Forest Labs Had Effective "Co-Sponsor" for Ceftaroline Review

FDA got a chance to show off its ability to stimulate antibiotic development during an advisory committee review of a new cephalosporin from Forest Labs. In the past, the agency has been faulted for failing to set clear targets for anti-infective trials; with ceftaroline, the agency went to the other extreme, stepping in to support an application with key re-analyses of data.

By Laura Helbling

Pharmaceutical companies leave no stone unturned when it comes to finding outside experts to help support a critical NDA with key analyses of complex data. But Forest Laboratories Inc. had the best possible help on its "next generation" injectable cephalosporin antibiotic ceftaroline: the Food & Drug Administration's Office of Antimicrobial Products.

During the September 7 Anti-Infective Drugs Advisory Committee review of Forest's application, FDA assumed an active role to make sure that studies developed by the sponsor could be interpreted by the advisory committee in light of evolving endpoint guidelines.

The agency took it upon itself to commit reviewers and statisticians to make sure that the Forest application would not run aground on the shoals of out-dated endpoints.

The sponsor used primary efficacy endpoints looking at relatively long term cure rates (8-15 days after the last dose). That is out of step with the evolving view of clinical trialists and regulators about study methodology. Ongoing discussions, workshops and committee meetings since January 2008 have focused on shorter-term endpoints as more accurate.

To bring the efficacy assessment in line with newer endpoints, FDA used historical data and looked for signs of activity at earlier endpoints: Day 4 for community-acquired pneumonia and Day 3 for complicated skin and skin structure infections.

In CABP, for example, the agency looked back at symptoms (cough, dyspnea, pleuritic chest pain and sputum production) in addition to vital signs. Responders were patients who improved on at least one of the four symptoms and did not worsen on any.

The advisory committee was very impressed with the agency's effort to complement the sponsor's work and bring the analyses up to new standards, with members praising the quality of the agency's work and even offering outright expressions of gratitude.

"With regard to clinical efficacy endpoints," said Committee Chair Thomas Moore, Ochsner Health System, "I want to thank the FDA for their hard work in crunching the data and presenting those data together."

The compliments to FDA translated into two overwhelming votes for approval for ceftaroline: 21-0 for the CABP indication and 18-0 for the cSSSI indication, putting the product on track potentially for approval by its user fee deadline at the end of October.

Good Gloom-Breaker: Clear Efficacy and Low Likelihood of Resistance

There are at least three reasons why ceftaroline qualified for active help from FDA:

(1) because of its attractive profile in fending off resistance;

(2) because efficacy data appeared strong enough (pushing beyond non-inferiority towards superiority) that it was likely to hold up under the new endpoint analyses; and

(3) to send a signal to other sponsors that products can successfully meet the evolving new antimicrobial standards for efficacy.

The work that FDA did on ceftaroline is a big step towards breaking the regulatory gloom around the anti-infective class.

A former FDA official involved in the anti-infective area explains that the agency occasionally selects projects to assist for a variety of reasons. In the case of ceftaroline, the ex-FDA staffer suggests that the resistance profile may have been of the attractive features.

FDA highlighted that aspect of the compound in a summary of the application for the advisory committee. FDA reports that in vitro studies "indicate a low propensity for the development of ceftaroline resistance following serial passage experimental studies compared with comparator agents."

Committee members were impressed with the drug's efficacy. Committee chair Moore said it seemed at times that the drug "was strong enough to perhaps star in its own Old Spice commercial." Several members noted that in the comparator trials the new product pushed beyond non-inferiority towards signs of superiority.

Moore further commented on the ground-breaking role for ceftaroline in charting the route through new endpoints. The committee chair said that ceftaroline will be the "poster child" for how to meet the new endpoints.

Underneath the very positive votes and reactions to the presentations on September 7, the advisory committee did express some concerns about the appropriate use of ceftaroline following approval. The committee raised issues for FDA to work out with the sponsor in labeling: preventing use for MRSA in CABP patients and discrepancies between the sponsor and FDA's breakpoint calculations.

Despite those caveats, the ceftaroline review demonstrates how much the climate for anti-infective drug development has improved in the past year. Just fourteen months ago, another sponsor, Advanced Life Sciences, had a much different experience with the developing endpoints.

A June 2009 Anti-Infective Drugs Advisory Committee voted (11-3) against approval of the oral antibiotic Restanza (cethromycin) based on a new draft efficacy guidance for CABP, which had just been released three months prior to the meeting. That led to a complete response letter from FDA in August of that year.

At a June Congressional hearing on promoting antibiotic development, Advanced Life Sciences submitted written testimony recounting its experience with the changing targets that it faced in antibiotic development to illustrate the need for regulatory clarity in the field. (Also see "Antibiotic Development Incentive Menu: Options Getting Longer" - Pink Sheet, 1 Jul, 2010.)

FDA's effort to work more productively with anti-infective sponsors is also evident in a restart for the development effort by Advanced Life Sciences. In March, the company announced that it has agreed with FDA on a Special Protocol Assessment for prospectively designed superiority studies in CABP. ( See "Restanza's New Hope: Advance Life Sciences To Conduct New Pivotal Trials," The Pink Sheet Daily, March 11, 2010.) Cethromycin was previously tested against clarithromycin; there are no superiority studies underway yet, according to NIH's Clintrials.gov database.

