinary partnership between AHRQ and the Food and Drug Administration--more about that in just a second.

We have seven centers out there already, with four more currently being considered, and shortly, I hope, to be approved and reported. And that gets us about halfway there to the total number of 22 which, at least our steering committee feels, the nation needs. There's an opportunity for PDUFA if there ever was one.

We have almost 300 projects up and going. And if there was ever a success story, it was the public-private and public-public partnership that was part of the FDA Modernization Act mandate, with over 130 partners working with these seven centers. And over 200 peer-reviewed publications--obviously publications aren't the output; improved health is the output. And so one of our accountabilities is: so what?


Let me just touch on the Congressional authorization. You my handout, and I don't plan to read this slide in any great detail, except to point out that in its wisdom, I must say added by Ray Woosley who is a member of our CERTs steering committee, the Chair of the Arizona CERT, and one of the inspirations for the CERTs movement, Congress realized that we have to have research in order to communicate more effectively, then we have to communicate more effectively and have research to document that we have done so, and provide the objective clinical information to all of those in the decision making system.

Finally, of course, and quite critically, Congress also suggested that we have to have research on comparative effectiveness, cost-effectiveness, and safety of drugs, biologicals and devices--some of the things that a marketplace funded primarily by the research-based pharmaceutical industry simply can't and won't do by itself. And it represents a significant new role for the Food and Drug Administration, mandated by FDAMA, but not funded yet through PDUFA.


The model for public-private partnerships is shown on the next slide. And again, without going to great detail, let me just point out that public-private partnerships are taken deadly seriously by the CERTs. We have a mechanism to review them and ensure the independence and trustworthiness of the academic process that gets brought to bear on this process, without turning our backs on industry, regulatory and commercial partners, who know more about the subject than we may, and certainly have a major stake.

So creating the ground rules for this--the "neutral harbor," to use the term that's already on the table--was a critical objective for CERTs. And we created a vision statement to reflect that; namely, "to serve here as a trusted--"--with that as the operative term--"--a trusted national resource for all the people who are seeking to improve health through the best use of medical therapies.


This organigram simply documents the points that I've made. The Food and Drug Administration work collaboratively with AHRQ to oversee this program. There is a coordinating center located at Duke, and seven centers which work collaboratively with the coordinating center, listed here, including Arizona CERT. And there should, of course, be a dotted line out there to the C-Path Initiative, which is one of the CERTs partners, co-located by and fostered through the University of Arizona; the University of Pennsylvania, Vanderbilt, University of Alabama at Birmingham, the University of North Carolina--go 'Heels!--and the HMO Research Network, as well as Duke University, a separate CERT.

This entire process, however, is guided by a national steering committee, upon which the Food and Drug Administration, AHRQ, and the Centers for Disease Control all participate. There's also at-large public participation, most recently through the National Health Council, and before that, through the National Consumers League; and professional oversight, most recently through the American Nurses Association, and currently through the American Public Health Association. And big pharma has a seat at the steering committee table as well because, of course, they are essential partners in moving this forward.


The next slide shows the inventory of centers, and I leave that to your reading. But suffice it to say: centers, in addition to be generalists in improving the nation's therapeutics, have their own areas of specific focus and expertise, ranging from infection control to addressing the problems of children.

Incidentally, watch this space for the announcement for the next four CERTs which will include, among others, one in the long-neglected area of devices, and another critically needing advancing: that is the consumer perspective, particularly risk and benefit communication involving consumers.


Well, all right. So what do the CERTs bring to this table? And why is this an item for PDUFA?

Well, the answer is: the CERTs do research. And here is an inventory of the sorts of research the CERTs do: patterns of use; inappropriate, unsafe use; understanding risk management; documenting that risk management tools may or may not be effective, and how they might be effective; and particularly, of course, apropos of Steve Galson's critical comments, safety surveillance methodology, in partnership with the Food and Drug Administration.


I list a couple of examples on the slides. And I don't want to go into them in any great detail. I just wanted to put some flesh on these bones, looking at something as important and expensive as transmyocardial revascularization, for example. To understand when it is used appropriately, and when it is not, will help the Centers for Medicaid and Medicare Research decide whether they do or don't wish to fund, and under what circumstances. So being a partner with CMS represents a critical dimension for the CERTs, as well as partnering with other Federal agencies.

Here the possibility of monitoring patterns of use will help us to understand and learn from off-label use. Off-label use isn't good or bad. It's just off-label, and it represents use without the data available, and therefore a great opportunity for us to use PDUFA funds to learn from that experience.


FDA is co-sponsoring some work with the CERTs that is extraordinarily important, I think, looking critically at the large automated population-based data sets out there. HMO Research Network is one of our seven CERTs, for example, and has the population of the sixth largest state in America of covered lives, for whom we have automated data of all prescription drugs, and all major medical outcomes. And yet we don't have a proper demonstration of their value in generating and documenting signals of possible adversity in drug use. Well, Food and Drug Administration is partnering with us to do so.

And Ray Woosley pioneered the QT drugs registry, and from that a tremendous groups of learning opportunities, including curricula for medical education.


CERTs are a convener. We've convened a series of think tanks, workshops. And it is said by many of our colleagues at the Food and Drug Administration who collaborated on five, looking at risk-management, its communication, assessment; working with media and the risk; balancing benefits against risk and so forth--that this thinking from these workshops and think tanks was instrumental in helping the Food and Drug Administration to develop its response to Congress for a program of guidance for risk management.


All right. So here's the inventory of the things that I've said; represent things that Food and Drug Administration, as it contemplates PDUFA, particularly in the face of the drug safety work, which you already heard from Dr. Galson represents great progress, but a work in process, needing more work, might wish to pursue.

Particularly here, the Food and Drug Administration has an extramural grants program to fund research in the development of methodologies and tapping into large automated population-based data bases, the so-called extramural program. Its external advisory board--I've sat on several of those study sections in my own jaded past--has recommended for years that that program is not simply underfunded, but it's underfunded by an order of magnitude; that is, a million dollars barely skims the surface; $10 million might help.

And, of course, finding a partner to do the work with you; the partner who understands the use of population-based data and can work at arm's length as a trusted resource, represents the way forward, in my view, for PDUFA.

And therefore, here's our critical path. It's working together. The CERTs are there. Use them. The CERTs are yours. Build them. The CERTs represent an opportunity for PDUFA. Fund them.

Thank you.

MS. HENDERSON: Thank you, Dr. Tilson, very much.

We will now take a 10-minute break. I will ask all of you to be back in your seats by 10 minutes after 11. And I'd ask our third panel, which includes Dr. Cohen, Ms. Dorman, Dr. Sigal, and Ms. Ireland to be seated and ready to go at 11:10.

Thanks a lot.

[Off the record]

Panel III - Presentations by Patient Advocacy Groups 

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