FDA's Internal Advisory Committee Meetings

Avandia. Vioxx. Ketek. Elidel. Palladone.

What do those drugs have in common? The obvious answer is that they are all associated with a major safety problem that resulted in a significant FDA regulatory action—either a “black box” warning in product labeling, or, in the case of Palladone and Vioxx, outright removal from the market.

But they have something else in common as well. In the months preceding those major regulatory steps, each product was the subject of a relatively unknown internal meeting at the Food & Drug Administration: a regulatory briefing.

Regulatory briefings can be described as “internal advisory committees” at FDA—a chance for review divisions to ask others in CDER for advice on how to handle a tricky regulatory or scientific decision. (For more on regulatory briefings, check out our coverage in The RPM Report. If you’re not a subscriber, you can sign up for a free trial to view the article.)

If you’ve never heard of a regulatory briefing, you’re not alone. Regulatory briefings have been kicking around FDA’s Center for Drug Evaluation & Research for more than a decade, but because they are closed to industry—and review divisions don’t always inform sponsors when one is held—many companies are unaware that they exist. But now FDA is holding more of them, as many as one per week. And they are quite popular with reviewers.

The good news for drug sponsors is that regulatory briefings are not intended to be decisional meetings; the final approvability decision remains with the review division after the meeting is over. But given the typical attendance list—John Jenkins, Janet Woodcock, Bob Temple, Doug Throckmorton and 50-100 other drug reviewers—it would be hard to ignore any advice.

A drug does not have to rise to the level of an Avandia or a Vioxx to be discussed during a regulatory briefing—given the frequency of such meetings, that could not possibly be the case. But, as the list above indicates, they do tend to skew toward the more problematic end of the continuum. The need for a regulatory briefings should not spell doom and gloom for a sponsor, but it could be an indication that something is wrong. That alone makes them worth watching.

image via FDA

Telavancin Delayed By Grassley's Ketek Data Integrity Rule

FDA is adopting whole-heartedly at least one of Iowa Republican Senator Grassley's new de facto rules for drug approval reviews: the agency is not going to risk its public credibility by continuing to consider for approval applications where there is even a hint of a data integrity problem.

That's one of the lessons of the Ketek investigation and one that Theravance experienced painfully late last month. On March 3, Theravance explained more about the last-minute cancellation in the planned February 27 FDA advisory committee review for its injectable antibiotic, telavancin.

The delay stems from FDA's unwillingness to review the application after the removal of data from one study site. Theravance said that the agency asked the company to remove the data from the site on January 30, twenty-seven days before the scheduled Anti-infective Drugs Advisory Committee and nineteen days after the agency first announced its intention to hold the advisory committee review of the drug.

Theravance maintains that the "removal of these data had no material impact on the overall efficacy and safety results or conclusions of the study previously reported, and we believed the site issue had been adequately addressed by the data removal."

In that case, the company was too focused on its own application and not paying attention to the overall environment and the pressure on FDA from Grassley's intense oversight -- focused in particular on the agency's willingness to overlook some questionable data to keep an applicaiton on track for approval.

Grassley sent FDA a letter on December 19 in his continuing review of FDA's handling of the Sanofi-Aventis Ketek (telithromycin) application that created a de facto standard: a sponsor cannot resolve a data integrity issue by just removing the results from the questioned center or investigator.

In his mid-December letter, Grassley made it very clear that he expects FDA to halt the approval process on applications if the agency finds any problems with data integrity. (See here for our previous coverage of Grassley's Ketek rule.)

Grassley's letter coming right before the Christmas holiday break was probably ignored by much of the financial community. It was also overshadowed by Theravance's December 27 announcement that it was getting ready for an imminent advisory committee review.

FDA tried to work around questionable data before. It asked an advisory committee previously to review the Ketek application with some suspect data from a clinical investigator removed. Based on the heat it has taken from Grassley for that review, FDA was unlikely to repeat that process of a quick fix for the data in the case of another drug, especially another antibiotic.

Theravance says it is "committed to working with the FDA to resolve outstanding issues related" to the telavancin clinical trials for complicated skin and skin structure infections, the "ATLAS program." The company reports that FDA wants to "further evaluate study site monitoring and study conduct to ensure data integrity in the ATLAS Phase 3 program." The agency wants to look into monitoring at other sites and not just take the word of the contract research organization.

