FDA Commissioner: 'Safety Science' Key to Drug Regulation

Eli Y. Adashi, MD; Margaret A. Hamburg, MD


February 02, 2011

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Eli Y. Adashi, MD: Hello, I am Eli Adashi, Professor of Medical Science at Brown University and host of Medscape One-on-One. Joining me is Dr. Margaret Hamburg, Commissioner of the US Food and Drug Administration (FDA). Our topic is drug safety. Welcome.

Margaret A. Hamburg, MD: Thank you very much.

Dr. Adashi: When you were appointed FDA Commissioner, the agency was criticized for deficiencies in scientific expertise and for antiquated information technologies. And you yourself stated that regulatory science was going to be a priority during your tenure. Can you tell us what you mean by "regulatory science" and describe how you think it will transform the FDA's drug safety program?

Dr. Hamburg: First, let me stress that the FDA is an agency with a long and really distinguished legacy and tradition, and of course our mission is to promote and protect the health of the American people. I do think, however, that it has been underappreciated, and in many ways underfunded, over a prolonged period of time.

This is a critical moment to really galvanize the FDA into action and to work with our critical stakeholders to make sure that we're positioned for the 21st century. A big part of that is strengthening science, because we are a science-based, science-driven regulatory agency with a public heath mission. And that means strengthening science within our walls so that we are fully equipped in terms of our scientists and our capabilities to review and make decisions on all of the medical products that come before us.

It also means we need to work with academia and with industry and other government scientists to make sure that the field of regulatory science is fully developed and fully applied to the regulatory process. By "regulatory science" I mean the knowledge and the tools that we need to evaluate the safety, effectiveness, quality, and performance of medical products that come before us. It cuts across disciplines. It cuts across stages of the medical product research and development process. It's really an essential bridge from discovery and the recognition of opportunities in science and technology today and the ability to have a fully formed product that people can use and rely on.

Dr. Adashi: Would it be an exaggeration to suggest that regulatory science is in effect a new discipline?

Dr. Hamburg: Well, I think it's been long standing in terms of aspects of it, but what I'm trying to do is focus new attention on it, strengthen regulatory science, and in a sense, build it out as a new field in terms of its recognition and place in the overall scientific enterprise. Because if, as a nation, we don't pay attention to strengthening the field of regulatory science and better applying it to our research and development efforts, and of course the review process, then I think we will increasingly lose our competitive edge: We will fail to realize and harness all the potential of scientific research today, and at the end of the day, we will fail to give the American people, and people around the world, what they badly need and deserve.

Dr. Adashi: The FDA has always had to balance the competing interests of speeding new drugs through, while at the same time ensuring safety. You have said that you intended to be a "tough cop," but you have also highlighted the need for new treatments, such as new antibiotics. How do you strike a balance?

Dr. Hamburg: It's a continuing challenge, but it's at the core of what we need to be all about. We joke sometimes that from the outside, there are only 2 speeds at which the FDA operates, too fast or too slow. But what we're trying to do is find a way to look at products across their lifecycle in a way that's constantly balancing risks and benefits. We have to make sure that we are harnessing all of the opportunities in science today and that we are making sure that important new discoveries and existing knowledge translate into products that people need.

We also feel that we have a very important role looking out the other way at what are the unmet public health needs and trying to galvanize action to move new products through the pipeline to address that unmet public health need.

We have a real responsibility not just to review products that come before us and to approve them if the data support that decision, but then to follow them once they're in the marketplace. Those of us in the medical scientific community know that you can never expect to understand everything about a drug when it's in the early basic and clinical studies, that the numbers are too small and the patients are selected in more targeted ways to be able to answer critical questions about efficacy and about safety. But when it goes into the marketplace, and you're going from maybe thousands of patients in clinical studies to hundreds of thousands or millions of people taking them, including patients who have other complicating medical conditions or are taking other drugs, you start to see potential issues with drugs that you might not have seen in the clinical research setting.

So it's very important to have this lifecycle approach, and we are increasingly engaging in new ways to study drugs in the marketplace and look for emerging safety signals and analyze them. At the same time, Congress has given us new tools and authorities to help support the appropriate use of medications when they're in the marketplace: new standards for safety warnings, new abilities to approve a drug but require additional ongoing clinical studies, mechanisms that allow us to both help move products out into the marketplace but continue to monitor them so that we can protect the safety of the American people over the longer term.

