The View From Inside

When Andrew von Eschenbach, MD, was sworn in as commissioner of FDA late last year, he walked into an agency that was under fire but also in the midst of immense and complicated change.

Institutionalized Ethics

Part of the maelstrom was inherited from the previous commissioner, Lester Crawford, whose abrupt departure was surrounded by a cloud of questions over Plan B and who later pleaded guilty to conflict-of-interest charges. But in many ways, those issues paled in comparison to what loomed ahead for von Eschenbach: reinventing the way FDA thinks about drug safety, responding to the demand for a regulatory pathway for follow-on biologics, and, yes, even ensuring that the nation's supply of bagged spinach was free of E. coli. Of course, the truly difficult part was to provide leadership to enact change when public trust in FDA was at an all-time low.

But in many respects, there may not have been a more perfect time for von Eschenbach—a seasoned oncologist and three-time cancer survivor who wears the yellow rubber bracelet of the Lance Armstrong LiveStrong campaign—to lead FDA. As former head of the National Cancer Institute, he understands the need to improve access to cutting-edge drugs and the need to get out in front of the science through initiatives like Critical Path.

Speaking slowly and deliberately, von Eschenbach clearly has a strong sense of institution and of how to make an agency run. And rather than finding him resistive or paralyzed because of the critics, we found Commissioner von Eschenbach cautiously hopeful, with a fairly clear vision of how to move FDA into the future. What follows is an edited transcript of our interview.

We read in the papers that FDA is in total disarray and that Americans are dying because it can't control the safety of drugs. That's the picture from the outside. But what's it like on the inside?

When you look at the depth and breadth and complexity of the portfolio FDA is responsible for, not a day goes by that we don't address issues that are of great significance and urgency to the American people. With so much going on that is of such importance to every single American—covering food and drugs and biologics and devices—it's easy for someone looking in from the outside to see a maelstrom, to see this tremendously bubbling cauldron of things that are happening. And yet, from the inside, what I see is an enormous degree of professionalism, experience, competence, talent, and commitment that manages things effectively day in and day out. I have an enormous amount of confidence and respect for the capabilities of this agency, and I don't see it as in disarray. I see it as an agency that is just simply dealing with an enormously large and complex set of issues on a day-to-day basis.

One of the big topics, of course, is safety. It was only 10 years ago that Newt Gingrich denounced FDA and pressed it to more quickly approve drugs. Now critics are calling on you to take more time to evaluate drugs. Do you think that we're at the end, or merely the middle, of the safety pendulum swing?

Just recently, Mark McClellan wrote an article [in the New England Journal of Medicine] that described this seeming societal pendulum of "we need to get things out there much more rapidly," like for HIV/AIDS, or "we need to be much more cautious about what we are approving because of unexpected potential problems," like with the Vioxx story.

Von Eschenbach says the agency is committed to improving patient information but notes that more in–depth, scientific research is needed to best structure risk communications

I frankly reject that premise. In the modern era of molecular medicine, we shouldn't see things as being at either end of a spectrum—where drugs are either effective or safe.

We are growing our ability to understand these products and their impact on patients in a way that helps us manage both safety and efficacy simultaneously—so we see the science of safety emerging as well as the science of efficacy. Even in experimental models, we are now able to determine the effectiveness of a drug by understanding its on-target effects—for example, in the tumor for which it is designed—and to understand at the molecular level its off-target effects in terms of what might be happening to the liver or the endothelium of a heart or to the nervous system.

As we bring those two pieces of the equation closer together through the prism of science, we're going to be able to more rapidly approve drugs and do it more reliably with regard to understanding the risk/benefit ratio. I see things going rapidly and safely all at the same time.

A Brief History

The parameters around safety seem to be growing and changing at the same time. Where have you seen progress?

Protecting patients when they receive these drugs is something that really begins at the very front end of the process—and it carries through the whole continuum. FDA is going to be engaged in the full life cycle of that product, whether it's providing good agricultural practices for farmers to protect food from contamination, or whether it's collaborating with the vaccine developers to help create pathways to develop vaccines, like we did this past year for vaccines for influenza. Similarly, the ability to develop biomarkers in our Critical Path initiative helps us work more effectively on that front end.

And we don't simply disengage after we've made a decision about an application and the drug goes out into the market. We're going to be even more actively engaged in the postmarket aspect. By collaborating with CMS and VA and private companies like UnitedHealth, we'll get access to databases that will help us track and learn about these drugs as they're used in diverse populations. And by using modern information technologies, we're able to understand issues of safety earlier, but also—and more importantly—to see where these products are having unexpected efficacy. There's tremendous opportunity for us to understand how drugs can be used even better to get the right outcome, not only how to contain them to avoid complications or adverse events.