Other NDA sponsors would be well advised to pay more attention to all pending data integrity issues for products nearing the review stage. The agency's division of scientific investigations is clearly emboldened and carrying more weight within FDA from Grassley's attention (See here).

Theravance's follow-up statement, however, at least begins to peel back the cover from the mystery of the recent wave of meeting cancellations. For a while in February, it looked like FDA did not want to bring any products to advisory committees. The agency canceled three meetings last month (see here).

Investigating the Investigators: Another Headache for Drug Sponsors

This would be a good time for biopharma companies to review their ongoing clinical trials to determine whether any investigators involved in the study are vulnerable to potential disqualification proceedings by the Food & Drug Administration.

All signs point to a crackdown coming from the agency, likely to take the form of a spate of proceedings to disqualify individual investigators from participating in clinical trials.

That in turn means a big headache for any drug sponsors that relied on those investigators in pivotal trials of their drugs—any trial those investigators participated in, not just one that prompts a fraud investigation.

What tea leaves are we reading? How about these comments by the Center for Drug Evaluation & Research’s Office of Compliance director Deborah Autor, who told the Food & Drug Law Institute’s annual Enforcement & Litigation Conference yesterday that the Division of Scientific Investigations is “becoming more activist. I think that they are really gaining momentum in what they do from an enforcement context.”

The agency is working on “streamlining” the process involved in disqualifying clinical investigators when FDA uncovers fraudulent or violative practices, Autor said. She acknowledged that the process currently is “Byzantine” and slow-moving—a fact that works to the benefit of investigators facing potential disqualification.

“The agency is working to clean up those procedures,” she told the audience, adding the wry observation that “I’m not so sure this is good from your standpoint.”

Autor’s comments verify the observations of two attorneys sharing the dais with her—Douglas Farquhar of Hymen Phelps & McNamara and Philip Katz of Hogan and Hartson—who sense greater urgency and a tougher stance from the agency in cases involving clients potentially facing disqualification.

A crackdown on investigators accused of fraud would hardly be surprising, given the recent round of hearings and Congressional reports focusing on claims that FDA failed to take action quickly enough to respond to allegations of fraud in clinical trials of the antibiotic Ketek.

We won’t rehash all the allegations here. Suffice it to say that there is bipartisan concern that FDA is not sufficiently vigilant in overseeing the conduct of clinical trials. The debate on the Hill focuses on whether FDA needs new enforcement powers (the subject of the most recent Ketek hearing in the House) or simply needs to use its current enforcement authority more aggressively (as recommended in a report by Republican Representative Joe Barton).

Any move by FDA to step up disqualification proceedings against investigators means headaches for industry.

It's not just the individual accused of fraud or that investigator's clinical center that suffers in a disqualification proceeding, Katz pointed out. “What you then quickly get to is: what do we do with the data that this disqualified clinical investigator has been involved with?”

And it “is not just the data in the study that was the subject that led FDA to the disqualification proceeding,” Katz said, “but also other data with which that investigator was affiliated. That becomes suspect as well.”

In some cases, there may be nothing sponsors can do to avoid the taint—except hope that their clinical trial findings are robust enough to support safety and efficacy even if the investigator’s site is excluded from the analysis of the trial.

But sponsors can also prepare by double checking whether their investigators have been cited by the agency in public inspection documents (known as FDA 483 reports) or, even more critically, in warning letters from the agency. Those are warnings signs that an individual may be vulnerable in an enforcement crackdown.

Autor added that the agency is not relying on enforcement alone, but is working to modernize its overall regulatory approach to clinical trial monitoring.

“The regs, as everybody knows, are outdated and don’t really fit the way trials are done today,” she said. “Hopefully, over time you will see that changing so that clinical trials will really be subject to appropriate regulation for how they are conducted today.” The goal will be “putting the onus on sponsors and monitors to ensure quality in clinical trials.”

That may sound like yet another regulatory burden on drug development (and it is), but if the alternative is a series of enforcement actions that knock out individual trial sites from multiple applications at a time, this may be a case where industry has a lot to gain from moving to a new regulatory model.