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Scott Gottlieb, MD - The Manhattan Institute

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
The Manhattan Institute
New York, New York

on
New Steps to Improve Drug Safety

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

November 13, 2006

As you know, issues relating to the safety of new medical products, and in particular new drugs, have been at the forefront of recent policy making at FDA and discussion inside Washington. These issues are likely to be front and center when the new Congress convenes next year. This focus follows a string of some high profile drug recalls and safety alerts, and more recently, the release of a report from the Institute of Medicine (IOM) that was commissioned by FDA to take a hard, objective look at the agency’s drug safety programs. While the IOM report reaffirmed the competency of FDA’s central programs, it also found that there are some more steps that we could be taking to continue to improve our ability to detect and monitor safety-related issues with new medicines. At FDA, we agree. It is these efforts, and some of the challenges we face when it comes to taking steps to improve the safe use of life saving medical products, that I want to discus here today.

I think the findings made by the IOM mirror our own judgments at FDA, and the report’s recommendations track closely to where we have been spending much of our time in trying to improve our existing programs. I know that the IOM report, and the high-profile recalls over the last several years as well as the newly-emerging safety questions with a handful of drugs, have all called into question among some people whether FDA is doing enough to make sure that drug safety issues are taking a high priority in the development process and during our review process. The truth is we are doing an awful lot, but we know there are steps we can take to do even more, to make sure we have a robust and well-resourced drug safety program.

The bottom line is this: New drugs and devices and diagnostics present the greatest opportunity currently available to improve health care and the way medicine is practiced – in other words – the known benefits of innovative new therapies – from improved patient outcomes to reduced longer term health care costs – these known benefits outweigh virtually all known risks whether its advances in the treatment of heart disease to cancer to diabetes. The number of lives saved and prolonged by new therapies vastly outweighs the risks that the treatments themselves pose, by any logical accounting. It’s the responsibility of all of us engaged in the healthcare enterprise, and especially those of us making policy decisions in Washington where many are removed from the daily struggles faced by patients and doctors and therefore apt to make bad decisions, to make sure that we find ways to make more of these breakthroughs a reality through appropriate incentives to innovate, and to ensure that patients who are suffering with little or no available treatment options get access to these life extending and quality of life improving medicines as early as possible.

But it is also true and we must recognize that all drugs pose potential risks. An active molecule that impedes one biological pathway to help cure or mitigate an illness will inevitably inhibit other pathways that are at the route of normal biology. It is almost inevitable that unwanted side effects, and often very subtle or rare side effects, could be the result. Our challenge is to have systems to unearth these side effects early after new drugs are launched, or during the development process itself. Then we need to make sure we have efficient tools to get information about these potential problems to practitioners and patients so they can make informed, personal decisions about the medical products they use. People need reliable, timely information about drugs so that the can most appropriately balance the risks and benefits of a treatment of their particular health problems.

But in all of these things, we also are challenged to make sure that we are balancing access and innovation against the steps we take to improve our approach to safety issues. This is the fundamental question: will we achieve increased safety and vigilance by leveraging new tools and improving our science of drug development, or will we opt for more expedient policy measures and other blunt instruments that all come at the expense of innovation and serve to thwart new science development rather than leverage it. We need to make sure that our efforts to improve on drug safety do not dampen the process of medical innovation that could itself enable safer approaches to drug development and drug use. Most of all, we need to make sure that the steps we take today do not impede access to new medical products that can be used safely and effectively by patients suffering from too many unmet medical needs today. I am deeply concerned that some of the ideas that have been discussed in broader policy circles for improving on drug safety measures will do little to make our drugs safe, but will do a whole lot to limit access to needed medicines and to slow down the development of new innovations. With so many people today suffering from so many diseases that can be more successfully treated or even cured in the near future, but for continued innovation in new medical products, I don’t think we can afford to take steps now that will only serve to dampen the pace of innovation.

