FDA says it will release new guidance for advisory committee appointments

But says the current system works, & works well, because it places primacy on certain values that are not politically or personally motivated, but are motivated by science

July 25, 2006 — /MEDICAL INDUSTRY E-MAIL NEWS SERVICE(TM)/ — COSTA MESA CA — Yesterday, Monday July 24, the FDA disclosed details of its ongoing efforts to improve the composition of its important advisory committees of experts.

In a speech before the Center for Science in the Public Interest, at the Conference on Government Advisory Committees in Washington DC, Dr. Scott Gottlieb, FDA Deputy Commissioner for Medical & Scientific Affairs, described the kind of experts the FDA wants to have serve on these advisory committees. His unedited comments are below.

Last March, FDA held an advisory committee meeting to examine whether we should bring a drug for multiple sclerosis back to the market, after sales of the drug was voluntarily suspended by the manufacturer after post-approval safety concerns emerged. The drug in question is by all accounts is highly effective, but also has certain rare but serious safety concerns.

The meeting was held in a packed room. Many patients were on hand to participate in the discussions. The available science we had was subjected to intense scrutiny: scrutiny applied by smart and dedicated doctors and patient representatives, all of whom continue to face difficult questions about how to treat multiple sclerosis and how to balance the need for effective therapies against the need to make sure that new treatments are safely deployed.

And it was all done in public view, like most of our advisory committee meetings, by experts accustomed to weighing clinical evidence, to making difficult medical choices, and who also have the collective experience with both clinical research and scientific discovery to objectively evaluate all sides of a complicated therapeutic question: To assess and examine the scientific opportunities and shortcomings revealed, sometimes very subtly, in the results of clinical research along side the needs of patients and the practical issues of clinical medicine — in short, to probe the nexus between clinical practice and clinical research.

That is why it is so imperative that our advisory committee members comprise the most experienced and insightful clinical minds our nation has to offer.

The advisory committee process is integral to examining this intersection between medical practice and research, to sparking debate about it, and to subjecting scientific work to the kind of close scrutiny that only those who hail from both sides — the research and the clinical — can provide.

In fact, these advisory committees have become so important to our work at FDA, and such a fixture to those who follow this agency, that it is easy for all of us to forget a time when we did not have these kinds of meetings, or to remember why Congress, in its wisdom, created them in the first place.

Go back a few decades or so, and the criticisms of the FDA and our processes were decidedly different. There was a lag in the time it took drugs to reach Americans, compared with Europe and other countries. This was especially true for diseases like cancer. And when drugs did get approved by FDA, there were not a lot of opportunities for FDA to make the findings from its deliberations over individual product decisions public. Nor was there any opportunity for the agency to deliberate in public, let alone have its point of view publicly dissected by experts. From the viewpoint of the public, FDA was a black box.

There also were not a lot of opportunities for FDA’s decisions to be informed by perspectives from ordinary clinical practice, outside of the practical information that was gleaned from clinical trial results and the perspectives of the FDA career staff — a growing number today I am pleased to say — who also continue to practice clinical medicine and to care for patients.

A consensus of patients and doctors and scientists came to believe that the drug review process itself could benefit from these perspectives, and from more transparency and public scrutiny, and so they agitated for change. In large part to bring more transparency to the review process, and to subject it to the scrutiny of expert, independent practicing doctors and patients drawn from the clinical research community, the advisory committee process was first created more than 30 years ago and expanded greatly in more recent years.

The results are plain to see. Today, our drug review process is the most open and transparent in the world, bar none. In Europe and Canada, they also have advisory committees, but these expert bodies meet in secret. They deliberate out of public view, behind closed doors, opening them up only after they have reached a decision so that they can announce their conclusions to those waiting outside.

Not here. Here in the U.S. these open meetings are available to anyone who wants to attend. Anyone can ask questions. And the FDA is put to the test, to explain and defend its scientific thinking in public, before a panel of experts with the breadth and depth of experience to dissect the results, to challenge our conclusions, and to make sure that no rock goes unturned.

To maintain these committees, we are dependent upon many people. We are dependent upon a hard working staff inside FDA that maintains a careful system for soliciting and vetting candidates. We are dependent upon experts in our medical and scientific centers who assemble panels balanced by experts with the requisite scientific background to weigh in on difficult matters. And most of all, we are dependent upon some of the most sought-after external experts, who serve on our committees without their usual compensation other than the reputational value and more importantly, the opportunity to perform a public service.

