Phase IV Advice & Consent: Managing New Regulatory Power 

The Food & Drug Administration is quickly learning how hard it is to design adequate and reasonable postmarketing safety studies. Faced with implementing new authority to demand mandatory postmarketing trials for drugs instead of the long-time policy of negotiating with sponsors over the nature of the sponsor’s proposed follow-up studies, the agency is finding out just how hard it is to define the right size – and a feasible size – for the trials.

To get some expert advice and political cover for its decisions, the agency is ready to go to the tried-and-true formula of asking its outside advisory committees for opinions and a public record on the decisions to mandate Phase IV trials.

Office of New Drugs Director John Jenkins described the agency’s plan to ask the advisory committees for more help at an Institute of Medicine forum on drug safety on Sept. 2 in Washington, DC.

“As we have been thinking about these large studies that we may be requiring” in the post-market setting, Jenkins said, the agency has decided to ask its existing advisory committees for help deciding “what is an acceptable study design, how large is an acceptable study, what are the right endpoints, what risks are we trying to exclude.”

The advisory committees may get their first large outcomes study proposals for review very soon. Jenkins said.

“You are likely to see some advisory committee meetings coming up in the not-to-distant future asking for input on” the size and duration of specific post-marketing studies, Jenkins informed the IOM meeting.

CDER Director Woodcock Supports Using Advisory Committees

Jenkins did not identify the first Phase IV trial suggestions that the FDA staff might submit to an advisory committee. There are some likely candidates, however. Perhaps the most logical candidate is the Bayer AG and Johnson & Johnson anticoagulation drug, Xarelto (rivaroxaban). The direct thrombin inhibitor got a favorable advisory committee vote in mid-March for use against deep vein thrombosis in patients undergoing hip or knee replacement surgery (See “The Pink Sheet”, March 19). But FDA sent a “complete response” letter in May to allow for time to review additional safety data (See “The Pink Sheet” Daily, May 28). One of the sponsors, J&J, has said that the agency does not want more clinical trials before approval. If the agency were, however, to seek Phase IV safety follow-up, it might need the help of an advisory committee to help determine the size and the search for safety issues from off-label use. For its initial limited indication, the drug might not require a large postmarketing trial but there was interest in monitoring how widespread the use could get for the drug which will offer an alternative to the traditional, oral anti-clotting agent for DVT, warfarin.

The idea for bringing advisory committees into the review of post-marketing drug safety/outcomes trials comes directly from the senior management of the Center for Drug Evaluation & Research.

“This is not my idea,” Jenkins told the IOM meeting. CDER Director Janet Woodcock came up with the idea, he reported. “It seems like a really good way to have some transparency, to have some discussion of all these complex issues.”

Jenkins told the IOM meeting that the agency’s new authority to initiate the discussion of post-marketing trials and to set mandatory objectives and timelines puts FDA in a new position.

Before getting the FDAAA authority to mandate post-market trials, the agency was in the position of reviewing post-approval study proposals coming from sponsors. FDA negotiated with the sponsors on the size, term and objectives of the trials. Now, the agency will be held responsible for requiring the studies and setting the parameters.

That puts a new burden on FDA. There are “a couple of big issues that we are facing now that we did not have to face as much” before FDAAA, Jenkins observed.

“Often we are not very well informed, quite honestly, about how long it might actually take to do a 30,000, 40,000 or 50,000-patient study,” the OND director acknowledged.

In the past, the sponsor proposed the timeline for starting and completing a Phase IV trial. FDA now feels the burden falling on it. “We have to spend a lot of time and energy thinking about is this a reasonable, feasible timeline because we want to limit the number of times that we have to revise it down the road,” Jenkins said.

Prospect of 500,000-patient Phase IV Trials Worries FDA

Initiating the discussion of the size of trials is also tough for the agency. Jenkins noted that within FDA some of the first proposals for outcomes studies have generated very big study numbers. “We are having some real examples of that right now where depending on the endpoint that you choose and the background risk, we have seen sample size estimates of 500,000 patients per arm. Truly, I have seen those within the agency.”

Jenkins said the agency management knows that there has to be “a balance between what is feasible, what is practical and acceptance that that is the best that you can do in that circumstance.”

In addition to providing a way to get practical advice on outcomes trials, the FDA plan to go to advisory committees for review of post-marketing safety trial design provides FDA with political cover on the decisions that it makes.

There is more than a hint of battle-fatigue from Jenkins in his description of the new use of advisory committees. The drug review management has clearly been chastened by the criticism that the agency has faced on drug safety issues in the past six years.