Now let me be clear, I don’t necessarily think improved drug safety is simply a matter of extending new legal authorities to FDA that serve only to add additional burdens to the development process. Instead, it is a matter of ensuring the agency has appropriate resources and the capacity to develop better scientific tools and approaches to drug review. Nor do I think safety and innovation, as well as efficiency in drug development, are in conflict. In fact, I think safety and innovation and efficiency are actually all dependent on one another. Steps we can take to make the drug development process more efficient, more modern, and more risk-based will also improve our ability to detect safety related problems earlier. Steps we can take to improve the way that we monitor drugs after approval will also help healthcare providers have more information about how to effectively target new medicines to make sure that they are maximizing the benefits of new products and personalizing care based on who is most likely to benefit from a particular treatment. In short, we will not achieve enhanced safety programs without also pursuing innovation in the way that we develop drugs, and we will not be able to pursue those innovations if the policy decisions we make today end up creating costly and inefficient obstacles to the development and adoption of new technologies.

This is a truth that I think has been given short shrift in Washington policy circles. Instead, I think most of the focus when it comes to improving drug safety has been fixed on process changes and structural changes in government programs, and not on making fundamental improvements in the science of drug safety. The fact that seems most overlooked is that the current drug safety system – combining pre-market review with post-market surveillance is a complementary one. Both parts of this delicate equation must work effectively together. There has been so much focus on post-market surveillance and even more focus on whether even more hurdles need to be put in place even after efficacy has been proven before providing access to medical therapies to patients. The bottom line is that both parts of this equation need to be transformed, but they must also be balanced. The pre-market review system was never intended to identify and address a potential adverse safety signal that arises only after a product has been in use for many, many years. Nor should the system be modified to delay access for that long because of the possibility some signal might arise. Instead we must build a better post-market system that, in turn, should provide opportunities to streamline development and approval side of the equation. If we do this right, efficacious medicines can reach patients faster with an understanding that assessing safety is both a pre-market obligation and a post market responsibility.

Yet sometimes in the policy debate we hear of proposals that don’t respect this natural balance and these proposals would unnecessarily delay access. Now some policy changes are needed, no government system is perfect and any program – FDA included – can benefit from a hard look at how we can make the management of our programs even better. But like the IOM, we at FDA are at our core a scientific organization. And so I think there should be much more emphasis on the science of how we can improve our drug safety programs today. The IOM, despite its scientific roots, didn’t focus a lot of its analysis and attention to these scientific issues but it is these challenges that I want to concentrate my remarks on today.

This is urgent, because the tools that we use for probing safety-related issues have been underdeveloped for many years, not just within the FDA but across the broader scientific community. Research into new approaches for developing new medicines, research into improving the tools and approaches to clinical research -- everything that happens from the investigational new drug phase all the way through the three phases of clinical trials and through the manufacturing process – all of this science has not received as much attention as preclinical research into uncovering new molecules themselves. The result is that while there is a lot of innovation in the early drug discovery process, there has been a corresponding lack of innovation in the development process itself. Many of the innovative tools and approaches that we use in preclinical development are not being used when it comes to the development of new drugs and the regulatory process itself. This almost guarantees that our approach to developing drugs and evaluating them, are less efficient, less precise, and less revealing than they ought to be.

Through our Critical Path initiative, led by Dr. Janet Woodcock in the Office of the Commissioner, and Drs. Steven Galson and Shirley Murphy in our drug center, we have taken steps in recent years to improve the scientific tools that we use during the development process, to incorporate modern approaches such as pharmacogenomics and proteomics and biological assays to help better inform safety-related questions in drug development. While we have done a lot of work on these things, there is much work that remains. But we cannot do these things alone. While I think that there is opportunity to make a lot of progress by leveraging better scientific tools, we will need a lot of help from the broader medical and scientific communities to develop these tools.

These scientific endeavors will give us the tools we need to improve our approach to safety, but they are just one part of the solution. At FDA, improving on our approaches to ensuring drug safety really boils down to three areas of work that we need to undertake. I want to briefly lay out these three areas, and then, in turn, spend the balance of my time discussing each of them in greater detail.

First we need to improve the information that the agency receives with which to make drug-safety related decisions, including the spontaneous reports we get from sponsors and providers as well as out ability to tap into epidemiological data sets to probe more routine questions and to be able to marshal the resources to conduct more rigorous post-market studies to answer, when they arise, very subtle but important safety-related questions.

Second, we need to improve upon our analytical tools and approaches for evaluating this information and turning raw data about drug-safety related questions into practical medical facts that can be communicated to providers and patients to help them better inform their decision making.

Third and finally, once we draw a conclusion about the data we have, or we are made aware of a potential drug safety problem or an emerging safety issue, we need to do much more to improve the way that we effectively communicate these findings, as well as communicate what the agency is doing to continue to investigate them.

