Print BCTV: FDA's Hamburg -- FDA's Hamburg on personalized medicine, globalization, budget, patients

FDA's Hamburg

Transcript of BioCentury This Week TV Episode 166




Dr. Margaret Hamburg, Commissioner, Food & Drug Administration




President's Council of Advisors on Science and Technology (PCAST)

American Society of Clinical Oncologists (ASCO)

New England Compounding Center (NECC)


National Institutes of Health

Dr. Francis Collins, Director, NIH

New England Journal of Medicine

Bio Markers Consortium



Steve Usdin, Senior Editor




STEVE USDIN: The FDA has made a bold move to advance personalized medicine. What will it mean for patients in the search for new therapies? We'll ask FDA Commissioner Margaret Hamburg.


I'm Steve Usdin. Welcome to BioCentury This Week.


NARRATOR: Your trusted source for biotechnology information and analysis, BioCentury This Week.


STEVE USDIN: Precision medicine is getting the right drug to the right patient at the correct dose. This has been the goal since Genentech's Herceptin was approved for breast cancer 15 years ago.


The idea is to target the cause of a specific patient's disease, often by using tests to reveal genetic mutations. But progress has been slowed by the expense and time needed to develop unique tests for each drug.


News from FDA last week could break the one drug, one test model, making precision medicine more widespread. It approved a next generation gene sequencing technology from biotech company Illumina that quickly and cheaply sequences a patient's genome or her tumor's genome.


Instead of ordering a battery of tests, a doctor can treat a patient based on a single result. NIH Director Francis Collins and FDA commissioner Margaret Hamburg profiled the possibilities in a New England Journal of Medicine article.


Today, we'll discuss this new technology and how sequestration is affecting FDA's ability to assess breakthrough technologies with Commissioner Hamburg.


The article Dr. Hamburg co-wrote with Francis Collins says the technology FDA's approved opens the door for the transformation of research, clinical care and patient engagement.


Dr. Hamburg, thank you for joining us again at BioCentury This Week. That's a pretty bold statement. What did you mean by that?


MARGARET HAMBURG: Well, I think we are at a critical point in the road, where science and technology is evolving to a point where we have to think about and use this important genetic information in new ways.


And certainly, it means we have to rethink something about our paradigm for how we review diagnostics and how we link diagnostics to the ultimate treatment of disease.


STEVE USDIN: Do you think we're going to get to a place where the idea of one drug and one companion diagnostic that goes with it is going to go out the door, and instead we'll have these broad screening platforms, and the competition will be around how do you interpret that data, rather than making expensive tests?


MARGARET HAMBURG: Well, I don't think one drug and one diagnostic link to it is going to completely go out the door. But it can't be our only strategy.


We need to think about the fact that if we can get this whole array of genetic information, it will give us insights into the nature of a particular individual's disease and then we will be able to be much more flexible in determining what are the right interventions.


There may be, of course, multiple interventions that are indicated by that information. But I think we have to really think and act in new ways.


STEVE USDIN: So one of the things that's interesting about this news that came out last week is that FDA really -- and I suppose working with NIH -- really took a proactive approach in trying to come up with a way to get this platform, get this technology out there.


In general, do you see that as FDA's role, to try to facilitate and move forward science and medicine? Or is it more reactive that you just wait and you get applications and see what comes across the door?


MARGARET HAMBURG: Well, my attitude is that we want to be full partners with the broader scientific and innovation enterprise, and that we are a critical piece of what it takes to actually translate discoveries in science and advances in technology into real world applications for patients.


And it's hard. I mean, we do have to operate within, number one, our legal regulatory frameworks. And we have to always be thinking about, what are the appropriate standards of evidence? What is a framework for regulatory review that is consistent and clear and can be used by the many different players and stakeholders in these efforts?


But I think we have to recognize that we have to change and modernize and adapt to a scientific landscape that's changing very rapidly.


STEVE USDIN: And one of the other things you mentioned in the New England Journal of Medicine article is the notion that patients and physicians are also going to have to adapt. What did you mean by that? What are those kind of changes?