“We think it is important to get some community, societal buy-in” beyond FDA staff on the development of safety requirements, Jenkins said.

FDA frequently asks advisory committees for suggestions on Phase IV trials. But generally these are efforts to get the committees to comment on what subjects should be addressed in the trials. And these discussions can often start to run a bit beyond FDA’s authority.

At the discussion of Merck &Co. Inc.’s application for a genital warts prevention indication for Gardasil in males on September 9, the advisory committee members went beyond discussing the need for postmarketing trials to offering their opinions on how the product should be presented to the public – an example of the dangers sponsors face when issues about postmarketing controls are turned over to advisory committees in public.

The new discussions that FDA has in mind over Phase IV appear aimed less at product control commentary and more specifically to get the advisory committee to react to design protocols generated by the agency. That should keep the discussions more focused but it still threatens to remove an element of control over information about the product in the postmarketing environment away from the sponsor.

Jenkins noted that the agency feels it is being closely watched for how it handles its new postmarketing authority. “There is going to be a lot of scrutiny by outside parties if for very valid reasons we later have to change those timelines – because it will be assumed that we are not exercising our authority to make the companies stick to the timelines” for finishing trials, Jenkins said.

The OND director had the timeline issue on his mind at IOM because he was preparing to hold a press briefing the following day to give updated figures on the number of pending Phase IV trial commitments. (See “The Pink Sheet” September 7).

Coincidentally, the day before Jenkins’ presentation to IOM, one sponsor, Genzyme, was taking criticism at an Oncologic Drugs Advisory Committee meeting (See “The Pink Sheet” Sept. 7) for taking more than six years to start confirmatory Phase IV studies on Clolar (clofarabine).

Diabetes Trials, Process Are Models for Phase IV

FDA officials at the IOM meeting discussed the new cardiovascular outcomes requirements for diabetes drugs as a model of the type of postmarketing trials that can be expected in the future.

The diabetes guidelines that define the safety trial requirements derived from an open discussion of diabetes safety issues at an advisory committee in July 2007. That meeting presumably sets an early model for the type of Phase IV safety requirement discussions that Jenkins has in mind.

CDER director of medical policy Bob Temple told the IOM meeting that the 1.3 hazard ratio in the diabetes postmarketing outcomes trials “came from experience with the NSAIDs, where everyone was sort of happy.”

With a glancing reference to Cleveland Clinic cardiologist Steven Nissen who initiated the diabetes cardiovascular safety review with a study of Avandia risks, Temple noted that the 1.3 ratio “reflected a proposal from Steve Nissen; so how could we not agree?” Jenkins corrected Temple: “I believe Steve Nissen actually recommended 1.4 and we decided on 1.3.”

Temple reiterated the balance between designing trials to demonstrate safety and maintaining feasible trial requirements.

“You are right,” he noted in response to Jenkins, “the public will have to understand that here is what we know, here is what we have ruled out; here is what we haven’t ruled out.”

Temple also noted that the hazard ratio is not the only measure of risk. “I’m not sure that I can tell you what is an acceptable risk, but I just want to remind everybody that when you put an upper bound on a risk (say 1.3) that is not the only measurement that you are looking at. There is also the point estimate.”

Scott Korn, VP-clinical risk management at Merck Research Labs, told the IOM meeting that the discussions around diabetes safety trials set a reasonable model. “We need to have reasonable expectations for post-approval trials,” Korn said, noting “it is often difficult to prove a negative.”

“What you can often do is instead cap the risk: you can exclude a risk above a certain amount. The example was the diabetes guidance that the FDA issued last year where the community and the agency reached a consensus that we would exclude a relative risk of 1.8 as the upper bound in order to get approval and if we fall within 1.3 and 1.8 then we have to do a post-approval trial to better define that risk.”

The diabetes guidelines accept an element of risk and try to put a cap on it, Korn observed. “That is a realistic assessment. We look forward to having a discussion around that to help define and develop feasible clinical trials that will be informative.”

If advisory committees do become more frequently involved in discussing the design and safety issues for Phase IV trials, that is going to put an extra burden on those groups and could impact their ability to handle the current role in drug approval decisions.

Merck Exec VP-regulatory affairs Peter Honig referred to the challenge that FDA faces in getting advice on outcomes studies from the advisory committee at the IOM meeting. After Jenkins’ announcement of the new use of advisory committees, Honig said: “Hopefully you can field some good cohorts for advisory committee members that will give you thoughtful input.”