As I said, I would like to talk about each of these three areas of activity in turn, and what we are doing to address each of them. Then I want to close by telling you about some announcements we will be making soon to make clear how we plan to evaluate and respond to the recommendations made to us by the Institute of Medicine, including the formation of an internal task force that will release its findings in December. This task force and the corresponding teams already at work in our drug center since the IOM report’s original release, are implementation teams; and not just another group to come up with another blueprint. The Commissioner-Office-level task force has been charged with evaluating the proposals put forward by the IOM and it will make recommendations about which steps proposals by the IOM report that we can work to implement right away to improve our safety program and which steps will require more time to evaluate and implement – and what we are doing to pursue each of them. We are setting forth a comprehensive process to consider all of the report’s various recommendations. This process includes work groups that are comprised of experts from all of FDA’s medical centers and is benefiting from strong leadership and a lot of ongoing work taking place in our drug center.

Improving the Drug Safety Information FDA Receives
Now onto the three areas of work that comprise our approach to improving upon drug safety, I want to start with the steps we are taking to improve the quality and effectiveness of medical information that FDA receives on which to base its decision making when it comes to important drug safety questions. When you think about what FDA does, at the core of our activity, fundamentally we are an intellectual enterprise engaged in the business of managing information. The agency receives a lot of raw data about new medical products, as well as products already on the marketplace. With the help of our tools, with the expertise and energies of our professional staff, and the aid of clinical guidance we get from experts such as those on our advisory committees, we turn this raw data into medical knowledge about drugs that doctors and patients can use to help guide their decisions about how to most effectively use a medical product to improve health. That knowledge is translated to the labels we help to write. It is what appears in our public health advisories, and what guides our decisions about whether to approve a new medical product and how to most effectively define its intended indication.

But our ability to generate and share this knowledge is only as good as the information we receive. It is dependent upon our ability to get good raw data into the agency. This is an area where we need perhaps the most help from the broader healthcare community.

For one thing, we need access to better post-market information in order to monitor for, and evaluate, potential drug safety concerns. The simple fact remains that all drugs have risks, and not all of these risks are going to be revealed during the pre-market approval process in any reasonably-sized clinical trial. Many of these risks are rare, occurring in fewer than one-in-thousands of patients, and still others wont be revealed until drugs are used in real-world settings, in much larger, more heterogeneous populations where patients take a lot of different medications, have a lot of different co-morbidities, and do not always take their pills as prescribed.

To obtain better information about the post market use of medicines, and in particular post market safety information, we are taking new steps to get access to more post-market information that is being collected as part of health records and other medical databases. For example, earlier this year, we awarded four contracts that give the agency access to databases containing pharmaco-epidemiologic information, which will be used to study the association of various medicines with serious adverse effects.

We also recently worked with CMS on a proposed regulation on using Medicare Part D claims data for research and quality initiatives. Under the proposed regulation, Medicare drug claims would be linked to other Medicare information on patient care such as hospitalizations and physician visits, and made available to researchers and Federal agencies such as FDA for studies, only with appropriate privacy protections and safeguards, as required by the Privacy Act and HIPAA regulations. The proposed rule would provide for the use the claims information that is now being collected for Part D payment purposes for obtaining more accurate, complete, and timely information on potentially serious side effects associated with the use of prescription drugs in certain clinical circumstances.

FDA will also be holding a workshop this spring that will be aimed at exploring better approaches for how the agency can collaborate with third parties, including payers, who may have access to post market information and be interested in partnering with FDA to make this information available to us.

While this kind of retrospective post market information, drawn from large non-randomized, prospective epidemiological data sets, can help FDA spot potential safety problems earlier and can reveal some important answers about safety-related problems, there are also scientific limitations to what this information can tell us. There are always going to be circumstances, for example, where more rigorous, prospective, randomized trials will be needed in order to more carefully answer certain, safety-related questions. This may be the case, for example, in circumstances where the side effect we are evaluating may be very subtle and rare or may already occur as a natural consequence of the disease that a drug is intending to treat. Trying to detect cases where there may be a slightly increased rate of a common adverse event as a result of the use of a drug could be hard and in some cases could even require very rigorous studies like randomized, placebo-controlled evaluations.