You're talking about using and collecting more information on drug safety, but does FDA have the authority it needs to accomplish all these things?

At least in the 18 months that I've been here—and following on our previous efforts—we've been working to modernize FDA and better equip the agency to meet a new vision of our role. That will require us to define the plan: Where will we be engaged—like in postmarket surveillance? What kind of resources will be required to support that effort? And then we'll ask if there's the need for additional authority to be able to accomplish those goals.

That's been an iterative process we're engaged in as we speak. I've been trying to maximize utilization of what we already have, both with regard to resources and authority. And we're talking with Congress as it is addressing these issues and providing technical assistance, where it's been requested, to inform things like the Kennedy-Enzi bill.

How is FDA reorganizing to make the best use of its current authority?

Within CDER itself, we're driving much greater collaboration, cooperation, integration, and communication between the parts and pieces. There's much greater interaction between the Center for New Drugs and the Center for Surveillance and Epidemiology so that those who want to approve drugs and those who are responsible for the safety of the drugs are integrated and working effectively. By effectively, I mean by bringing the various perspectives and points of view together to debate, discuss, and analyze vigorously, and then to make an informed decision of what's best. So it's integration within CDER, it's integration of CDER within the larger FDA portfolio, and then it's the integration of FDA with the other parts and pieces.

When you talk about integration, it sounds as if the safety part and the efficacy part of drug oversight are going to continue to be engaged together. This is one of the ideas that some of your critics in Congress don't like.

In the old model, we are dealing with a pendulum that swings from rapid approval of effective drugs to slowing down approval to be even more certain of safety. In that model, you see things as separate. Efficacy's here, and safety is there.

In the new model, I believe science becomes the unifying factor from the molecular perspective, not from the phenotypic perspective. And so from that point of view, it would be actually detrimental to separate these two and put them in different silos. Rather, they would benefit from even greater cross-fertilization.

I came from an environment where if you looked at cancer care and what was best for the patient, it wasn't a matter of saying it's surgery or radiation or chemotherapy, but to realize that a woman with breast cancer needed a solution that required the integration of these pieces because there was a dynamic that had to occur. And yet, as chief academic officer and someone responsible for program development, the last thing in the world you wanted to do was to homogenize that into one thing, because you always wanted the surgeons to be the surgeons, the medical oncologists to be the medical oncologists, and the radiotherapists to be the radiotherapists. You wanted each group to bring to the table its own perspective on what it believed would be the impact of its intervention—even if they argued about what could serve that patient best. But what you come up with out of that rich discussion is a decision as to what's best for that patient.

So you don't want to separate them—but you don't want to homogenize them either into a place where they all think and act the same, because that doesn't benefit anything. You want to create this environment that I call, not the melting pot, but the stew pot. And you need to have a place where that kind of discussion and difference of opinion could go on in an appropriate way.

If you look at the figures on patients with severe arthritis who'd been on Celebrex and Vioxx, something like a third of them now take no medication at all. That probably doesn't mean that they got better, but more likely that a large number of patients have basically been deprived of a viable drug. Now Vioxx is off the market, and Arcoxia doesn't look like it's got a fantastic chance. What about those patients and their right to make a decision for themselves?

First of all, there's the important perspective of public health as well as personal health—and all the decisions have to be made in the context of what is best for the public at large.

Now we've come to appreciate that within the overall population, there may be subsets of patients that may not appear to have an alternative. There may also be subsets for whom this particular drug might have extraordinarily increased risks. The decision [to approve a drug] is in part based on the serious nature of this problem and the level of risk tolerance for an overall population. Because if it's an overall population of cancer patients as opposed to an overall population of patients that have a non-life-threatening condition, that shapes and alters the decision. What is the potential benefit to be gained in terms of the potential adverse event if the adverse event is life threatening and the benefit is merely a mild improvement of a symptom and not elimination of a disease? Are there other alternatives? Are there other drugs that could achieve a similar, if not identical, outcome so that patients are not totally without any hope of alleviation of their problem?

We're making decisions based on populations; eventually, we're going to move more toward making decisions based on subsets and even perhaps, ultimately, on individuals. So if you can identify ahead of time by virtue of genetic makeup who is at risk for a serious adverse outcome and you eliminate them from the population, you're able to make approval decisions that are much more liberal in terms of access. I don't think we're there yet—I think the pendulum still is based on populations.