MARGARET HAMBURG: Well, there's so much new information out there. And it is unfolding very rapidly. So physicians can't rely on what they learned in medical school anymore.


The necessity to keep up with the evolution of new information and new treatment strategies and approaches -- and for patients, who are less familiar with the sort of background context of some of the science, it's an even more challenging situation. But patients want to be very involved, and with the internet and other technologies are reaching out and getting information for themselves.


So really, the physician-patient team determining what is the best treatment strategy overall for an individual case and the individual needs is just a more demanding task than it was when I trained.


STEVE USDIN: And so having this gene sequencing information is going to be really important for that.


One of the things that you also mentioned in the article, and you mentioned it in a speech that you made last summer at ASCO, the American Society of Clinical Oncologists, is that you think that FDA needs to regulate what are called laboratory developed tests. Basically, the kind of test that got approved last weekend that are pushing cancer therapy and other therapies forward.


What's happening with that? I know there's been a proposal in to the White House for more than a year, probably, about that.


MARGARET HAMBURG: Well, we do feel strongly that we need to look across the array of diagnostic tests and technologies, including developing technologies, and really take a risk-based approach.


What we care about is not the specifics of where the test was developed, but whether the test does what it says it does and whether the claims being made are, in fact, accurate. Because we want to serve the needs of the patients and, of course, the healthcare providers.


And there have been instances where tests have not gone through the FDA review process, have not been held to a standard of evidence to really ask and answer the important questions of analytic and clinical validity, and patients have been harmed.


So we think that, especially as we're moving into this next era with whole genome sequencing and an array of important information that can bear on a patient's health, that we really need to have a more comprehensive, but risk-based, strategy. We don't want to review everything.


STEVE USDIN: So are you going to get that authority, and you're going to be able to get that draft guidance out to tell people how you want to do it?


MARGARET HAMBURG: Well, we are trying to move forward on it, because we think it's important, and we can see how science and healthcare is moving around us. And so I think everybody wants to see this information. And I am hoping we'll be able to get it out for comment and feedback and a continuing shaping in.


And all of this is going to be a dynamic process. The science and technology is moving too fast for us to put rules in place that are rigid.


STEVE USDIN: Thank you, Dr. Hamburg.


Precision medicine is already transforming medicine. FDA approved record numbers of drugs, including targeted drugs, in 2011 and '12. Can they keep it up?


NARRATOR: You're watching BioCentury This Week.



STEVE USDIN: We're talking with FDA Commissioner Margaret Hamburg about personalized medicine. Dr. Hamburg, we just saw that list showing an increase in the rate of FDA approvals of new drugs.


There's this new program that's just kicking in called Breakthrough Therapies where FDA is getting more involved in developing new breakthrough drugs.


There have been 30 drugs that have been designated like that, 100 applications. First, do you think the Breakthrough program's really going to make a difference, and how? And second, do you have the resources to be able to keep this up?


MARGARET HAMBURG: Well, two really important questions. I do think the Breakthough pathway is going to make a difference. Frankly, we've been a little bit surprised by how popular it's been. And actually, in recent weeks, we've approved our first two drugs using the Breakthrough designation.


One of the things that's really important about Breakthrough is that it reflects the importance of a discovery that's going to make a difference for patients. And that the more we can engage early, the more we can help shape the development process, in terms of, what are the right kinds of studies, what is the data that's going to be required for the ultimate review and potential approval, the more efficient it will be, the more targeted the scientific development.


And of course, the review will be more efficient as well. The challenge, of course, as you rightly note, is that this is more resource-intensive for us.


And while it makes a huge difference, it is something that actually wasn't factored into the User Fee negotiations that were part of the PDUFA V, and part of our current budget allocations.


And it has been more popular than we expected, and it is resource-intensive in terms of people and ultimately, dollars as well.


So that's going to be a challenge, but I think it's sufficiently important that we have to work together to try to find a way to make it work.


STEVE USDIN: So another thing, shifting on, another thing there for the future, the PCAST, the Presidential Committee of Advisors on Science and Technology, recommended that FDA create, and the Congress create something called, Special Medical Use, a new pathway for approving drugs for limited populations.