It is a fact of life that the best scientific advisors will have a premium placed on their experience and their knowledge. It is a fact of life that they will be engaged in other enterprise. But the value of the advisory committee process is measured most of all by the quality of the people who serve on these panels. So far, we have been able to attract some of the top doctors and clinical trialists in the country. But I am worried that this may not continue to be the case. And that could have significant consequences on the types of meetings we are able to hold, and the types of issues we are able to take before these panels.

I am particularly worried that the value of these committee meetings could be eroded, as well as our ability to attract the experts we need, if some current legislative proposals become law, and FDA is hampered in its ability to put experience and expertise as the paramount criterion when recruiting members to serve on these committees.

I am worried by some who want appearance to trump acumen — some who want the lack of private sector work to trump a plethora of scientific experience as the principal measure when we are selecting who to put on our committees.

It would be a significant step backwards if our primary criterion for selecting members to our committees becomes their lack of private sector work, if we exclude people for deep experience rather than embrace them for it. The public health will not be served if we are no longer able to attract the kind of very active medical practitioners and clinical trialists who are able to inform our meetings with some very unique medical insights that only comes from years of experience both seeing patients and developing and looking at clinical data, sometimes in some very narrow fields or for specific indications.

Now don’t get me wrong, our current system is not perfect. In fact, we have recently set on a course to adopt policies that we believe will improve the process. But first, we should all be clear on what we are talking about here today.

When it comes to our waiver policies at FDA, we are talking about relationships that some of our advisory committee members might have that could present the appearance that they have a conflict of interest that could impact their impartiality. Not all of these relationships are equivalent, and so our process does not treat them all the same. Sometimes, for example, these relationships are service on a data safety monitoring board, yet people who serve on these expert, independent safety monitoring boards are precisely the kind of experts I think most reasonable people would agree we want on these advisory committees.

Other times, the conflicts involve research that people might have been engaged in that was partly funded by a sponsor, or grants that their academic institutions might have received, even in cases where the individual themselves weren’t involved in the grant. Sometimes these relationships are more personal, involving limited amounts of stock that they might own in regulated companies or consulting work they might have done, often as members of research advisory boards or speaker’s bureaus, or even the professional situation of a spouse. When a real conflict exists and the magnitude of the conflict outweighs the agency’s need for expertise the committee member will provide, we recuse that individual from the proceedings and will continue to do so.

It is simply the case that top experts are going to sometimes have these kinds of relationships. In some cases, such as the case with the data safety monitoring boards, we want these experts on our committees precisely because they have this experience.

Expert scientific acumen and deep clinical experience is valuable knowledge in high demand, by government, by patients, and also by medical product developers. The band of people who have this kind of expertise, especially in narrow therapeutic areas and rare diseases, are widely sought and often just as widely employed. In fact I think it is fair to say there are few academic experts engaged in research who don’t have some scientific ties to industry, especially since FDA defines what a “tie” is so broadly.

For example, consider the way we define it now and how it affects an academic department chairman who has a junior faculty member who received a research grant from a drug company. That department chairman could be said to have a potential conflict under our current approach, even if he or she had no role in securing or administering the research grant or even supervising the research. In fact, some of the current rules make the department chairman responsible for knowing all of the grants anyone in their supervisory chain received, no matter how distant from the chairman’s own work.

We define things broadly because the vetting process is designed to identify potential conflicts, and we want to make sure we capture all possible relationships that could be reasonably interpreted as a conflict. That is a useful goal, and I think the right approach, but it is also an approach that leads us to have to grant more waivers to people who have what we deem to be relationships that while significant enough to warrant proper disclosure, are not deemed to be the kind that would affect their judgment or impartiality or outweigh the benefits of the contribution offered by their participation.

People ask us all the time, why we cannot just appoint panels with experts who do not have these kinds of potential conflicts that need disclosing. We would not need to go through the process of granting these waivers. They ask us why we cannot end the waiver process. Some have proposed to do just that. I would like to briefly explain why this is so hard, and potentially problematic.

We do not appoint advisory committee members as issues come before us. Instead, we have standing advisory committees, with members recruited and appointed sometimes years in advance of meetings, who serve for defined terms of up to four years. This serves us well, since there is a value from having people who have institutional experience from serving on these committees and who have learned how to work together as a scientific group. It is similar to the way the Senate works, where you don’t want all the members being brand new each year, or appointed just to vote on each individual issue.

This leads me to the heart of the problem: When we appoint these committee members, it is impossible to tell who will eventually have relationships that could present the potential for an appearance of a conflict around a specific issue, since we don’t know what issues are going to come up before our advisory committees a year or two in advance. If we err on the side of caution, and only appoint members who have had absolutely no associations of any kind with any regulated products or industries and are unlikely to develop such relationships for the length of their term, then we are going to be hard pressed to find people that have also been engaged in relevant and unique scientific endeavors, since a lot of medical product research today is done in collaboration, at least in part, with sponsors.