Dr. Adashi: So in a way, much of this is undergirded by the realization that there is no amount of premarket study that can actually project safety, with certainty, when the drug is out in the market.

Dr. Hamburg: That's right. We all understand that nothing is absolute. There isn't a drug out there that is 100% safe under all conditions, and there's very little in life that is 100% safe under all conditions.

Our responsibility is to continually be gathering the best possible information that we can and applying it to the circumstances before us, and recognize that the balance between safety and risk has to be a dynamic one, and we have to be thinking about the circumstances. The level of risk that an individual is willing to accept is very different if they have a life-threatening disease and no other options, than if they have a minor condition and lots of other options. So, you have to factor in a number of things as you look at that important safety-risk balance. Getting information out to healthcare providers and to consumers is a critical part of our mission.

Dr. Adashi: Counterfeit and tainted drugs: How much of a problem is it, and where does it end up in your list of priorities, in your overall focus?

Dr. Hamburg: I view this as a very serious concern, one that is less of a burden here in the United States in large part, because we do have a strong regulatory system of oversight and work closely with the industry to ensure the safety of drugs here in this country and of the supply chain. In many parts of the world, particularly the developing world, some estimates are that as much as 30%-50% of drugs in the marketplace may not be what they purport to be, and that is just extremely troubling.

As the world gets more globalized, all nations have to come together to think about and address this problem and find meaningful and sustainable solutions, because the supply chain for drugs is now very international. Just think about the fact that in this country, 80% of active pharmaceutical ingredients in drugs taken in this country actually come from other countries. It means that we have to not just be a domestically focused agency; we have to be global in our presence, in our outreach, and in our interactions. Looking forward, a focus on ensuring the safety of the supply chain and the safety of all drugs (imported and domestic) is absolutely essential. We know that the problem of counterfeits is real, and we cannot be complacent.

Dr. Adashi: Speaking of globalization, clearly the supply chain is a big issue, and then there are the clinical trials themselves that seem to be transpiring all over the world now. How well situated are you -- because this has been a challenge in the past -- to actually increase the level of oversight as much as possible, looking to these ongoing issues?

Dr. Hamburg: It's a very, very interesting time for us at the FDA because the world is increasingly globalized, and it matters for product safety and imports, and it matters because science is a global enterprise as well. More and more we're seeing research studies that we're using as the basis for approval of medical products that come before us that have actually been undertaken in other countries often networks of other countries. So it's very important that we work on the international stage to ensure the appropriateness of the science and the ethical conduct of those studies.

It's very valuable in many ways to be able to work internationally with partners, to be able to do certain studies. If you have a disease that's relatively rare, you can amplify the numbers of patients in clinical studies by working in partnership with people around the world. If you have a disease that's endemic in one part of the world but not here, but still matters to us here, then there obviously are important opportunities to study that disease in other countries. And of course, for many reasons, research done in other countries is used for the approval of drugs here, so we have to think in new ways globally.

We work closely with sister regulatory authorities around the world. We're actually asked very frequently to offer technical assistance for good clinical practice and the oversight of clinical studies for the regulatory process, and we are also making a new commitment to work with regulatory authorities in the developing world, in particular in other parts of the world where the regulatory systems are much less mature, so that we can raise standards everywhere, and that will benefit us all.

Dr. Adashi: It's a small world after all.

Dr. Hamburg: That's right.

Dr. Adashi: When a drug that was already approved is pulled from the market, does that represent, to your way of thinking, a failure of the process? Or was that simply yet another example of the inevitable imperfections of passing judgments during premarketing and even after advisory committee evaluations?

Dr. Hamburg: It's a complex process to review a new drug or other medical product, and it's one that we shouldn't be thinking about in terms of, "Are we going to make a mistake?" or, "How is this going to play out in certain quarters?" What we need to always be looking at is what do the data tell us now and what additional data do we need to make the best possible decision? Then we need to constantly be revisiting our decisions if new data come in.