So it is important that as we recognize what we can learn from epidemiological data, we also acknowledge the type of cases where more rigorous evaluations will be beneficial. I worry especially about a world where more of these epidemiological data sets will be available where the information was not rigorously collected and the data is very dirty, or where a lot of private third parties like payers, who may not have appropriate expertise in using these data, or have conflicting financial incentives, nonetheless try and draw authoritative conclusions from them. Having poorly done epidemiological studies revealing a lot of poorly-formed conclusions is not going to help advance the public health if all it does is increase the signal-to-noise ratio and obscure the more rigorous and useful information.

To lay out the most appropriate use of epidemiological data sets, to lay out the opportunities that these data offer as well as their limitations and the most rigorous tools and approaches for making effective use of this information, FDA plans to develop a series of new guidance documents. These scientific documents will lay out approaches to making the most efficient and effective use of epidemiology data for analyzing post-market safety, for managing emerging safety information, and for carrying out scientifically sound observational studies using quality data resources. At the same time, with the support of sponsors, I am hopeful that we will be able to use some of the new resources from the re-authorization of the Prescription Drug User Fee Act (PDUFA) to expand on the post-market database resources that we have access to, along with FDA’s capability to carry out targeted post-marketing surveillance, to look at class effects of drugs for example, and potentially carry out signal detection using external data resources.

Existing epidemiological data sets provide one resource for collecting post-market information, and an important one. But there are other tools for collecting this information that we also need to take new steps to expand and improve on. One of these tools is our Med Watch system at FDA, which is the tool we use to collect spontaneous adverse event reports that are filed by patients, practitioners and sponsors. Med Watch is a valuable tool, but we know that it is not being used as effectively as it ought to be. We know, for example, that most adverse events go unreported; in fact, FDA estimates that it only receives about 10 percent of the entire adverse event reports that we could find helpful, and even most of the reports that we do receive are submitted to us by drug developers and not by individual patients and practitioners through our web portal. We think that we can improve reporting by taking steps to make our web portal more automated and easier to use.

So, under the leadership of Drs. Gerald Dal Pan, Paul Seligman, and others inside our drug center, we will be re-launching our Med Watch portal with a new, easier-to-use interface that will allow us to collect more information more easily. We are also working to develop a downloadable software program that can be used by providers who have existing electronic medical records. It will create modules that will enable more regular reporting to Med Watch from the health information systems that providers are already using. We will also be making more regular reporting from the Med Watch database, while preserving commercial confidential information. One of the things that Dr. Seligman is creating, for example, is a regular report – perhaps similar to CDC’s Morbidity and Mortality Weekly Report – that will provide more regular updates on what signals are being reported to FDA as part of its Med Watch system. We think that by making more regular reporting from the Med Watch database, we can better inform the public of emerging safety information that FDA is receiving, as well as prompt additional reporting to the system by prompting healthcare providers who will look out for, and file with Med Watch, certain signals that other people may already be reporting to FDA.

But in the end, the kinds of reports that are made available through post market databases and spontaneous reporting to the agency has one other limitation -- the reports are often old by the time we receive them. We need to take additional steps to try and develop more systems for real-time or near-real-time reporting of adverse events. With the advent of electronic medical records, there is a lot of opportunity to develop more active reporting systems that can scan medical information – real-time, or near real-time -- and look for the tell-tale signs of a potential drug safety problem much earlier than the passive reporting systems that we rely on today. The idea here is that we would be able to spot whether patients started on a newly marketed drug might be showing up, for example, with slightly elevated liver enzymes on routine blood tests and perhaps detect an impending liver toxicity problem much earlier in the life cycle of a new drug, instead of having to wait for a handful of patients to show up with fulminate liver failure and requiring liver transplants.

We already have such active reporting systems on the medical device side of our house, with our Med Sun program, under which we collaborate with a select group of 350 hospitals to collect real-time information about safety-related problems with new medical devices. We announced last Thursday that we will be expanding Med Sun as part of a new post-market safety plan announced by our medical device center. To develop similar systems on the drug side of our house, we recently announced a collaboration with the Massachusetts Institute of Technology to provide technical assistance on the best methods and framework for developing an automated system to detect unanticipated problems with prescription drugs. We are also exploring similar collaborations with other academic groups. Such systems could scour federal and private health care databases in real time for unusual and emerging patterns that could indicate potential safety concerns. A more automated system capable of mining on the fly multiple databases, including those compiled by health insurance providers and agencies like the Veterans Administration, could be better at recognizing patterns suggestive of emerging problems. The specific system being developed by MIT, for example, would build on methods developed to identify infectious disease outbreaks, detect bioterrorism attacks and model the spread of bird flu.