STEVE USDIN: Is that something -- do you think it's a good idea? And do you think it could actually happen?


MARGARET HAMBURG: Well, it's another example where we're trying to think in some new ways, and to try to be flexible, smart regulators.


It was really developed recognizing that there's some critical, as yet not fully met, public health needs in areas like antibiotic-resistant infectious diseases, or broad chronic disease problems like obesity where the incentives for sponsors and drug developers to come in really have been misaligned.


That in order to do the drug development and really study a new product in these areas, you have to, historically, look at a very heterogeneous population.


And it can take large numbers and long periods of time, and the risk assessment is quite different in that context. But if you could narrow in on the population that really is in the most desperate need, from a medical care and public health perspective, and really develop the drug with that target in mind and do the assessment with that, more limited, target in mind, it will help to enable promising drugs to get to people.


STEVE USDIN: And so the criticism that I've heard from people in the pharmaceutical industry is, they're saying well, that's one thing to be able to develop a drug for a limited market, but on the other side of it, their concern is that FDA is going to be restricting the practice of medicine and telling physicians, you can't use it in this more heterogeneous population. What would be your response to them?


MARGARET HAMBURG: Well, a couple of thoughts. One is that we clearly don't regulate the practice of medicine. And that's one of the complexities of a narrowed intended use, is that once it's approved, it can be used by physicians according to their own sense of best practices and patient need.


So we have to really work through what this new designation would mean and how it would actually be implemented.


I think the second point though, is that as we are moving into precision medicine, as we've just been talking about, we're looking at sub-populations and more targeted groups anyway. So this sort of fits with the models that are being developed in terms of drug development and in terms of thinking about populations differently.


So I think it's a new era. And I think what we need to do is to have open minds, work together, and find the ways that we can get important and necessary drugs to meet needs of patients and public health more broadly.


STEVE USDIN: Dr. Hamburg, when you're surveying the, kind of, the whole list of things that maybe keep you up at night, I imagine one of them has to be globalization.


Eighty-percent of the ingredients in American drugs come from overseas, and FDA simply doesn't have the kind of inspection capabilities overseas that it does have here. Is that a problem?


MARGARET HAMBURG: You're absolutely right, and it is one of the things I worry about a great deal, and one of the things that I've put a huge amount of time into during my tenureship as FDA commissioner.


It wasn't something I expected to do, but when you look at the numbers, it's startling -- 80% of active pharmaceutical ingredients used in drugs that Americans take come from other countries.


About 40% to finished drugs are made in other countries, about 50% of devices. So we can't view ourselves as a domestic agency looking in. We need to reach out.


And we've really been doing that in dramatic ways, in terms of having a presence overseas in important regions of the world, with offices, new working relationships with counterpart regulatory authorities, of course, working also with the industries, wherever they are located --


STEVE USDIN: But you don't have the kind of thing like, in the United States, you can go into any drug facility -- and FDA inspectors do it all the time -- without any notice and go in and look and see what's happening, and you find violations, even in some of the best companies in the world. You can't do that overseas, can you?


MARGARET HAMBURG: Well, we do go in and do inspections. We do it on the drug side, and we do it on the food side as well.


And there are actually more than 300,000 different facilities that we, in theory, want to be monitoring and inspecting. And it becomes very complicated, and it's not just where is the product being made, but also, how is it being distributed, and packaged, and repackaged, and shipped. And that could involve multiple countries.


So assuring the integrity of the supply chain, as well as the quality of the initial manufacturing, is enormously challenging, but very important to health and safety.


So that this is one of those areas where we are pushing forward. We are doing a lot. We are at the limits of the resources, human and dollar. And it's an area I've talked a lot with Congress about in terms of its importance.


Because it really is a matter of health, safety, and frankly, national security that we be able to really assure the integrity of these supply chains, and that we can really know what's in the products that Americans are using.


But again it's one of these areas where we have to completely shift our paradigm.


STEVE USDIN: For a public health agency, FDA relies, to an unusual extent, on fees collected from industry. We'll talk about that and budget sequestration when we return.






NARRATOR: Now, back to BioCentury This Week.