Easy Vote on CABP Indication

For ceftaroline, the CABP vote on Sept. 7 was a "very easy decision to make," committee chair Moore commented at the meeting.

"In terms of the FDA analysis, I thought it was very helpful and particularly [...] the daptomycin data," Moore said. "I thought that was contemporary and relevant." FDA did a post-hoc analysis of daptomycin versus ceftriaxone to examine the non-inferiority margin in the ceftaroline trials. The agency used data from a failed CABP application for Cubist Pharmaceuticals Inc.'s daptomycin (Cubicin) to establish the comparator effect for ceftriaxone. Daptamycin did not show antibacterial activity against pneumonia in the lung; FDA used that data to construct a placebo effect.

Erica Brittain, a statistician from NIAID, "really liked" the FDA analysis and noted that she wished all non-inferiority trials were as easy to interpret. "I also liked that the FDA's sensitivity analysis, even though in their presentation they seemed to be kind of critical of what they did," Brittain said. "I felt very comforted by using the daptomycin trial results to justify the margin and all the various sensitivity analyses that were done."

Yu Shyr, Vanderbilt University School of Medicine, praised FDA Statistical Reviewer Daniel Rubin, who conducted the CABP analyses. Shyr thanked the FDA team for the "thorough" analyses, adding that this was an "easy case" from a statistical point of view.

Peter Kaplan, Texas Children's Hospital and Baylor College of Medicine, noted that the multiple analyses were "quite helpful."

"In essence, the mortality effects through a non-inferiority analysis have not been established, but there's adequate evidence in my view of symptomatic benefit," said Thomas Fleming, University of Washington. "In this regard I think the analyses that were done by the FDA are extremely important in the spirit of the National Institutes of Health Foundation working group consensus." Fleming, a member of the Foundation for NIH Biomarkers Consortium working group on CABP and cSSS, noted several times during the ceftaroline review the confluence of FDA activities with the markers being proposed by the non-governmental group.

FDA Analyses Helps Overcome cSSSI Hesitancy

Many committee members observed that the decision on ceftaroline for CSSSI was not as clear-cut as the CABP decision – although both votes were unanimous for approval. NIAID statistician Brittain again cited FDA's analysis as the key factor in swaying her vote for approval.

Fleming was less enthusiastic for cSSSI than in for the CABP indication. "The analyses by the FDA allowed us to really drill down to an area of much more interpretability and sensitivity focusing on day three or four, which is certainly critical if you want to a non-inferiority margin in this setting."

A take-home message, Fleming said, is that "relative to the clinical cure at test of cure, these analyses that the FDA has provided are much more sensitive to being able to detect true differences that actually exist."

"With all the approaches that were taken, we find that a threshold [non-inferiority margin] of 10 percent was satisfied," said Matthew Goetz, David Geffen School of Medicine. "I was particularly pleased by the FDA analysis and the analyses that were done on subtypes of infection."

Increased Clarity, But Path Not Yet Crystal Clear

Panel members were hopeful that the FDA's analyses could be incorporated into future trials - but they recognize the analyses will not always be as easy or as clear.

"I found the FDA's sensitivity analysis very helpful," said Jan Patterson, University of Texas Health Science Center at San Antonio. "In the future of course it would be very helpful to incorporate prospectively in the design. Also, I think mortality rate, as we've seen from this and other studies, is not going to be very helpful as an endpoint, and so early evaluation, studies designed to look at early evaluation on symptoms and validation of signs would be very helpful in the future as well."

"Certainly Dr. Rubin's [FDA statistical] analysis was very helpful" on CABP, said Bernhard Wiedermann, Children's National Medical Center. "I hope that will be sort of a prototype for future analyses. But we also have to remember that a lot of this is post-hoc subgroup analyses, and there are a lot of pitfalls to that. When it comes down the pike for the next drug, the next combination, it may detract from supporting the drug's indication."

Moore said that applying the analyses to less effective drugs in the future could be a challenge but still insisted it was a "superior job."

Fleming said he felt somewhat flexible on the irregularities in the CABP data given the nature of post-hoc analysis. "I recognize that the FDA analyses were done as best possible in a trial design that hadn't been specifically targeting looking at these symptoms at day three or day four and there are some issues of missing data," Fleming said. "Hopefully, in the future, as these measures are used, those irregularities would be less."

Fleming notes that the CABP and cSSSI endpoints are both works in progress – meant to "bridge us" until there are more validated rigorous measures. On August 27, FDA released its draft guidance document on developing drugs to treat acute bacterial skin and skin structure infections (ABSSSI, the agency's new term for cSSSI). The September 7 committee made several comments on lesion size as a measure.

FDA's CABP guidance is currently undergoing revisions following the December 2009 Anti-Infective Drugs Advisory Committee meeting to discuss the comments to the draft. ( See "(Forest's Ceftaroline Data Robust Even Under New Antibiotic Efficacy Standards, FDA Says," The Pink Sheet, September 2, 2010.)

Ceftaroline's positive advisory committee experience – with assistance from FDA – is a good first indicator that the road to a new regulatory climate and clear endpoints for anti-infectives is getting smoother.