But the rate limiting step for all of these efforts, at the end of the day, is having enough people with the requisite training and experience to work on these things. We have outstanding people in our drug safety office, but there is no question that given the increasing work we need to do, our programs will benefit in the future from additional personnel. Not only more epidemiologists but more clinical pharmacologists, especially people with quantitative analysis and programming skills that have experience building computer-based information tools to manipulate vast amounts of biomedical information. These experts are clearly hard to recruit. There aren’t that many of these people to start with, and aside from those inside FDA, most of them reside inside private enterprise. Government pay scales don’t make our recruiting job any easier. But I am hopeful we will be able to marshal more resources for these things from our existing streams, including new money that the drug industry can allocate as part of the re-authorization of the Prescription Drug User Fee Act (PDUFA) toward hiring these additional personnel.

Getting better information to make drug safety decisions doesn’t just comprise efforts to improve our post market data systems, but also efforts aimed at improving our pre-market data. The fact is that there is a lot we can do to improve the drug development process itself, and especially the tools we have for evaluating common drug safety problems like liver toxicity or cardio toxicity. Developing these kinds of tools, whether they are better assays to screen for drug safety problems or better clinical trial designs so that we can learn more information about drug safety questions, are at the heart of our Critical Path initiative, led by Dr. Woodcock.

A lot of this scientific work is being done through collaborations the FDA has struck with academic medical centers and not-for-profit scientific institutions. One such collaboration, with the Duke Clinical Research Institute, is working on mining data from more than 250,000 electrocardiograms to identify trends and early indicators of cardiovascular risk in new and existing drugs. Some of these collaborations are also with private industry. FDA’s new Liver Toxicology Biomarker Study, to be conducted under a Cooperative Research and Development Agreement between the FDA's National Center for Toxicological Research and a small, Massachusetts-based biotechnology research company, is aimed at developing assays that will help better predict signs of human liver toxicity in the initial stages of drug development. A similar effort was recently begun through a consortium of pharmaceutical companies, about twelve in all, that agreed to collaborate with the not-for-profit Critical Path Institute, headed by Dr. Ray Woosley, in order to share data on predictive tests used to assess the safety of new molecules during preclinical drug development. The Predictive Safety Testing Consortium between C-Path and some of America’s largest pharmaceutical companies will enable the companies to share internally developed laboratory methods to predict the safety of new treatments before they are tested in humans. The FDA, while not a member of the Partnership, has been providing advice on an ongoing basis.

This unprecedented sharing of potential early indicators of clinical safety is enabling sponsors to share knowledge and resources to determine which of the lab tests that they have developed individually should be recommended by the FDA to screen drugs and better understand the potential side effects before the drugs enter clinical testing in humans. Companies will share the details of the methods that each has developed for specific kinds of tests and then agree to test another’s method to determine if it is reproducible. The results of the comparison will be collected and summarized by C-Path for submission to the FDA. Those methods that the FDA finds to be reliable and reproducible will form the basis for agency-issued guidelines about which safety tests should be used in the drug development process. Currently, predictive safety tests internally developed and used by each individual company are of limited value to the FDA because the methods used have not been validated by an independent party. Under this Consortium, member companies will share the information that will enable them to have their tests validated by C-Path’s outside experts and other members of the Consortium.

Getting better information about drug-safety related issues also means we have to develop tools to make more efficient and effective use of the information we already receive as part of marketing applications. To these ends, the FDA is going to be holding a public Part 15 hearing on December 18th to discuss the next steps for moving toward the electronic submission of all regulatory information; and on creating a platform to enhance the electronic exchange, access and management of information submitted as part of an application. The purpose of the hearing is to solicit general information and views from the broader community on the impact of an all-electronic submission environment, and to receive input on important design elements of an electronic regulatory information exchange platform so we can provide the greatest effectiveness from such a system, at the lowest cost.

