Washington Editor

WASHINGTON - The head of a House subcommittee that oversees the FDA has demanded answers from Commissioner Margaret Hamburg about why the agency is considering "outsourcing" the efficacy analyses of older marketed antibiotics to a nonprofit standards-setting group, whose 2,000 members include numerous drugmakers.

The FDA is considering using Wayne, Pa.-based Clinical and Laboratory Standards Institute (CLSI), a nonprofit organization that promotes the development and use of voluntary consensus standards and guidelines, to provide postmarket information for updating the labeling of the older antibiotics.

The FDA said it is facing the enormous task of ensuring that drug labeling for older antibiotics, which are mostly made by generic manufacturers, many of them foreign firms, are updated to ensure appropriate use against organisms. Many antibiotics have become resistant to certain bugs, but the product labeling does not reflect that information.

But in a letter this week to Hamburg, Rep. Rosa DeLauro (D-Conn.), chairwoman of the House Subcommittee on Agriculture, Rural Development, Food and Drug Administration and Related Agencies, raised concerns that CLSI lacks experience in reviewing human clinical trial data.

"FDA decisions about antibiotic resistance and efficacy of drugs already on the market should be based on data from outcomes of clinical studies in humans, not the kinds of test tube studies or animal studies that CLSI primarily relies upon to make its determinations," she told Hamburg. "Any proposal that would outsource this work is highly questionable and would reflect poorly on the FDA."

While DeLauro said CLSI was a "well-respected" organization with "highly regarded" work, developing standards is a "very different task" than interpreting the results of studies to evaluate disease outcomes for drugs taken by patients.

DeLauro expressed concern that "test-tube" evaluations of the older drugs may compare "unfavorably" to newer, more expensive drugs. "The older drugs still could provide treatment results that are equivalent, or even surpass the newer, more expensive drugs," she argued.

The congresswoman also raised concerns about CLSI's membership, which includes drugmakers and other industries regulated by the FDA.

While the FDA has "essential safeguards" in place to minimize potential conflicts of interest among those making decisions about the efficacy and safety of products, the consensus process used by CLSI includes drug companies, and "that approach is not appropriate for research interpretations used by a regulatory agency," DeLauro charged.

The Connecticut Democrat also noted that some members of the FDA's Anti-Infective Drugs Advisory Committee, which met on Oct. 26 to discuss CLSI's role in updating antibiotic drug labeling, also were members of the standards group.

"But that information was not made public and no waivers were required for these very obvious conflicts of interest," DeLauro said.

She noted that three of the panelists stepped aside after it was brought to regulators' attention before last month's meeting that they were CLSI members. But, she said, "others with CLSI connections continued to serve."

DeLauro also accused the FDA of stacking the deck in favor of CLSI at the meeting, which included supportive presentations from the Pharmaceutical Research and Manufacturers of America and other groups.

But Glen Fine, CLSI's executive vice president, said DeLauro had been misinformed about the role his group may be asked to play in updating antibiotic labeling and the way the organization functions.

CLSI's membership includes representatives from government, industry and health professionals, he explained, noting that the FDA also is a member.

"In everything we do, we seek balance, openness, transparency and have very sophisticated administrative procedures of how we conduct the proceedings to develop the best practice standards and guidelines," Fine told BioWorld Today. "We follow very rigidly the requirements of the American National Standards Institute, which accredits us as a valid, highly credible standards development organization."

While none of CLSI's 210 standards and guidelines are required to be followed by U.S. law, they carry "the weight of the law" because "everybody involved with them are the best thought leaders in the world," he said.

Fine noted that all members of CLSI must fully disclose their conflicts of interest and "check their guns at the door."

The role the FDA is considering for CLSI is "not outsourcing," he insisted.

"I personally take offense with the term 'outsource,'" Fine said. "The FDA has not given up its legal or authoritative responsibility to a private entity. It is merely using the advice from an organization like CLSI to help assist it in looking at revising drug labels."

The FDA is facing a choice of requiring generic drugmakers to conduct clinical trials to establish the current efficacy of the older antibiotics in combating pathogens - which regulators have expressed is an unfeasible option, given the expense to do so - or force the drugs off the market, which also would not be feasible given the need for the drugs.

The other option is to use the data already collected and analyzed by CLSI or another standards group, Fine said.

"In our process, people make those decisions on the best available data out there, and whether it is clinical data that exists or test-tube studies or other mechanisms these scientists use, they use the best available data to make the best available decisions on what the most effective use of these antibiotics is," he said. "We have a very sophisticated model to make those decisions," which he said is the same one the FDA uses when it is studying initial breakpoint - the point at which the bug is susceptible to a drug.

But Diana Zuckerman, president of the National Research Center for Women & Families, who testified at the October advisory meeting, argued that the FDA should evaluate antibiotic resistance using "the gold standard" of clinical trials.

The FDA, she said, should not rely on analyses from CLSI, whose membership includes companies with a financial stake in the game.

Drugmaker members of CLSI, Zuckerman said, should play no role in a process where they could tip the balance in their own favor.

Published  November 12, 2009