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Non-Inferiority Studies May (Bio)Creep Out Of Limelight After GAO Report

Executive Summary

A report on FDA's use of non-inferiority trials by the Government Accountability Office could in fact signal the end of the political wrangling over the study method

A report on FDA's use of non-inferiority trials by the Government Accountability Office could in fact signal the end of the political wrangling over the study method.

The most important conclusion of 1 GAO's report, released Aug. 30, was that non-inferiority trials do not appear to have produced "biocreep" - the potential that newly approved drugs, while statistically comparable to another drug, are at the lower end of the margin of error. The concern was that a series of such comparisons could lead the FDA to approve drugs that are no better than placebo.

"FDA's review . . . minimized the potential for biocreep," the GAO found. "Similarly, our examination of the trials' characteristics also revealed no evidence of biocreep."

GAO reviewed 175 new drug submissions filed between 2002 and 2009 and identified 29 that included evidence from at least one non-inferiority trial, usually done because denying an available therapy to patients in a placebo-controlled trial is unethical. Nearly two-thirds of those trials (18) were pivotal, and anti-microbials comprised two-thirds of that group (12). It found no evidence that inferior drugs had entered the market.

FDA's Approach May Blunt Congressional Pressure

The report was requested by Sen. Charles Grassley, R-Iowa, and Rep. Edward Markey, D-Mass., and despite GAO's relatively upbeat assessment of FDA's handling of the study method, they both issued statements expressing continued concern.

"This study gives the FDA another reason to carefully consider its use of these sorts of trials when approving new drugs for the market," Grassley said.

"The GAO report shows that these so-called 'non-inferiority' trials have often proved to be an inferior means of reviewing the safety and efficacy of new drugs," Markey said, a conclusion that seems at odds with the report's findings. "I will continue working to investigate and implement empirically sound changes to ensure that the FDA can protect the public's health."

These pressures will likely be counterbalanced by two factors. Rep. Henry Waxman, D-Calif., is supporting FDA's approach to the studies, and FDA's approach itself appears to be toughening.

Waxman, a long-time industry critic who chairs the House Energy and Commerce Committee, recognized the report offered support for continued use of non-inferiority trials in specific situations. "Non-inferiority trials are an essential tool for evaluating the safety and effectiveness of certain kinds of critically important drugs such as antibiotics - but they pose difficult scientific issues," he said.

"Although the pipeline for antibiotics is critically bare, no one benefits from ineffective drugs - and so I encourage FDA and industry to continue to collaborate to do everything possible to ensure that safe and effective antibiotics are developed."

GAO concluded that "the agency has become more conservative in allowing evidence from non-inferiority trials to demonstrate a drug's effectiveness."

FDA, in its comments on the report, did not challenge that assertion. "Based on the fact they didn't have anything other than technical corrections, I'm taking that as an admission that they agree with what's in that report," said Kurt Karst, an attorney at Hyman Phelps & McNamara, which represents industry clients. "FDA is going to be scrutinizing non-inferiority [trials] more and when possible prefer that they not be used."

The agency's most recent formal tightening of standards is a draft guidance released Aug. 26 on drug development for acute bacterial skin and skin structure infections, which offers some flexibility in justifying a non-inferiority margin (see 2 (Also see "FDA Skin Infections Guidance Spurs Debate On Endpoint Relevance" - Pink Sheet, 6 Sep, 2010.)).

Advanced Life Sciences Tacks Into The Wind

The political controversy over non-inferiority studies came to a head with whistleblower hearings on the approval of Sanofi-Aventis' Ketek (telithromycin) (3 (Also see "FDA Safety Decisions On Ketek To Get Formal Review By House Committee" - Pink Sheet, 20 Feb, 2007.)). Products currently under development may ultimately face the full impact of it.

The scientists in charge of Advanced Life Sciences Inc. of Woodbridge, Ill. opted to avoid the non-inferiority issue and collaborate with FDA on a superiority trial for Restanza (cethromycin), an experimental oral antibiotic for community-acquired bacterial pneumonia that was previously rejected on the basis of non-inferiority trials. A special protocol assessment for the superiority trial design, which pits cethromycin against zithromycin, was approved by FDA on Aug. 10, company officials said (4 (Also see "Restanza Superiority Trials Intended To Avoid Non-Inferiority "Quagmire"" - Pink Sheet, 1 Sep, 2010.)).