The scope of this public hearing will focus on three issues in particular: The FDA’s intent to require the electronic submission of investigational new drug applications, new drug applications, abbreviated new drug applications, and biologics license applications to the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER), and the effects of such action on stakeholders; the eventual extension of the requirement to submit electronically required documents and information for other regulated products, for example adverse drug reactions, other pre-market applications, and amendments to applications; and the concept of a public-private partnership to initiate creation of and demonstrate the feasibility of maintaining an electronic platform that facilitates the exchange of clinical research information and other regulatory product information. Once feasibility is demonstrated, it is anticipated that these functions could be assumed by a private entity or entities with the relevant expertise and organizational leadership to provide specific services related to creating and managing an electronic platform to facilitate the exchange of clinical research information and other regulatory product information that also protects commercial confidential information. Such entities would continue the development and execution of these services in support of government, industry, and academic stakeholders. The bottom line of all of these efforts is that if more of the information we receive about drugs were submitted to the agency in electronic formats, there is no question that we would be able to make more effective use of this information. The FDA sits on the world’s singular repository of drug safety and effectiveness information, but so long as a lot of it remains locked away in paper archives, it is hard for us to explore ways to leverage this knowledge while protecting commercial confidential information.

Finally, getting better information about drug-related safety issues also means we need to take new steps to get better information about drug efficacy, and in particular, how certain drugs work in particular populations. If we can develop more information about who is likely to experience more of the benefits of a new medication, we can target drugs much more efficiently and effectively, by using them in people who are likely to experience more of the benefits and perhaps fewer of the side effects of a particular drug.

All of the resources that are used for probing safety-related questions, whether they are prospective trials or retrospective epidemiological data sets, can and must also be used to probe questions related to effectiveness. We need to be equally focused on finding new applications for medicines, and for refining our existing knowledge so that we can more precisely match a drug to a patient. To these ends, earlier this year, we also announced that under the leadership of Bob O'Neill in our drug center, we are working on a series of guidances to establish a clear framework for how product developers can user adaptive approaches to designing clinical trials and enriched clinical trials where the population of patients that a new drug is tested on are selected based on clinical characteristics that are believed to predict their likelihood of benefiting from an intervention, or avoiding certain side effects. The most significant advantage of these approaches is that they allow sponsors to develop a lot more specific information about who is likely to benefit from a new medicine, and the clinical characteristics and markers that can be used to guide new drugs to those patients. The problem is that right now; medicine itself is highly empirical, meaning that we expose populations of patients to a drug based on evidence that a certain percentage of patients are going to experience a benefit. We have very little information, in many cases, to tell apart patients who are going to respond to a treatment, and those who will not. When patients don’t respond to a drug therapy, we simply assume they were part of the percentage of patients in the clinical trials that didn’t benefit from a treatment, and we try a new approach. Adaptive approaches can help make medical practice itself much more personalized, by enabling the drug development process to yield much more useful clinical information about which patients are more likely to respond to a treatment or avoid an unwanted side effect.

To help facilitate these approaches, FDA committed to producing a series of guidance documents to drug developers – five in all – that will help articulate how sponsors can take more adaptive approaches to clinical trial design. We are also taking other steps, some of which will be spelled out in guidance as well, to enable much more personalized approaches to drug development. For example, one of the guidance documents we are working on right now will help tell drug developers how they can seek approval for a drug and a diagnostics used to guide the drug to the right patients, all within the same registration trial. To help create additional incentives and efficiencies to this kind of drug development, we are going to explain how sponsors can seek accelerated approval for a drug aimed at a front-line indication like stage one cancer, in cases where the drug, by being coupled to a diagnostic test that guides treatment decisions, shows superior efficacy in a subgroup of patients over and above the available therapy that is being used to treat a serious and life threatening medical condition.

Improving Analytical Tools for Evaluating Safety Information
These are just some of the steps we are taking to improve the information that FDA has available to it on which to derive sound clinical information about medical products that can help guide more personalized, more informed decisions by providers and patients. But the next step, improving upon our analytical tools and approaches for evaluating this information, is also critically important. This is the part of the process where I believe FDA excels -- where we are truly world class. But like a lot of other parts of our complex work, our analytical approaches have not benefited over time from some of the same resources and tools used in other similar intellectual enterprises, and in particular, from sophisticated bioinformatics tools and applications. So while our analytical approaches are first rate, here again, there are steps we can take to make our work even better.