STEVE USDIN: We're talking budgets and sequestration with FDA Commissioner, Dr. Margaret Hamburg. Dr. Hamburg, sequestration -- what effect did it have on FDA? What effect is it going to have going forward?


MARGARET HAMBURG: Yeah, well, sequestration, as you know, was across the board cut to the FDA, which, for an agency with huge and expanding roles and responsibilities, already straining in terms of budget, it's been a hard blow.


In addition, it wasn't just the government dollars, the budget authority dollars, that were cut as part of sequestration, but user fee dollars negotiated with the industry to support a key set of programs and activities were also cut at the same level, so that, you know, it has been a huge source of worry and concern.


It has resulted directly in cuts in some key areas of activity. And even where we have the user fees, which give us additional resources for programs, critical activities, including travel, participation in conferences, training, really have had to be dramatically cut back as we try to juggle available resources to make sure that core functions continue.


STEVE USDIN: I want to ask you about something else -- Congress just passed new legislation on compounding. It was in response to a tragedy at a New England Compounding Center where what, there were 60 or so more deaths, hundreds of people were injured.


This new legislation relies on a kind of voluntary oversight program on the part of the compounding companies. Are you really confident that it would prevent a tragedy like that from happening in the future?


MARGARET HAMBURG: Well, I think, you know, to be honest, we had hoped for a broader set of authorities in new legislation, but this will enable us to be more effective.


It clarifies some things in the old law that were problematic in terms of roles and responsibilities. And it does create this new category for FDA regulation, but it's voluntary.


And I think what we have to work with the healthcare community and the broader set of stakeholders to achieve is a recognition that this should not be optional. That if you're making these high-risk products-- sterile injectables being the major focus -- that there really should be a set of uniform standards, and the FDA will be soon, you know, putting out information about how we're going to run this program.


But we hope that people will see this is as the real standard of care.


STEVE USDIN: OK, and thing that I worry about is, it's not even just about sterility, for example, which is a huge issue in itself, but how would you even know if the drugs were sub-potent? I mean is there any way that you're going to be testing? Physicians wouldn't know it, necessarily.


MARGARET HAMBURG: Well, I think that's the challenge is that there will be facilities that choose to be regulated and overseen by the FDA, and we will have a set of clear and consistent and science-based standards.


Those are the products that I think most patients are going to want. But it will be difficult for both healthcare providers and patients to always know what they're getting.


So we need to work hard to make this legislation as effective as possible. We're certainly committed at the FDA, and we are rolling up our sleeves to start the implementation.


STEVE USDIN: But it sounds like it could have been better. We're going to continue our discussion with Commissioner Margaret Hamburg in just a moment.





STEVE USDIN: We're back with Commissioner Dr. Margaret Hamburg. Dr. Hamburg, one of the commitments in the Prescription Drug User Fee Re-authorization Act, and something I've heard from you, and from other people at FDA is the need to involve patients more in drug regulation and developing drugs. What does that mean in real terms?


MARGARET HAMBURG: Well, you know, we really have found this to be valuable, because as we think about not just the science that's coming before us, but how to balance the risks and benefits, and are we actually measuring the right things, the patient perspective really matters.


And so we have really begun a process of engaging with patients, and other experts in a given area, in a focused way, having a series of meetings on specific diseases to get this patient perspective.


STEVE USDIN: So, and you mentioned, so you're engaging with patients, you're engaging with other people. Does FDA need to do more to be able to kind of tap into the expertise that lies outside of the agency?


No matter how big it is, and how smart the people are at FDA, obviously they can't know everything about everything.


MARGARET HAMBURG: Absolutely. And that, you know, that's much broader than just patients, although the patient input is key and really matters in some of how we're thinking now about clinical trial design and other things.


But yeah, we will never have all the expertise within our walls that we need to address the complexity of the science and technology that's embedded in the products that we regulate and the issues that we have to deal with.


And so the engagement with critical stakeholders and with outside experts is key, and it's always a dynamic process working within both the bureaucratic rules of government agency, and also making sure that important issues of conflict of interest are balanced with the need to access expertise.


