Regulation
Guest Commentary: Re-inventing FDA's adcomms
Why FDA adcomm process should focus on regulatory science, not approvals
When Congress first expanded the use of advisory committees as part FDA's drug approvals, it was seen as a way to imbue the agency's decisions with the perspective of practicing doctors drawn from the front lines of patient care. There was a sense that the FDA's drug review process had become too insular, and too removed from the travails of the clinic, given that many FDA medical officers and their supervisors were no longer practicing physicians.
Since that time, adcomms have drifted from some of their original mandate. It's time we revisit the utility of this institution. One idea is to refocus the adcomms on helping FDA answer a different set of questions, by structuring the entire process around the adjudication of the clinical criteria that underlie the drug review process, rather than merely providing up and down votes on discrete approval decisions themselves.
Advisory committees had long existed as an adjunct part of FDA's premarket review process, and the agency had a history of seeking expert input as part of its policy making. But in re-imagining this process, Congress wanted to formalize the role of outside advisors and expand the places where adcomms would weigh in on FDA's normal business. In the FDA Modernization Act of 1997, Congress got its chance, passing an expansive new requirement for adcomms and formalizing the role of these committees.
In first expanding the role of adcomms, Congress made some decisions in statute that reflected the concerns of legislators. Many of these original mandates have been weakened as the process has evolved.
For one thing, there was an expectation that the process for appointing adcomm members would reside outside of the specific review divisions whose work the panels would be reviewing. Congress wanted these panels to provide a check, of sorts, on the prevailing orthodoxies inside FDA. At the time of FDAMA's passage, existing regulations already lodged the appointment responsibility with the FDA Commissioner. Since FDAMA, however, the spirit if not the utility of that process has largely faded.
Today, the Office of the Commissioner is little more than a rubber stamp for the nominees put forward by review staff. As a consequence, the decisions that adcomms reach are increasingly pre-ordained by the selection process. Former division directors have referred to this as the advisory committee "home court advantage." Savvy review divisions will also influence adcomms with ad hoc members (or convene a "joint" committee, with members from multiple committees), partly as a way to steer meeting outcomes. In more and more instances, the advisory committees are a predictable ratification for the FDA's predetermined conclusions.
At the same time, activists and other parties have succeeded in lobbying for rules that make it hard for FDA to recruit physicians who have been involved in clinical trials and have practical experience in drug development or research on the increasingly narrow areas of science that underpin drug reviews. Since most trials are industry funded and the new rules make it hard to seat adcomm members who have received industry support, the rules disqualify many capable experts. This diminishes the utility of the advice that FDA can get from these meetings. Another result is a growing number of adcomm members drawn from government agencies like the National Institutes of Health. While these experts are highly qualified, they seldom practice medicine full time in private settings, obviating one of the singular reasons Congress expanded the adcomm process in the first place.
It's also noteworthy that the adcomms have become hugely expensive. Drug companies report that they spend upwards of $1 million preparing for an adcomm. FDA can easily expend more once all the preparation, staffing, and travel costs are fully tabulated. The meetings have also become somewhat of a spectacle, where participants can be hard pressed to fully balance the notoriety that these appointments can bring. Academic doctors have sometimes brought the public relations staff from their institutions along with them to adcomm meetings to help them manage their personal press. It's not to say that sensible participants titrate their public comments owing to the scrutiny, but on occasion, such behavior has been known to occur.
New remit
The adcomms are such an established aspect of FDA's process, it may seem hard to consider a wholesale redesign of their structure and purpose. But it's worth considering reforms to put the practice more firmly on the footing of its original purpose, and align it better with FDA's modern needs.
The FDA review process itself has become more organized, predictable, and transparent. To these ends, adcomms may be able to take on a new purpose. Congress' original imperative -- to imbue the review process with real-world, clinical perspectives -- may best be accomplished through other avenues.
One idea would be to re-orient the mission of the adcomms. Instead of taking up individual drug applications, the adcomms could be largely charged with adjudicating the more fundamental policy issues that underpin regulatory science. These questions could include the appropriateness of specific clinical trial designs and statistical approaches, proposed biomarkers, or the suitability of certain clinical endpoints and the threshold of response needed to support evidence of benefit.