I don’t want to dwell too much on this second point. But will leave you with one example of how I think a better information technology backbone, along with dedicated resources to develop bioinformatics applications, can improve the tools we have to do our analytical work.

The system that we use to collect and process the adverse event reports that are filed with the agency as part of Med Watch is called the Adverse Event Reporting System or AERS. This is an application that was developed about a decade ago, and to distill it down to its core function, it is basically a routing system. It will do some preliminary analysis of the particular adverse event report in order to find out the drug involved and the nature of the observed problem, and it will then route the report to the most appropriate medical reviewer inside the agency, whose job it will be to further evaluate the report. This often requires safety evaluators to call the physician or patient who filed the report or to collect other information that might help inform the agency about whether the observation could be related to the drug, and what the most appropriate next steps are to investigate it. This, I think you would agree, is hardly the most robust use of information tools. A better system, that makes more effective use of technology, might scan other databases to try and cull out similar observations, or scan the medical literature for case reports or letters with similar reports. A better system might apply some preliminary statistical analysis in order to determine whether other similar observations are occurring at a higher rate with the drug in question. A better system might scan databases to find other similar reports that might have been casually linked to another drug, but where the patients were also on the same drug that the current report is related to.

To help develop a better system like this, which leverages basic tools to enable a higher level of analysis to assist medical reviewers and help them more easily gather pertinent information, we have recently formed a bioinformatics board headed up by Dr. Janet Woodcock inside the Office of the Commissioner. This new board will be charged with overseeing the development of common bioinformatics applications across all of FDA’s centers. By pooling resources, and developing common applications that can then be tailored or modulated to suit the individual needs of the different programs, we believe we can make more effective use of our infrastructure to develop more advanced tools. Among the first priorities for the new board is development of a second-generation adverse event reporting system that makes the inclusion of more sophisticated evaluative tools possible. In this effort, the Bioinformatics Board will be working closely with Dr. Gerald Dal Pan, who will be spearheading an effort underway inside our drug center to build a second generations AERS system.

Steps to Improve Risk Communication
The third and final area I wanted to discuss is communication. Once we draw a conclusion about the data we have, or we are made aware of a potential drug safety problem or an emerging safety issue, we need to improve the way that we communicate these findings, as well as communicate what the agency is doing to continue to investigate them. In short, we need to approach the social sciences in the same kind of way that we have approached the hard sciences, by focusing on developing better tools, and more consistent and modern approaches. The truth is that we have not, until more recently, consistently viewed social science as something that can be approached as a hard discipline with its own tools and metrics for measuring effectiveness. I think that has changed for a lot of reasons, and we are increasingly focusing on risk communication but also on the social science of improving the ways we can present information more effectively, and then equally important, measuring the impact of those communications.

One reason we are focusing more attention on this is simply that the complexity of the products we regulate has grown. They have more complex labels and more complex sets of indications and warnings. And there is a greater reliance in healthcare generally on the products FDA regulates. These are all good things, because they suggest that more people are benefiting from more medical products. But these things also make communicating risk and benefit information more complex. In addition, we are increasingly talking much more about unsettled science, because people want that information but also because that information is important to medical decision making by patients and providers. Talking about unsettled science is a much more complicated communications challenge than simply disseminating hard conclusions. It has required us to calibrate our speech and the tools we use more closely to match the type of information we are disseminating. The truth is, until recently, we never gave as much thought to how our information was being presented. We saw as our mission to develop useful medical information out of the raw data we analyzed, but we didn’t spend as much time worrying about how that information was being picked up by the broader community once we posted it on our web site or put it out in an advisory. I think we need to think more about these things, especially as we communicate much earlier in the process, not only about proven risks that have been shown to be causally linked to the drug, but also risks that we are worried about and still actively investigating.

To these ends, we have taken a number of steps recently to not only improve how we communicate information, but also to build new tools to measure the effectiveness of our communications strategies and our social science endeavors. Our drug center has been reorganized to include a senior office devoted to risk communication. We will be putting out soon a final guidance that will codify new steps we have been taking to communicate important drug safety information more effectively. We are committing to developing new tools for improving the way we approach social science endeavors such as evaluating drug names for whether or not they might present confusion to providers. More specifically, on this point, we will be developing guidance that will spell out how sponsors can rigorously evaluate their drug names, in a scientific fashion, to objectively measure whether they might present confusion. Instead of evaluating drug names through our own subjective and objective tests, we will instead be more in the business of evaluating rigorously-derived social science data about those names. We have also taken new steps to leverage providers in many of our risk communication endeavors, partnering for example with the Heart Rhythm Society to improve the way that we communicate safety-related information about electrophysiology products. And we have dedicated resources inside our Commissioner’s office to building collaborations with medical professional groups to engage them in more of our risk communication and risk minimization endeavors.