As you shift to a more individualistic type of treatment, it raises questions about appropriate use. One of the big problems with the COX-2s is that they were being promoted among people who were perhaps not the most appropriate. What is the appropriate role for marketing and promotion and what is the FDA's role in that area?

We're emphasizing our own efforts at risk communication. For example, we've changed our label processes to improve how the information is being presented and disseminated. When we move to an electronic format, we'll have the opportunity to update that information in real time and provide it more effectively at the point of care or point of service. With the pharmacy industry, for instance, we look forward to when patients have their prescriptions filled and get an electronic version of the printout that has the latest and best information FDA has about that specific drug.

At this point, we expect to have some increased resources from the PDUFA negotiations that will enable us to more actively engage in consultation with the industry around marketing materials and direct-to-consumer advertising. I think it's a part of how FDA can do even better with regard to the role that it plays—and how it partners with the industry in terms of maximizing how that information is provided to patients in a way that is appropriate, understandable, and with the correct emphasis. Industry is, I think, taking more ownership and responsibility for this, from what I've seen, in terms of helping to set standards.

It seems that FDA is really rethinking the way it provides information to consumers. Can you ever see a time when FDA's information will replace DTC advertising?

I'd like us to find ways to be a very rich and effective resource for the public. When I first arrived at the agency, I said communication was one of five areas I wanted to focus on. And we have begun to look at how we can improve our own vehicles of communication.

We're in the midst of a major commitment to revamp our Web site, and the first phase of that is focused on the pages that are directed to consumers. We want to have the best Web site for finding out about a drug or any issue.

What's more is that this pathway of modern communication enables FDA and the public to have a much more dynamic interaction. We are no longer producing the magazine FDA Consumer, which is shifting to an electronic format. Instead of something that comes out from time to time, we're moving to something that is more relevant, interactive, searchable, and timely.

The other side of the equation is that we don't have to repeat what others are doing. For instance, we are providing AARP with FDA educational materials that they may add into their publication so we get the benefit of their enormous distribution and can target messages on the safety of products their members may frequently use.

So it's more strategic, it's more targeted; it's expanding our impact by finding ways to partner and not simply doing it all ourselves, and really modernizing our communications tools. Now ultimately, at the end of the day, will that perhaps make it less necessary to have other forms of direct-to-consumer advertising? I can't speak to that. I only want us to be the source of expert opinion or information for the public that we serve and for them to see the FDA as their champion in protecting and promoting their health.

The system you describe depends on the idea that patients and doctors are going to talk about risk and about what's appropriate. But there's reason to fear that that kind of discussion is not taking place as often as it should.

There seems to be a problem perhaps in the way in which patients judge risk versus benefit. They say, "Risk is something I might have later. The benefit is, I've got the problem right now, the pain right now, and I want relief right now." It doesn't necessarily follow that the FDA should therefore be more stringent with regard to its approvals and not allow certain drugs to go out into the market. What should follow is that we have to view this as a systems problem that needs a systems approach. Yes, FDA has to be much more precise, much more effective at communicating the knowledge upon which those conversations should occur. We have been able to define with as much precision and as much accuracy as is possible the actual facts and the actual data.

FDA is not providing direct patient care. FDA is making decisions about the things that are going to be used in that direct patient care. Medical professionals have a responsibility to find more effective ways to take that data and that information and integrate it into patient care.

Patients have a responsibility in that too. And I think the tools are evolving where patients are much better informed than they were before. They're not passive recipients to the extent that they were when I started my career in medicine, when they were totally dependent upon what I told them or didn't tell them about their disease. Toward the end of my career at MD Anderson, invariably every patient who came in had a stack of papers that they'd gotten off the Internet, from Web sites like WebMD. It was more like a quiz than it was an informational process, because they already knew about radical prostatectomy and radiation therapy and hormone therapy. It was a matter of saying "What's right for me?" or "Doctor, what should I do?"

We've heard it argued, most recently by law professor Richard Epstein, that the fair-balance approach tends to overstress the negatives—that when you're trying to motivate the patient to go to the doctor, it may not be the moment to mention every single drug side effect. Do you think there's merit to that argument?

I honestly don't know. I don't know that we really do have an in-depth scientific understanding of risk/benefit communication at this point, and I think that that's an important issue that we're going to have to address from an academic as well as a practical perspective. Certainly, it's an issue that is important to FDA. I think we need science here to guide us just as much as we need science to guide us in coming up with the next EGFR receptor inhibitor. We need to make sure that the communications are guiding people to wiser and better choices and care.

