Prepare More Data Earlier For Advisory Panels In Era Of Low Risk-Tolerance

A stricter risk-tolerance environment at FDA means sponsors need to engage more in the advisory committee process and prepare to address real and perceived or hypothetical "data gaps."

FDA has become more conservative about risk when considering new drug applications and looking at broader issues such as the safety of OTC cough/cold products, experts say.

"There is no question in my mind that [FDA's] risk-tolerance is changing," says Ed Kuffner, a toxicologist and senior director of Global Medical-Clinical Affairs with McNeil Consumer Healthcare.

Kuffner spoke about the evolving advisory committee process at the Consumer Healthcare Products Association's Regulatory and Scientific Conference in Washington May 8. In October, he participated in the Nonprescription Drug Advisory Committee meeting on the safety of OTC pediatric cough/cold medications.

"The safety bar is continually getting higher," says Cindy DiBiasi, a partner at Bethesda, Md.-based 3D Communications, which consults with the pharmaceutical industry and specializes in advisory committee preparation.

"At the same time, it's somewhat ambiguous" what safety data and clinical trials FDA and advisory committees may expect, she told "The Tan Sheet."

That safety threshold can be a moving target, creating problems for sponsors who are trying to determine what safety standard they need to meet. In some cases, DiBiasi says, companies have invested in R&D, including years of trials, "and [they're] talking to the FDA about where the safety bar is supposed to be and [they're] going back and forth and then [they] get to the meeting and [hear], 'Well, no, not any more, we didn't mean that.'"

Advisory committee meetings have become more frequent because FDA relies on them more for "political cover" since the fallout from Merck's Vioxx withdrawal and other high-profile safety and efficacy issues, she says.

Panels "used to be called upon to answer really technical or scientific issues, very specific issues," says DiBiasi. "More and more you're seeing them convened to judge everything from the safety of the drug to marketing practices. They're weighing in on a lot of broader issues that the FDA is grappling with."

Anticipate Data Gaps

In response to the increased scrutiny, drug sponsors need to "be even more vigilant in presenting risk/benefit analysis" in the context of evolving risk-tolerance and research standards, says Kuffner.

It is especially important when the data support a point of view that the committee members may not have understood from briefing materials, Kuffner explains.

Specifically, he says, sponsors need to identify and address "potential or perceived data gaps" that an advisory committee may ask about.

Advisory committee members often ask complex or hypothetical questions that "lead to requests for additional data," he says. Sponsors who anticipate these questions and prepare the data increase the odds for a positive outcome.

Tell A Story

But it is not enough to let the scientific and risk-benefit data speak for itself, says DiBiasi.

"You need to have context, a story around the data" to effectively communicate a safety message to advisory committee members, DiBiasi says, adding, "It is really not fair to the members to be just basically doing a data build."

Putting data in context is important because "not everyone follows the pharma world," and some advisory committee members may not be as familiar with the "realities of the OTC world" as the sponsor, says Charles Ganley, director of FDA's Office of Non-prescription Products at the Center for Drug Evaluation and Research. He also spoke at the CHPA conference (¹ (Also see "FDA Works To Ease “Traumatic” Advisory Committee Process – Ganley" - Pink Sheet, 12 May, 2008.), p. 3).

DiBiasi agrees, saying sponsors "really have to understand who is on their committee and where those people are coming from," in order to tailor their data presentation and adequately anticipate questions.

In that same vein, she adds sponsors must have an articulate, charismatic speaker who can quickly answer committee members' questions.

Speakers "don't have a lot of time to answer the question. The chair will cut them off ... so they have to really cut to the chase," and "be really targeted with their answer," she says.

Sponsors also have to be "very specific about what [they] are going to present" because they "only have 60, 75, maybe 90 minutes, if [they're] lucky, to do the entire presentation," she adds.

Start Preparing Early

While the actual presentation may only be an hour and a half, sponsors should begin preparing for an advisory committee meeting before their Phase III trials, DiBiasi says.

In the case of OTC switches, DiBiasi says sponsors should consider and plan for potential concerns, and the possibility of a panel meeting, when they are designing their self-selection and actual use trials.

In Phase III and consumer behavior trials, "You're committing to things that you have to live with later. And so it's really important to factor in the possibility of an advisory committee even when you're putting those trials together," she explains.

Sponsors' "biggest mistake" in the advisory committee process is starting to prepare too late, either because they do not expect a panel will be convened or because of a lack of resources, she explains.

Most companies begin preparing for an advisory committee meeting when they file their NDA. Because the team that files the NDA often becomes the advisory committee team, it may be "too overwhelmed" to work on both at the same time, DiBiasi says.

However, some companies are starting to dedicate full internal divisions or teams to prepare for the advisory committee, she said.

In addition, "there's got to be an internal commitment ... from the top down" to the prep work, she says.

This was one reason GlaxoSmithKline successfully switched its prescription weight loss drug alli to OTC, she added. "They wiped the slates on everything else they had to do, and they were laser-focused on [the meeting], and that made ... the biggest difference, because it's a big job," DiBiasi explained.

3D worked with Glaxo on the alli program.

Working Together Industry-Wide

When advisory committees involve multiple companies or the entire industry, as in the case of a widespread ingredient concern, competitors need to work together to represent the industry, Kuffner says.

He praised the industry's "somewhat unprecedented" cooperation late last year to defend their products against complaints that widely used monograph ingredients, including phenylephrine and pediatric cough/cold ingredients, were ineffective or unsafe ("² (Also see "FDA Panel Narrowly Votes Against Cough/Cold Drugs For Children Up To Age 6" - Pink Sheet, 22 Oct, 2007.) p. 3).

In these cases, sponsors worked together to coordinate safety surveillance and adverse event data about cough/cold ingredients to demonstrate the safety of different monograph ingredients in a way that no individual company could, he says.

This cooperation "not only helped the industry clarify its position, but I think it really helped FDA and the committee, and it provided clarity to consumers and patients," he said, adding it "was one of the greatest accomplishments in '07 and I'd like to see that continue going forward."

- Elizabeth Crawford ([email protected]) and Chris Walker ([email protected])