On this last point, I want to close with one thought that I think is important for all of us to consider. I think there is an essential tension that emerges when it comes to the intersection between FDA’s work, and with the practice of medicine – that is; the work that goes on in thousands of hospitals and doctors offices every day. On the one hand, there is a desire on the part of some to see government agencies, including mine, take a more active role in minimizing risk from medical products by more actively setting forth conditions on how they should be used. I am speaking specifically about the growing attraction by some to the concept of risk management plans. On the other hand, these risk management plans address real problems. So in the absence of these plans; I think there is going to be a need for the medical profession, and particularly the professional societies, to take a more active role in enforcing clinical practice standards to achieve some of these same purposes.

The inherent principle that defines the concept of being a profession is self governance. While some may dispute whether the Federal government has the authority to regulate aspects of the practice of medicine, the bottom line is that practice conditions were typically a responsibility delegated to the states which in turn relied on a degree of self governance from the profession. If the profession does not take a more active role in addressing issues of risk associated with the growing benefits but also increasing complexity of the medical products we use, then I worry that there may be a growing desire by some to see the federal government intrude on these decisions, and that could have troubling consequences for patients.

Now don’t get me wrong, as I said, I think the places where FDA has employed these approaches have generally been judicious and carefully thought out. But I do worry about a future where these kinds of tools may become much more commonplace, because I think it will be too burdensome to the healthcare system generally. I also worry that the risk management plans could end up creating obstacles to access for patients who already face significant problems accessing innovative care. For example, some risk management plans could push complicated primary care drugs into the hands of specialists. That puts at a real disadvantage patients who often can’t get access to specialists. These are sometimes the very same patients who already face significant obstacles accessing quality medical care. In the clinic where I used to work for example, many diabetics never got to see endocrinologists on a routine basis. They got most of their care from generalists. So if we can achieve more of our risk minimization goals simply by making more effective communication of the risk and safety information we develop, and leveraging medical professional societies to enforce their own practice standards and approaches to safety, then I think we can mitigate at least some of the reliance on more prescriptive measures like voluntary risk management plans that restrict distribution or prescribing behavior. I am not trying to say that better communication is going to solve all of the challenges we see, but we need to make sure we have done all we can to make maximum use of better tools for communicating information and partnering with providers before we take more restrictive steps.

In these endeavors, and many others, we are going to need much more help from the broader medical community than we have enjoyed. I think it does little good when doctors who edit science publications, like the editor of the journal Science, or the doctors who run the leading medical journals pass their time throwing brickbats at FDA from the sidelines. If they really care about our drug safety system, and they want to make it better, then there is a lot doctors-editors can do by getting more directly involved. The medical journals for one are in a very unique position to help us in our risk communication efforts when it comes to informing physicians.

Some of our goals, such as improving the safety-related information we have and the analytical tools we use to evaluate it, as well as elevating the role of risk communication, are recommendations that were also made by the IOM and endeavors we think are critical to our achieving our mission. As I mentioned at the open of my remarks, we recently formed an internal task force to formerly respond to IOM report, to see what measures we can work toward implementing immediately and what measures will take some more time to fully evaluate and perhaps implement. It’s probably the case that there will be measures that we think are not compatible with an efficient, risk based review program. But I think many of the IOM’s broad ideas are helpful and still many more consistent with programs and efforts we have underway or have intended to begin working toward, but many of these ideas are going to require us devote new resources to improving the tools available to FDA and to better developing the science of drug development.

As the complexity of our mission increases, along with the complexity of the products we are asked to evaluate and oversee, we are going to need to work much more closely with, and receive much more support from the healthcare system and medical providers in particular, than we have in the past. We have taken to steps to enable that relationship, but we’re going to need more help to succeed. So I hope to work with many of you to achieve these goals, and appreciate the opportunity to be here today.