STEVE USDIN: So one other thing I'm wondering about, which also gets back patients.


European regulators recently wrote something saying that one of the things that's missed in regulatory decision making very often is the risk of not having a new drug.




STEVE USDIN: Do you think that that's something that should be more, kind of, explicitly factored into thinking about drug approvals?


MARGARET HAMBURG: Well, I certainly think that as we look at our role in the broader enterprise of medical product development, that we recognize that we shouldn't think of our role in this sort of static, insular way, but broadening our engagement so that we can help when there's a promising idea out there in a new discovery, we can help to sort of be almost like Sherpas in the development process, and that's what the breakthrough pathway kind of reflects.


But also that we don't have to just stop at approval. You know, we are responsible for the oversight of products throughout their whole life cycle.


So if we can collect meaningful, ongoing data in the real world once a drug is approved, or approved in a more tentative way with the accelerated approval process, we can require studies, we can do post market surveillance, and we can continue to know about the safety and efficacy of that drug in the real world, which is actually more meaningful and valuable than what's collected in the more pristine clinical trial environments.


STEVE USDIN: So if you're involved in this kind of, much more dynamically with patients, with drug developers, with physicians, do you have a concern that FDA at some point gets to a position where they're kind of picking winners and losers?


MARGARET HAMBURG: Well, I think that's probably always been how some of what the FDA does has been viewed, because we do the yes or no.


But that may be sort of a little bit intrinsic to what we do, but I think that we are committed to working with the science, understanding the science, and this broader approach to regulatory monitoring.


STEVE USDIN: Thanks, Dr. Hamburg. We could talk about this all day, but unfortunately, that's all the time we've got for this week's show.


For more of our interview with the FDA Commissioner, visit to watch a web exclusive. Remember to share your thoughts about today's show on Twitter. Join the conversation by using the hashtag, #biocenturytv. I'm Steve Usdin. Thanks for watching.




Web Extra


NARRATOR: Now a BioCentury This Week web exclusive.


STEVE USDIN: I'm joined today by FDA Commissioner, Dr. Margaret Hamburg. Dr. Hamburg, a lot of the programs that the FDA, for advancing medical product development, the Breakthrough program, Accelerated Approval, other things -- they seem to be aimed at acute, life-threatening diseases where you can really narrowly specify what the population is. But the big public health needs are a lot messier -- the things like obesity, Alzheimer's, diabetes. Do we need to think of new tools for advancing drugs for those kinds of priorities?


DR. MARGARET HAMBURG: Well, those areas you mentioned obviously are huge areas of focus and concern and represent a huge burden of illness on the American population. In some of these instances, like Alzheimer's disease, we still don't know enough about the nature of the disease, even how to diagnose and monitor its progression. So that's a fundamental challenge as we work with product developers and scientists around what are the opportunities for treatment and improved management. Then, like diabetes, we know a lot more about the disease itself, but we also are learning that even within diabetes, there's sort of subsets of diabetes that can be managed differently and may require different kinds of targeted therapies.


So yes, we very much want to make sure that our work recognizes the diseases that really matter to the population and the unmet medical care and public health needs, and see how we can help to be a gateway to new and better products and treatments, and certainly not a barrier. And certainly, I think some people would say that in the past for some of these more complex disease conditions, the kinds of clinical studies that we expected and the way we were thinking about them made the challenge of product development more complicated, not easier.


So we're trying to dial back and look at what are the critical questions that need to be asked. And how can we best get the answers. And it may require developing some new regulatory pathways, like the LPAD that we were discussing earlier. And it may require also recognizing that we need to carve up some of the disease conditions into their natural subsets, in terms of the actual underlying disease mechanism or the characteristics of that individual or a sub-population.


And in some of that, we just need better science. I mean, we are really eager to do everything we can to help the development of meaningful products for Alzheimer's disease and better bio-markers for diagnosis and monitoring of disease progression. But there still is some fundamental work that needs to be done.