If a drug that's approved is shown to have a safety concern, we need to take that very seriously. It's not that it necessarily reflects that a mistake was made; it may reflect new emerging knowledge about that drug in practical use. But I think it's very important that we always focus on what matters to people, what matters to the health of the public, and take our actions accordingly. That is certainly the motivating principle for everybody that works at the FDA: to be able to serve the health and well-being of the American people. I don't like to even think about it in terms of failure. It has to be a dynamic process, and we should never be afraid to look a problem in the eye and take the action that's necessary.

Dr. Adashi: Our viewers are providers; what would you like to say to them in terms of what they might be able to do to help us all keep drugs as safe as possible?

Dr. Hamburg: We have to work in very close partnership with healthcare providers. Getting the best possible information out to providers in a timely way is a critical part of our success in making sure that products that we approve are used as intended. It's also critical that it's a 2-way conversation in that we hear back from providers about problems that they may be seeing in their practices, and we rely very heavily on reports that come in about potential safety concerns, and issues of how medical products are actually being used in practice.

It's a critical partnership, and we're very grateful to organizations that help us both get information out to providers and remind providers about their responsibilities, in turn, to keep us informed about the use of these products in the real world.

To report drug problems, go to FDA's MedWatch site.

Dr. Adashi: Taking just one example for the sake of this discussion, the story of [rosiglitazone], this was on the pages of newspapers and in the news media for a long time through a torturous path. What can we say we have learned from that process? Has what happened in any way affected what we're doing now and going forward? Is there more to be said now that we are more or less at the tail end of that one?

Dr. Hamburg: That's just one example of the fact that science is complicated and that, as we look at certain drugs and at certain issues that have been raised around those products, we need to bring the best advice possible to the table. We need to hear all perspectives. We need proactively to make sure that the right studies are being done so that we can make the best possible decisions. However, there isn't always an absolute, clear decision to be made, and it requires this dynamic balancing of risks and benefits, asking questions about whether there are certain subpopulations of patients who may be most appropriate for targeted use of a drug, whether the safety concerns are, in fact, sufficient to mean a more active withdrawal of a product from the market.

Complicated questions have to be asked, and we need to try to make sure that we have all the best possible data to bring to bear in our decision making; we must rely on many external experts as well as our own internal experts, and sometimes we must have raucous debates about what are the best pathways forward. But it's not always either/or: Is it a good drug or a bad drug? Should it be on the market? Should it be off the market?

As we look down the road, some of these issues become even more complicated as we learn more about targeted therapies. It requires us to become more sophisticated in our science; how do we ask and understand the questions about subpopulations of responders, or subpopulations of individuals who may suffer specific or additional adverse events?

Of course, it also speaks to the question of regulatory science, the need to keep addressing the level of sophistication of application of advances in science and technology to the regulatory process, and a key area there is safety science. We really need to continue to develop the science of safety and what kinds of studies can be done to deepen our understanding of safety, how to use the data and what weight to put to different kinds of data. That's an area that we're getting much more deeply engaged in because it is so critically important to the safety of patients and consumers.

Dr. Adashi: On a personal note, your father was President of the Institute of Medicine (IOM), and you have served in a variety of public health roles. How do you view the evolving role of advisory and regulatory groups in protecting public health in general? Do you think that they are effective and that they are working collaboratively with healthcare providers?

Dr. Hamburg: First, let me say that entities like the IOM are invaluable partners in the work that we do at the FDA, and at many of our sister agencies in government, in terms of providing sound advice, bringing together experts to help grapple with some of the most pressing and important biomedical challenges before us today. Of course, the National Academy of Sciences -- of which the IOM is a branch -- was developed by President Abraham Lincoln to provide that kind of important counsel to government. We do rely on the IOM and other important professional organizations and societies, as we think about and address critical problems that come before us.

We also use advisory committees to the FDA as part of our decision-making process, and that is very crucial to what we do. Those engagements are very important. It's another arena where many of your viewers can really be of service to us in terms of participation in those advisory committees in areas where they have specific expertise. I would encourage viewers if they have an interest in participating with the FDA in a more formal way through the advisory committee structure, to let us know.

Dr. Adashi: Thank you. On that note, I would like to express my sincere thanks to Commissioner Hamburg and to you, our viewers, for joining Medscape One-on-One. Until next time, I am Eli Adashi.


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