For this reason, we are able to give certain individuals waivers to participate in meetings, when they have a relationship that is deemed — after close scrutiny — not to present a conflict that would outweigh the benefit of their participation. If we were prevented from being able to grant waivers in the first place, and we had to recruit only people who had no such associations and were unlikely to develop them, then I am not only worried that such people would be very hard for us to find, especially since it is sometimes not obvious to researchers themselves that they had a potential conflict; for example that their institution or academic department might have received a grant for research they had no involvement in. I am also worried that these people will not necessarily have the most experience doing clinical research and seeing patients, especially if our primary criterion for selecting them is not their abundance of work, but in some cases, their lack of certain work.

Even the medical journals rely on such folks as peer reviewers for the articles that the journals publish, precisely because of their expertise in evaluating and participating in clinical research. And while their system works well it is also far from perfect. But we must not allow the perfect to be the enemy of the good.

It is also worth noting another reason why these very experienced clinical trialists and academic thought leaders are so valuable. Academics and high-profile practitioners are generally really strong-minded people as I think any patient at a big-time facility can attest. I can surely attest to it thinking back to my days as a medical student and a resident. That is what industry wants in a consultant because shooting down bad ideas is the best route to progress in medical product development. So these highly experienced, strong-minded folks are sought after for their perspective. FDA needs to leverage this same kind of independent thinking at its advisory committee meetings — we need people with clear convictions and ideas and that comes with the confidence acquired from years of expertise and clinical work.

So if we do away with the waiver process and our primary criteria for selecting people to our committees is first and foremost: have they had any relationships that could present appearance problems in any context, the truth is that we are playing it safe rather than playing it smart. We will probably try to undershoot, and make sure the folks we target are so new to clinical research that they could not possibly have done any work with drug companies. This isn’t to say they are not still be capable people, but this is not the way you usually think when you are trying to seek out expert advice — you would not say to yourself let’s find the person with the minimal amount of practical experience. We should not seek the almost most experienced when it comes to the advice FDA receives.

In the end, we may find that the committees we are left with are still very capable, just not as helpful in evaluating clinical research. So we end up taking far fewer actual medical products decisions to them, and instead end up bringing more medical practice questions before them. I do not think this is going to serve anyone well, and I do not think it is going to add to the transparency of the entire medical product approval processes.

But as I said, I am not here to say our system is perfect. In fact, there is a lot we are doing to improve upon it. Among other things, we are announcing today that we will be revising the guidance document we use to determine how we grant waivers and what requirements we have about the disclosure of potential conflicts. I think we can make this process more transparent, and as I said, not all potential conflicts are equal. I think we need to do a better job distinguishing between them, and codifying in guidance more of the case-by-case, qualitative judgments that we make when we carefully evaluate each waiver situation.

We will also be developing a new guidance document that will govern how we disclose the reasons why we granted a waiver in the first place. We want to be more transparent, and specific, about these reasons, to the maximum extent possible, so people can better understand the relationships that we accommodate and our reasons for doing so. We want to make sure that our process is consistent, rigorous, and well understood so that people can have confidence in the decisions we are making when we select these committees. The bottom line is this, while there is a lot we can do to improve the way we hold these meetings, the basic architecture is one that has served the public health well. To those who want to re-write the rules, and remake that architecture, I would say, mend it, don’t end it.

These arguments, for barring certain people from these expert panels, reinforces the unfortunate sense that only personalities and alleged motivations count in modern public life, when in truth, it is the integrity and rigor of ideas that have lasting consequences and the willingness of government to subject those ideas to public scrutiny. These ideas are the final denominator computed out of these advisory meetings, the advice we get on the scope of a new indication, or the contours of an appropriate post market plan.

This advice is even more important and enduring than the tally of any vote, and it is in many cases some of the most important questions we are taking before these committees. In fact, most people have the sense that the advisory committees tell FDA whether a drug should be approved or not. But it is often the case that the basis for that decision is obvious to both the agency and the committee members. It is the scope of the approval, the clinical practice decisions that need to be made in the final labeling, that the advisory committees are so important for informing.

The system we have now can be improved upon, and I outlined some steps we intend to take. But the system works, and works well, because it places primacy on certain values that are not politically or personally motivated, but are motivated by science, and by the desire to draw upon the best minds in medicine to put government-decision making under the microscope, and to put the agency’s private scientific deliberations on public display.

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