STEVE USDIN: And do you think that there need to be new ways of collaborating among industry, among academics, among patients, among FDA to try to figure out what the paths forward for those are? It's hard for me sitting here now to see, well, whatever your goals are, there's a path forward that's going to lead to a therapy for Alzheimer's in any short kind of or even medium time frame. Do we need to have some kind of new forms to make that happen?


DR. MARGARET HAMBURG: I do think that the kinds of collaborations that we saw in the early days of AIDS drug development, that we've seen more recently in some more limited areas of disease like the cystic fibrosis drug development area, make a huge difference. And we have been greatly benefited by some of what people call pre-competitive collaborations that have brought different stakeholders together across sectors, across disciplines, to really look at what are some of the critical needs, the gaps in scientific understanding and, for us, the regulatory knowledge and tools that we need to be able to do our job better. The Bio-markers Consortium, for example, I think has been extremely helpful in deepening our understanding about the role of bio-markers in how you go about discovering, developing, characterizing and validating bio-markers for use.


STEVE USDIN: So those are kind of small -- I would say almost as baby steps. I mean it seems to me that the kind of the scope of the resources that have been devoted to those kinds of activities is not in proportion to the public health risk and challenge. That's just my thinking on it.


I want to switch and ask you about another thing which is there's some things that are kind of classic binds that FDA has put in. One of them, I think, is pain drugs. On the one hand, you've got pain patients who very legitimately need to have access to drugs, and they would argue they need to have better access to existing drugs. And the other hand, you've got people who are very concerned about abuse and overdoses, and they're calling on FDA to make it more difficult to have access to drugs. Is there a way out of that?


DR. MARGARET HAMBURG: Well, I think there's a big picture that we need to address as a nation and certainly from my perspective as a community of healthcare providers and public health professionals, where we really look at -- I mean, it certainly is what are the drugs that are available and how they're used -- but the cycle of appropriate use, misuse, and abuse is a really challenging one. And there's a broad sort of national agenda here that we're not doing a good job of addressing.


Then, there's also what is the FDA role? And it is very hard, because there is absolutely a very legitimate need for the use of these types of painkillers. I think we still don't fully understand the appropriate use of some of these drugs for certain kinds of conditions and importantly, chronic disease conditions. So there's an ongoing scientific agenda as well.


But we need to balance the appropriate needs for these drugs in treatment and their potential for abuse and misuse. And again, there are some ways that applying better science and technology can help us, not only in defining appropriate use, but also in making these drugs abuse-deterrent. And we've had one approval that involved an abuse-deterrent formulation. But it's not an easy task. And I would actually love to see some out-of-the-box thinking about how to really develop abuse-deterrent formulations.


And then looking further down the road, we still don't have really good treatment strategies for addiction, which is a huge problem. And so I think we need more development in that arena.


STEVE USDIN: And do you think that FDA has a role to play there? Does it need to do more to clarify or to facilitate a pathway for abuse, for addiction, for treatment?


DR. MARGARET HAMBURG: We can't do it all. We can identify critical needs. We can say we don't think there's everything out there that is necessary to address the magnitude of the problem. We can also look down the pipeline to see that there isn't as much activity in this arena and, at the same time, that the understandings of neuroscience are expanding dramatically and that there is a disconnect in terms of the potential opportunities for new approaches and new product development and what's actually happening.


We don't control all of the incentives to bring companies and investment into that area of drug development. But what we can do is work with the broader array of partners to say what, as the regulatory agency, can we do to help facilitate product development, to try to look at both the standards and approaches we've used, and can they be modified, made more flexible, apply new tools and scientific understandings to modernize or redesign? And also, are there ways that we can engage earlier on, so that as products are developed, they can follow a more efficient trajectory to make these areas of development more attractive.


STEVE USDIN: So for example, could an addiction product be eligible for the breakthrough pathway?


DR. MARGARET HAMBURG: You know, I don't see why not. I think that these are critical public health needs. In terms of how the language is actually written, I guess the lawyers will have to answer your question. But I think if it can't, then we ought to be having continuing discussions about how to think about using flexible and more engaged regulatory approaches to better assure that we're capitalizing on advances in science and technology today, so that we can deliver for patients that are suffering from serious problems and from problems that are actually impacting public health and society more broadly.