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Volume 86 Issue 15 | Web Exclusive
Issue Date: April 14, 2008

Cover Stories: An Uphill Battle

The Ketek Effect

Biotechs worry that FDA has gotten tougher on approving new antibiotics
Department: Business, Government & Policy

Thankfully, the pipeline of broad-spectrum antibiotics is relatively robust. But many companies developing antibiotics are concerned that regulatory agencies are making it harder to get new drugs onto the market. They worry that a perception of a difficult regulatory path will deter new players from entering the business and scare off investors.

The Food & Drug Administration appears to be taking more precautions after severe criticism, culminating in a congressional investigation, over the agency's handling of Sanofi-Aventis' Ketek, a semisynthetic derivative of erythromycin. The drug was approved in 2004 to treat respiratory infections, but concerns over liver toxicity cropped up soon after its launch.

After several Ketek-related deaths, a black-box warning was added to its label, and use of the drug was restricted to community-acquired pneumonia. The agency later came under fire after it was revealed that data from a key clinical trial for Ketek were fabricated.

Drug company executives see a correlation between the Ketek criticism and what they view as tougher parameters for gaining new drug approvals. In recent months, the industry has witnessed a handful of delays in the review or approval of new products. For example, FDA abruptly canceled its advisory committee review of Theravance's telavancin, a semisynthetic derivative of vancomycin used to treat complicated skin and skin-structure infections (cSSSI). The agency said it was concerned about how clinical-trial sites were being monitored, but industry observers say that explanation wasn't clear enough.

"The bottom line is that right now FDA has not given any specific reasons for doing this," says Robert C. Moellering Jr., professor of medical research at Harvard Medical School.

The news "may reflect the FDA anti-infective division's over-zealousness as opposed to something unique with the application," Credit Suisse stock analyst Michael Aberman commented at the time of the delay.

More recently, FDA issued an "approvable" letter for ceftobipole, a broad-spectrum cephalosporin being developed by Johnson & Johnson and the Swiss biotech firm Basilea. Such a letter typically says a drug can be approved but only with more data. The companies were also seeking approval to treat cSSSIs, and the agency again said it would delay approval until clinical-trial sites could be inspected and more data analyzed.

Executives contend that the agency is setting up new hurdles to winning approval for treatment of community-acquired illnesses such as sinusitis, bronchitis, and pneumonia, which in some cases are cured on their own. They argue that the agency is shifting its end point—the parameter used to measure a drug's efficacy—for clinical trials.

At issue is the complicated math used to determine whether a new drug is superior to one already on the market. Companies must prove their drug is significantly better at healing patients than "spontaneous cure," or getting better on their own. For illnesses such as sinusitis and bronchitis, that spontaneous cure rate could be as high as 70%, making it difficult for companies to show efficacy in the absence of other end points. For indications such as complicated skin infections, on the other hand, the percentage of patients cured by the standard medicine is relatively low, making clinical trials more straightforward.

Another catch is what appears to be a trend toward using mortality as an end point for infections such as pneumonia. "The idea that you have to show your drug produces less mortality than the control doesn't look at what is really going on in the clinic," Moellering says. "You need surrogate end points, such as eradication of bacteria."

"I think the biggest challenge right now for community antibiotics has been the changing rules at FDA," says Kenneth J. Collins, chief executive officer of Replidyne, which has dealt with regulatory headaches related to its lead product, feropenem. In 2006, FDA turned down Replidyne's New Drug Application (NDA) for feropenem; the agency asked for further studies to prove the drug's superiority to other agents used to treat sinusitis and chronic bronchitis.

Forest Laboratories, the company's commercialization partner, subsequently abandoned the drug. Replidyne is now conducting new Phase III trials in bronchitis patients, and it has designed another trial in community-acquired pneumonia. The company won't start that study until it finds a new partner for the drug.

"We've spent an awful lot of the past 12 to 15 months working with the agency to get clarity," Collins adds.

Yet others believe FDA is simply applying the firmer hand it should have wielded all along, and they say companies will need to craft their trials accordingly. "It's not changing the rules after you get to the finish line; it's simply enforcing rules that should have been enforced in the first place," says Mark Leuchtenberger, CEO of Targanta, which filed an NDA for oritavancin earlier this year.

 
 
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