Some of these new committees would need to have general expertise in drug development science (e.g., clinical trial design, statistical approaches to drug review, risk management). Other committees would need clinical expertise in discrete areas (e.g., cancer, cardiology, pulmonology) to assess things like the appropriateness of clinical endpoints. The meetings could straddle the line between the current configuration of fixed panels, and the workshops FDA routinely holds. FDA could invite other experts to present before the panels, and then use the adcomms to help adjudicate what FDA is being told.
One rule of thumb: FDA should assess whether any new review criteria it plans to promulgate in guidance would benefit from a public discussion before an adcomm.
Right now, some review divisions at FDA -- principally FDA's oncology division -- occasionally use adcomm meetings to seek input on these broader kinds of questions relating to drug review science. But with the oncology division forced to convene meetings for each individual drug review decision, there are few opportunities or time to take up these more fundamental questions.
Yet it's these underlying issues of medicine and science where FDA can often benefit most from the input of expert thought leaders and providers. Moreover, it stands to reason that FDA would seek outside perspectives when making determinations like how to decide when a certain response qualifies as a clinical benefit. Setting criteria such as these is the sort of determination that has far-reaching impact on the practice of medicine, and turns heavily on the judgment of practicing doctors and the aspirations of affected patients. As such, it would be advantageous for FDA to use adcomms as a way to broaden the consideration of how it establishes this sort of regulatory dogma.
New vehicle?
As for Congress' original mandate, that FDA should incorporate into its drug reviews the input of practicing physicians and clinical thought leaders, this obligation may be best achieved through a different vehicle other than the adcomms. Sponsors routinely bring key opinion leaders to meetings with FDA to provide expert opinion on the clinical aspects of a drug filing. This usually occurs on an ad hoc basis during end-of-Phase II or pre-NDA meetings. Since there's so much important work to cover during these typically hour-long meetings, the opportunity for these discussions is limited.
Instead, FDA can provide occasion for sponsors to make these expert discussions an explicit part of interactions with the agency at key points in the review process. FDA already seeks this advice on its own, through ad hoc interactions. This process is often informative to agency staff. It might as well be formalized. To provide transparency around these interactions, meeting minutes could be made public as part of an approved drug's package.
As it stands, FDA increasingly uses adcomms to air internal disputes, or to co-opt its critics by including them on panels (where agency hands believe that they can get more influence over anticipated criticisms). This is a very costly and inefficient way to try to resolve inevitable disagreements. FDA needs a better process for managing internal differences around how science and policy are interpreted. Toward these ends, FDA should have a regular process of academic peer review, to assess the quality of individual scientific work. FDA's review staff needs to be held accountable for the quality of their science. This same peer review process could be used to help adjudicate disagreements.
Political influence
What about the process for appointing members to the remaining adcomms? To re-establish the independence of the adcomms, Congress could create a new process for the selection of their members. That process should recognize that the adcomms themselves have become the focus of a lot of political scrutiny, with various interest groups jockeying for political leverage over how adcomm meetings are run, and who is a part of these panels.
One way to reduce the political influence may be to simply acknowledge it: Allow the appointment of members to proceed through a process where FDA, outside interest groups and Congress each has an opportunity to inform some of the composition of these committees. This is similar to the way other federal advisory committees already get appointed, like the Federal Health IT Policy Committee, of which I am a member. In many cases, Republicans and Democrats in Congress will each put forward a complement of advisory members, with the balance composed of individuals seated by the GAO and drawn from nominations made by the public.
If adcomms were charged with focusing on issues of drug review science, and not individual applications, it would call for fewer committees with more diverse membership. The need to focus committee membership on very narrow areas of clinical expertise would be reduced, making it easier for Congress, the GAO and the public to play a role in nominating members. FDA can balance these outside appointments with a certain number of its own selections, making sure the agency has the expert input it requires.
The adcomm process has been a key feature of FDA, and helps improve transparency. But one must ask if we're still getting sufficient benefit from these meetings given the enormous resources that they consume. Or whether the entire process should be fundamentally reconsidered.
Dr. Scott Gottlieb is a venture partner at New Enterprise Associates . He served as FDA's deputy commissioner for medical and scientific affairs during 2005-07, and before that as a senior advisor to the FDA Commissioner.
Companies and Institutions Mentioned
National Institutes of Health (NIH), Bethesda, Md.
U.S. Food and Drug Administration (FDA), Silver Spring, Md.