J&J Bedaquline and the Evolving Role for Accelerated Approval: Confirming Safety, Not Efficacy?

By Laura Helbling
FDA Beat

December 4, 2012

Executive Summary

Discussions during an advisory committee review Janssen’s TB drug bedaquiline showed some interesting thinking around accelerated approval and how much uncertainty can be acceptable—especially when it comes to safety.

Janssen Inc.’s bedaquiline is in many ways the ideal example of what “enhanced” Accelerated Approval might look like.

The tuberculosis therapy appears head towards Accelerated Approval after clearing the Anti-Infective Drugs Advisory Committee on November 28.

There is no denying the unmet medical need: multi-drug resistant TB is clearly an important public health priority, and especially so for FDA Commissioner Margaret Hamburg (who has experience with TB as New York City health commissioner during the city’s TB outbreak in the 90s). (“TB Drug Development: An Attractive Public Health Project for FDA” — The RPM Report, May 1 2010 12:00 AM)

And bedaquiline works where nothing else does; at least, the committee sure thought so, voting unanimously (18-0)that efficacy has been proven. The only caveat on the efficacy side: the committee clearly thinks the endpoint (sputum culture conversion) is a surrogate marker, not a clinical endpoint suitable for full approval. (“J&J’s Sirturo Gets Panel Endorsement For Accelerated OK, Even As FDA Broaches Full Approval” — “The Pink Sheet” DAILY, November 28 2012 11:05 PM)

The company was requesting accelerated approval, and FDA’s Office of Antimicrobial Products Director Ed Cox had instructed the committee to answer the efficacy question in the context of AA. So this looks like a great example of using accelerated approval beyond cancer and HIV – right after the passage of the FDA Safety and Innovation Act, which encourages the agency to use accelerated approval in more disease areas. (““Breakthrough Therapy”: New Pathway in FDASIA May Point The Way To Future Reforms” — The RPM Report, August 16 2012 12:00 AM) As an added bonus,the drug will also qualify for a priority review voucher, if approved.

TB Drug Headed Toward Accelerated Approval: Another Wrinkle for Priority Review Vouchers



A positive advisory committee for Janssen’s bedaquiline means the second priority review voucher is probably on its way. And it would be the first for an accelerated approval.



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Given all that, the surprising thing is how close bedaquiline came to being rejected by the committee.

The committee voted 11-7 that the data provide substantial evidence of safety – a narrow margin after the unanimous “yes” vote on efficacy. Given that the drug is intended to treat multi-drug resistant TB, you might think that efficacy was really all that counts: what else, after all, can you give someone whose TB is resistant to everything else?

The majority of the “no” votes however, explained that they were taking the question as it was worded—and raised concern about whether there is “substantial” evidence of safety. Most said they would have voted “yes” that the safety data was sufficient for accelerated approval, with the “substantial” part filled in later.

Cardiologist John Teerlink (UC-San Francisco) said he voted no because he wanted it “to be an uncomfortable experience going for accelerated approval.” Given increased and unexplained mortality in the bedaquiline group, Teerlink said, it would be “appropriate to proceed,” with accelerated approval “but with a lot of caution.”

But the committee members’ comfort with accepting the safety of the drug given the hope for more safety information from the confirmatory trial at odds with the point of required post-marketing accelerated approval studies: they are supposed to confirm clinical benefit. Indeed, the newly codified “accelerated approval” definition in FDASIA stresses that the pathway is for drugs approved on surrogate markers or early clinical evidence of benefit. There is no mention of approving drugs whose safety profile is not sufficiently characterized.

And not everyone is comfortable with that idea.

The concern about lowering the safety bar, in fact, likely explains a somewhat surprising negative testimony during the open public hearing, from National Research Center for Women and Families’ Jennifer Yttri. The NRC and its head Diana Zuckerman are frequent public speakers on regulatory issues, but they typically weigh in on cases where the potential use is broad (for instance, hip implants or the weight loss drug reviews in 2012).

In this case, the broader concern appeared to be less related to the likely use of the drug (probably only a few hundred patients a year in the US) than in the use of accelerated approval. Yttri specifically cited the Avastin accelerated approval in metastatic breast cancer and the subsequent withdrawal process, which she says included “delaying tactics and hostility.” (“How to Withdraw a Drug: FDA’s Final Decision on Avastin” — The RPM Report, November 20 2011 12:00 AM)

Yttri warned called “approval of drugs based on the promise of benefit” a “dangerous practice.” She praised the quality of Janssen’s trial – “the kind of the study that FDA should rely on”—but said it showed that bedaquiline isn’t as good as the existing drugs. (See Exhibit.)

Consumer representative Kathleen Young (Alliance for the Prudent Use of Antibiotics), who voted yes on efficacy, referred to Yttri’s remarks in her “no” vote on safety, specifically the idea of doing no harm to patients. Young compared holding back on approval to not treating certain patients with chemotherapy when it won’t really help them and said more data is needed on bedaquiline’s long half-life and its effect on cross resistance. Young explained that her vote was “not because I want to constrain the field. I want to move forward faster. I think by going to the next trial the Phase III and addressing some of the questions here and coming back quickly will learn a lot.”

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