by Susan F. Wood 

After the recent post here on KETEK, both the Wall Street Journal and Senator Grassley are on the move.  The WSJ reports today on another antibiotic Cubicin which has been seeking approval for use in endocarditis and discusses the competing issues of data quality and high standards, with the push for more antibiotics, particularly in the case of serious infections without effective treatment.  The case of Cubicin in some respects serves as an example of this, however Ketek does not.  They both illustrate problems identified by the recent Institute of Medicine Report on drug safety.

Ana Matthews reports:
“FDA officials battled earlier this year when deciding whether to approve the antibiotic Cubicin for heart-valve infections. Staff reviewers urged their boss to say no, citing “serious misgivings” about the drug’s effectiveness in the disease, according to documents reviewed by The Wall Street Journal. The head of the agency’s division for anti-infective drugs overruled the staffers, defending the drug and saying doctors need more weapons against dangerous bugs.

Behind the debate is growing concern among doctors about the rise of bacteria resistant to antibiotics. They want more investment by drug makers in the field, but many companies are hesitant. An antibiotic used for a day or two is far less lucrative than a pill that a patient might take daily for decades. What’s more, powerful antibiotics are sometimes kept in reserve for the most serious cases, which diminishes their commercial value.”

But the question of data quality comes into play:

“The pharmaceutical industry and the FDA have long tussled over standards for approving antibiotics, in particular how close a new drug has to get to the old one to be considered equivalent. Steven S. Projan, a vice president at drug maker Wyeth, says the FDA can deter the development of new antibiotics if it regulates the industry improperly. Tightening standards and requiring larger clinical trials “really do discourage companies from getting into the field,” he says.

In 2002, when some industry officials believed the FDA was trying to toughen its standards, a medical journal, Clinical Infectious Diseases, published a letter warning of the “end of antibiotics.” It noted that some big pharmaceutical companies had pulled out of the field. The letter argued that the agency’s actions had “already wreaked irreparable damage to our ability to provide a reliable pipeline of new antibiotics for treatment of serious infections.”

What do the FDA medical reviewers think?

“On March 14, the FDA told Cubist that it was willing to approve Cubicin for bacteremia but not endocarditis. Cubist fought back in letters and meetings with FDA officials in March and April. Mr. Bonney, Cubist’s chief executive, says a trial with enough endocarditis patients to meet the highest statistical standard for proving a drug’s equivalence to older treatments would take so many years and cost so much that it would never happen. “Let’s not let statistical perfection be the enemy of the good,” says Mr. Bonney. He says that the evidence about Cubicin, taken together, shows the drug is effective against endocarditis.

Dr. Sorbello [FDA medical reviewer] still wasn’t buying it. At an internal FDA meeting on April 20, he said he was “very uncomfortable” with approving Cubicin for endocarditis, according to minutes reviewed by the Journal. His immediate supervisor agreed, saying the review team had “serious misgivings about the ability of [Cubicin] to effectively treat” endocarditis patients. Even Dr. Jenkins, the FDA’s top-ranking official for new drugs, seemed to agree with the staffers, remarking that on the drug’s label, “you have to say something about endocarditis, but you can’t say it works.”

However, the company found a sympathetic ear in Janice Soreth, who had worked her way up the ranks at the FDA to become chief of the anti-infectives division.

In a review dated May 5, Dr. Sorbello refused to back down. His supervisor, two statistical reviewers and two microbiologists agreed in their own reviews.

Dr. Soreth overruled them. She granted approval for patients with bacteremia including those with right-sided endocarditis”\

“…An internal email sent out to staffers who worked on the Cubicin application by an FDA administrator said “this has been a very difficult application,” and promised that dissenting reviewers could note their disagreement for the record, with no retribution. Dr. Sorbello filed a brief memo saying that his participation in labeling discussions “does not necessarily reflect my endorsement of the product, the final product label, or any specific sections of the product label.”

This article connects the debate between management and the reviewers in the anti-infective drug division with the KETEK situation, which is approved for much less serious infections:

“More recently, questions over the antibiotic Ketek have led Congress to highlight the issue of antibiotic trial design. In many diseases where the patient isn’t in need of urgent care, human trials compare a new drug with a placebo. Scientists consider this the most rigorous way to prove that the new drug works. While it wouldn’t be ethical to give a patient with a serious infection a placebo, the FDA has hinted it may require placebo comparisons for milder conditions such as sinusitis and bronchitis. Ketek was approved for both conditions based on noninferiority trials.

John Powers, the FDA’s former lead medical officer for antibiotic development and resistance initiatives, says placebo trials are overdue in such infections. “The way we have evaluated antibiotics isn’t what it should be to meet FDA’s own standards,” he says. But the hint of tougher rules has sparked resistance from some companies and doctors, and executives say they’re having trouble figuring out what the standards are. The agency has said it is working on guidelines.”

KETEK is now officially what seems to be part of the reason that acting FDA Commissioner Andrew von Eschenbach is having difficulty being confirmed.  Apparently FDA is not being responsive to the Congressional inquiries about KETEK that Sen. Grassley has been pursuing.  With the Advisory Committee meeting coming up in mid-December, we should expect more information and more action from FDA, Congress, and from frustrated FDA reviewers and scientists.

Susan F. Wood is Research Professor at George Washington University School of Public Health and Health Services