"We've been at every workshop and we've heard every speaker. It's quite clear that this debate will rage on for a long time," said John Flavin, president of Advanced Life Sciences. "We chose to go down a different path by engaging the FDA as a collaborator to help them develop a new paradigm."

The company was one of several small start-up companies developing antibiotics that were caught in the backwash of the Ketek scandal, where research fraud in a pivotal non-inferiority trial contributed to the drug losing its FDA approvals for acute bacterial sinusitis and acute exacerbations of chronic bronchitis. In 2007 Ketek was also slapped with a "black box" warning because of its liver toxicities for its one remaining indication - community-acquired pneumonia.

While the Ketek scandal was making headlines, Advanced Life Sciences was in the midst of two Phase III non-inferiority trials for Restanza, which is in the same class as Ketek. While this new class of antibiotics - ketolides - has a similar mechanism of action as macrolides like zithromycin, erythromycin and clarithromycin, it holds out the promise of overcoming growing resistance to the class because it binds at two sites on the bacteria's target ribosome instead of just one.

Launched in 2006, Restanza's original trials involved 1,100 patients on four continents and took 24 months to complete. Though the clinical program met the non-inferiority criteria in place at the time it was started, when it went before FDA's Anti-Infective Drugs Advisory Committee on June 2, 2009, the agency held it to updated standards and the efficacy results were rejected (5 (Also see "Advanced Life Sciences Restanza Blocked By New FDA Efficacy Criteria" - Pink Sheet, 8 Jun, 2009.)).

Opting to avoid the "quagmire" of non-inferiority trials, the company has designed two superiority trials that meet FDA's tighter standards. The trials, which will launch later this year assuming the company finds the $15 to $20 million needed to finance the trials, will randomly administer cethromycin and streptomycin to 800 patients with community-acquired pneumonia. The company expects about a quarter of those patients will be macrolide-resistant. "That group - 100 patients in each trial - will represent the population for our primary endpoint, which is superiority," Flavin said.

"In a previous era, our drug would already be on the market," said Michael Flavin, chief executive of the company. "Although frustrated, we've set out on this task. With a win here, we will have a clear marketing advantage against the macrolide class and other agents on the market, which you couldn't achieve under the non-inferiority regimen."

Cystic Fibrosis Drugs Also Affected

Another company adapting to the tightening standards is Gilead Sciences, Inc., which last February won FDA approval for Cayston (aztreonam) for cystic fibrosis patients with chronic pseudomonal infection ("6 (Also see "Gilead Prices Cystic Fibrosis Drug Cayston At Slight Premium To Competitor" - Pink Sheet, 1 Mar, 2010.)). The drug, matched against tobramycin in its pivotal 268-person trial, had a 28-day non-inferiority endpoint as well as a six-month superiority endpoint. The superiority trial design was required to gain full approval in the European Union and Canada, which gave the drug a conditional okay in September 2009.

The short-term results, announced in June at a European scientific meeting, showed aztreonam was significantly superior to tobramycin in improving lung capacity. The six-month data will be available later this fall. Gilead said it plans to begin submitting data from this study to regulatory agencies later this year.

The Broader Impact On The Antibiotic Pipeline

Still, some industry officials and consultants are warning that FDA's tougher stance on non-inferiority trials could further reduce the already paltry pipeline for new antibiotics.

"The requirement for superiority studies for sinusitis, otitis and chronic bronchitis . . . effectively means doing a study versus placebo in these indications," John Rex, chief of antibiotics research at AstraZeneca, wrote in an e-mail. "I think pharmaceutical firms will defer work versus such indications."

Though antibiotic sponsors "are definitely incorporating the new ideas into their planning," he continued, "an obvious consequence is that new broad-spectrum antibiotics are being principally developed against indications that are associated with greater obvious morbidity and mortality, like community-acquired pneumonia."

- Merrill Goozner ( 7 [email protected] )

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