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Scott Gottlieb, MD - Speech before PhRMA Scientific Regulatory Meeting

This text contains Dr. Gottlieb's prepared remarks. It should be used with the understanding that some material may have been added or deleted during actual delivery.

Speech before
PhRMA Scientific Regulatory Meeting

Remarks by
Scott Gottlieb, MD,
Deputy Commissioner for Medical and Scientific Affairs,
Food and Drug Administration


November 29 , 2005

Thank you for the introduction and for having me here today. This is the time of year when the trade publications that follow the FDA print their annual stories on how the agency “is doing,” and by that I mean, how many new drugs we approved over the prior year.

And while I don’t have the final numbers with me here today, and cannot speculate precisely where we’ll end up owing to a long history of a lot of end-of-year activity -- it’s clear that the number of approvals for 2005, as well as the number of new molecular entities approved by the FDA, is going to be down -- perhaps significantly -- from the recent peak years in the 1990s.

This decline in research productivity is happening even as spending on the research and development of new drugs continues to grow at a rapid pace. Total research spending has reached record levels.

In fact, once you factor in spending on research by pharmaceutical and biotech companies, which makes up the biggest single chunk of the total spending on drug discovery and development, as well as spending by the National Institutes of Health and other academic institutions and spending by private foundations – then the total amount that we’re investing in research into new medical products and specifically new medicines easily tops $100 billion and by some estimates approaches about $150 billion every year.

Clearly there is a disconnect between the resources we’re devoting to developing new medical products and what we’re getting in return in the way of new and better treatments. And I don’t think the current situation is sustainable.

I don’t think we can continue to spend more money on a process that is becoming more and more costly – by some estimates the cost of developing a single drug now tops $1 billion – while the productivity in terms of what we’re able to produce continues to decline.

And I don’t think we can continue to do what we’re doing now -- pouring money into old ways of doing things when it comes to developing drugs, ways that are costly and not as efficient and effective as we can be.

In too many places, discoveries are made using advanced sciences, but when they are brought up to the preclinical stage we start applying technologies that have been used for 50 or 60 years, such as animal toxicology. This is a completely empirical approach, even though we have technologies such as predictive assays that in selected cases can be more predictive and less costly to acquire than animal toxicology data.

In too many places, for example, there is too much reliance of drug developers and regulators on trial-and-error methods, especially when it comes to drug safety questions.

This is especially true in the discussion about drug safety, where part of the debate is that people feel that all the questions about safety issues must be answered by large randomized controlled trials.

But this is something that is not always possible despite the size of the trials, because so many of the really serious side effects are also very, very rare, and hard to uncover in any reasonably sized clinical trial.

Instead, in this and other areas of drug development, we should be adopting approaches that increase the use of mechanistic data in preclinical and clinical research to actually intelligently target new medicines to patients who are likely to experience more of the benefits and fewer of the side effects of a new drug.

In short, drug development has to be moved from empirical process to a more scientific process, just as the discovery and early development phase of drug creation has moved to be less trial-and-error and more deliberate and scientific.

And finally, the FDA has among its ranks dedicated and outstanding experts on regulation and drug development, many at the cutting edge of their fields.

But here again, in too many places, the Agency itself has not had the resources, the opportunities, or the collaborative partners to be able to advance the science we work with every day. And that has made the process less efficient than it ought to be.

But in some cases, we have not had the resources and other cases the opportunities to do these things.

I don’t think we can continue to allow the cost of developing drugs to climb while the science for actually making drugs stagnates. I don’t think we can allow increasingly sophisticated new molecules to bump up against a regulatory process that isn’t able to take advantage of the same scientific tools in evaluating how these new medicines work.

That’s a recipe for declining productivity -- more money spent trying to push highly innovative new products through a development process that is forty years old.

Now don’t get me wrong. There are encouraging signs that we’re getting a lot for all of the investment we’re making in new drug development.

There are more highly novel treatments being developed than perhaps any time before. And more of the treatments that are being developed are based on a clear understanding of the biology they aim to target and the mechanism by which they aim to work.

And more of the new applications, whether its genomics or proteomics, are already finding there way into the development of new drugs, even though these tools have been around for a very short time.