Would it be helpful if newly approved drugs had no advertising for, say, the first two years?

This discussion ranges all the way from the perspective of First Amendment rights to the positive impact on public health by virtue of having disease information presented in a medium patients are paying attention to, like television. Within all of that, we're seeing the increasing emergence of advocacy groups, specifically with regard to the fields that I'm experienced with—like cancer—where they know about these drugs before they're ever approved by FDA or on the market. So it isn't as if a moratorium is going to somehow keep things a secret. I don't think that's realistic.

The question is, can the material be presented in a way that improves its positive impact? We've insisted that this information must guide patients with regard to its appropriate use, not simply so that the drug company can promote its product. And as we review these ads and things of that sort, we're going to continue to enforce those kinds of expectations.

You've been emphasizing that the pathway for follow-on biologics has to be based on science. It's pretty clear that the people who are most enthusiastic about FDA approving these products are really focusing more on cost. Do you think you've been successful in evolving the discussion?

It's a conversation that's taking place. It's dynamic, and I wouldn't draw any conclusions at this point. It would be helpful for the public to understand that we're committed to having access to drugs. And to me, access means they're affordable, available, and appropriate. People who are coming at the issue of follow-on biologics or follow-on proteins from the perspective that this is going to address the issue of affordable drugs—and to some extent, available drugs, because there will be more selection—are losing sight of the other "A," which is that they're appropriate. And by appropriate it means that when this drug is given to this person it is going to get this outcome. And so we need a regulatory pathway to make that decision, and that's what Congress is addressing right now.

But in addition to having the regulatory pathway, we have to recognize that the question over [the equivalency of follow-on] biologics must be answered by science. And so as we look at the complexity of these products, we'll use different scientific tools to conclude whether the new product achieves the same outcome as the innovator product. FDA doesn't deal with the issue of affordability or availability, so what I've been trying to help shed some light on is appropriateness. And we're going to use a portfolio of scientific tools that will address the complexity of these products. Some of these tools might not yet exist and will have to be developed, but technology is proceeding at almost warp speed with regard to our ability to understand protein structure, to get us to that decision point.

We can begin to set a trajectory to move through this in a systematic way. It's consistent with our mission—we've done this with small molecules—and it is now appropriate to address this with regard to the class of biologics and protein products.

Do you have a sense of where the frontier is for evaluating and characterizing proteins?

I'm not the content expert to really give you that type of visionary insight. But in general, what I've seen is that the technologies are emerging rapidly. I had a conversation about proteomics for biomarkers with a Nobel laureate who, a year ago, was somewhat pessimistic in terms of how rapidly we would get to a point of utility. But this conversation was all about incredible breakthroughs in technology, so that his message was 180 degrees the other way and he was saying, "I hope FDA is ready for this." So here you can see the weather change almost overnight from "this will take years before you're ever going to get there" to "oh my goodness, you'd better get ready because it's coming tomorrow." So I think there are experts out there who would say, maybe it's this frontier or maybe that frontier, but it's changing.

We began by talking about how people look at the agency as in disarray. But when it comes to the pharma industry, people see a bunch of crooks who put out bad products and use unethical marketing techniques. How does the pharmaceutical industry look to you?

There are people out there who are suffering and dying and whose health is dependent on what we do. At the end of the day, people are driven and motivated by that noble purpose. That may sound Pollyannaish to some cynics, but I tell you, I've spent my entire life looking into people's eyes, attempting to understand where they were coming from. I don't believe that there's anyone coming at this with anything other than a noble motive. That's been true of the pharma and biotech industry; it's been true of the industry that's engaged in information technologies; it's been true of just about every group I've ever spoken to—advocacy groups, medical groups, physician groups, it doesn't matter.

Now everyone else has a different stake in this and there are those companies that are addressing issues that have a bottom line or come at it from the perspective of meeting our public health mandate. We may have had differences of opinion, and sometimes when I'm in different parts of this city, it may even be a bit contentious. But I have never once questioned the motives of people that were on the other side. And from that point of view, I respect them all.

And I hope they respect FDA. There may be misperceptions on the outside, but I know why people are here. I also know that they're under tremendous duress. They have worked under very difficult circumstances, and it's my job and my commitment to address those things: to help develop the resources, to create the processes, and to communicate what's occurring within FDA so if there are misperceptions, we can correct those. At the end of the day, we need to do those things so that the American people who have placed their hope and trust in our hands will be confident to know that FDA is going to protect and promote their health—as this agency has done for the past 100 years. Even though the world is radically changed, we're just going to have to change along with it, but the outcome is going to be the same.