But the bottom line is this. With so much money being invested in drug development, and with so many people today still suffering from many chronic diseases, and dying from too many acute illnesses, people who could be treated or even cured in the near future, we cannot allow the process for turning new discoveries into practical benefits to continue to get longer, more costly, more uncertain, and more disconnected from the underlying science used in drug development.

All of us need to do a better job so that new scientific developments are able to be more quickly translated into practical benefits for patients. And we need to do a better job if we’re going to continue to maximize these investments and build a sustainable enterprise dedicated to the development of better medical products.

At FDA, these questions really boil down to two goals – how can we make sure that our own regulatory approaches are as scientifically advanced and predictable and efficient as possible. And how can we make sure that we’re taking every opportunity to continue to develop good information about new medical products after they are approved, so that doctors and patients can guide the most appropriate use of new innovations and so that we can quickly adapt new things that we learn about the safety and benefits of medical products into medical decisions that patients make.

I’m pleased to say that under the leadership of the heads of our medical centers and our dedicated career staff, as well as Janet Woodcock and Acting Commissioner Andy VonEschenbach, the Agency is working hard to achieve both of these goals.

On the first goal, there is a lot we’re already doing at FDA to make sure that the drug development process is able to benefit from the same advances in science that have generated new opportunities for discovering more effective treatments in the first place.

We’re working on a series of new policies that together constitute what we call a new and modern approach to regulation. We have found that in too many areas of our own work -- whether it’s the way drugs are evaluated as they are manufactured or the way that they are tested in clinical trials -- the standards for doing these important tasks have not advanced much, if at all, over the last few decades or more.

And so, even though, during this same time, the science and the sophistication of the medicines themselves have evolved and advanced significantly along with the tools and the methods for discovering them in the laboratory, the tools for actually testing them, to make sure they are safe and effective, and for manufacturing them, have largely remained the same.

Some of the projects we’re working on focus on devising better tests for some of the most common, and also troubling drug side effects, things such as kidney, liver and other toxicities and drug-induced heart rhythm problems. We’re also looking at opportunities to advance in vitro and animal studies that can better predict clinical outcomes than today’s in vitro methods, and providing regulatory support for more human testing before compounds formally enter the clinic.

Another area we’re we’ll be focusing more attention is in new and better approaches, such as adaptive protocols, to the rigid three phases of clinical study. In some cases, ideas such as enriched trial designs could provide better information about safety and benefits to guide medical decisions without needlessly exposing as many patients to experimental treatments. This is something that we have already begun to discuss in a few very novel areas of drug development, like cancer vaccines, where the old approaches are sometimes a hard fit.

In general, we need to get away from the empirical approach to drug development, where we just give new drugs to people, ask a particular set of questions, and then observe what happens. This is not just a challenge for FDA, but for science more generally, and for product developers.

With more new treatments highly targeted for specific sub-sets of disease, and with more treatments entering clinical development with a clear understanding of their underlying mechanism and their method of action in the body, the traditional empirical, controlled trial approach does not take advantage of the best opportunities to develop the most useful information about benefit and risk.

To help foster the development of these better scientific approaches to drug development, FDA will be issuing our list of Critical Path opportunities next week.

This first list, which is the work of the dedicated staff at FDA and led by Dr. Woodcock, will include a number of ideas for applied research, including a handful of projects where FDA will participate.

In response to comments from the medical community and industry, the opportunities list will emphasize clinical trial design and biomarker development.

But we’re not waiting for the list. In fact, these efforts are already underway at FDA. We have already announced a collaboration with NIH’s National Cancer Institute to work on validating advanced imaging technologies as clinical endpoints. And we recently announced collaboration with Duke University that will be looking for better markers of heart rhythm problems such as QT prolongation.

We also announced just a few weeks ago our Liver Toxicology Biomarker Study, which will look for better markers of liver toxicity. It will be conducted under a Cooperative Research and Development Agreement or CRADA between the FDA’s National Center for Toxicological Research (NCTR) and a start-up expert in this science.

The Critical Path program will provide a framework for combining the agency’s insights and authority with the expertise and resources of industry and academia in order to remove scientific hurdles to medical product development. Indeed, part of the rationale for FDA involvement in these efforts is based on experience, in which the lack of clear policies on how new approaches or measurements can qualify as endpoints for regulatory purposes serves to impede their adoption, even in cases where the new science is clearly superior.

This has been true whether its process analytic technology for manufacturing or biomarkers for measuring drug response. The transfer of advanced techniques used in discovery to registration trials has been stymied by a lack of consensus on how these approaches can be used as part of the drug registration process.

I said at the outset that improving the development process and infusing it with modern science was only one part of the challenge for helping to unlock the full potential of the enormous investments that we’re making in biomedical research and drug development.

The other part of the challenge is modernizing our approach to monitoring and measuring the benefit and risk of new medical products, so that we learn about these things more quickly after products are approved and integrate them into medical practice more efficiently and effectively.

It’s clear to everyone that it is not possible to learn everything there is to know about a new medicine at the time of its approval. Many of the most troubling side effects are also very rare, and become apparent only after drugs are given to many millions of patients.

And many of the most profound benefits also emerge only through the scientific process of actually delivering medical care.

For all of its modern rigor, after all, medicine remains very much a science, where new truths emerge through a process of discovery and only over time.

Now this is where my work at FDA, and the information I have seen about patient preferences, confirms what I see in my own clinical practice. It is where my anecdotal experience as a doctor is confirmed by the scientific survey data I have seen in my role as Deputy Commissioner.

Patients know life is not risk free, and most people accept a certain amount of risk in their medical decisions. What they dislike is surprises.

Most people are not statisticians, they have imprecise notions of risk, and their acceptance of risk is tied to very personal perceptions and their unique values and temperament. Patients see risk differently from clinicians, and yes, even from the FDA, and they value outcomes differently too.

Studies show, for example, that patients rate low risks with uncertain outcomes higher than known risks with clear outcomes, for example, and they generally want options as much as minimal risk, so that they can manage the risks.

And so as we do more to enable new and potentially lifesaving innovations to more quickly make it to patients who need them, we must also make sure we’re taking new steps to also collect information about new treatments after they are approved, to make sure that we’re learning of potential side effects quickly, and providing up-to-date information to doctors and patients on how they can more safely benefit from these advances.

This post-market monitoring could be one possible alternative to simply putting more and more patients into increasingly expensive and impossible to complete clinical trials to try and tease out subtle side effects that no reasonable trial could ever discover.

And this post market monitoring needs to be done with precision and within a framework that also allows us to use the information we gather to advance our knowledge about benefits and risks.

This is one area where FDA can help, perhaps with additional guidance and discussion on how to appropriately apply epidemiological data sets to the process of learning about drug safety and effectiveness. How we can agree on both the opportunities and the obvious limitations of this kind of data.

It is also another place where FDA can promote the development of safer and more effective innovations.

More than anything, the effective translation of medical innovations is dependent on effective, efficient medical delivery systems. And this is predicated on good information. Patients and doctors need complete, and up-to-date, and timely information to guide decisions about how to make optimal use of new medical innovations.

A lot of our efforts to promote drug and device safety are really aimed at promoting the collection of better information about the safety of new products and the safe use of new medical products after they are approved. And so, the bottom line is this:

Better information also promotes innovation because it enables better uses of resources.

We are also focused on how we can stimulate better reporting of safety information, and adverse event reports, through a new MedWatch Plus that we are developing which will, among other things, make the collection and analysis of adverse event reports easier, and more computer-based.

All of these things, I believe, will help us better develop new medical technologies, and adapt them to clinical practice, where they can benefit patients.

These things are by no means a sure thing, and with so much uncertainty and with the process for developing new drugs become more costly, we are facing a critical moment.

We must decide whether we’re going to take the hard steps that we need to in order to make sure that modern science is able to be used to improve medical practice.

Or whether we squander all of the scientific advances we’ve made recently on a development process that is old and costly and not very effective.

This is going to require a certain amount of scientific risk taking by drug developers. You’ll need to embrace these opportunities to improve the science of development, even if it means moving away from the tried and true, and in some cases, leaving the comfort zone of the way development work has been done for decades.

We have the tools, and we have the approaches at hand. And its time we went about adapting them to the clinical challenges that we face today.

This is the only way we are going to be able to advance the science of drug development, and above all else, the critical path initiative is an open invitation to bring new and better science to FDA to the task of doing these things.

This is a challenge we hope you will take us up on. Because it may be one of the most important ways we’re going to make sure that the enormous investments we’ve made as a society in biomedical research and drug development are able to make there way into new and better approaches to treating and curing diseases -- and to promoting the public health.