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FDA Mulls Alternative Approval Path, Feedback Mostly Positive

By Catherine Shaffer
Staff Writer

The FDA convened a public hearing to receive input on its proposal to expedite development of new drugs for serious or life-threatening conditions with unmet need. The pathway, which is being considered primarily for development of agents to combat antibiotic-resistant infections, would involve smaller, faster clinical trials with narrow, tightly enforced labeling for use in patients without other options.

The agency received feedback Monday morning from pharma and biotech companies, patient advocates, policy experts and others.

Robert Guidos, a representative of the Infectious Disease Society of America, supported the FDA's proposed alternate pathway, stating that companies are dropping out of research in the area of antibiotics. "Company after company is withdrawing while the death toll climbs," Guidos said. "There are half a dozen large and a few small companies left . . . and rumors that additional companies could withdraw."

Guidos said that new approval pathways are urgently needed due to an uncertain U.S. regulatory environment, and that many companies are focusing their development efforts overseas.

"When it comes to antibiotics, the FDA's risk benefit equation has been out of balance," Guidos said. The new approval mechanism could be a path to restoring that balance, according to him.

Under the new approval pathway, a drug's safety and effectiveness would be studied in a smaller subpopulation of patients with more serious manifestations of a given disease. In those subpopulations, it would be understood that a higher degree of risk, or uncertainty, would be acceptable for severely ill patients without other options.

"Traditional drug development programs are designed to evaluate the benefits and risks of treatment with a high degree of precision for the range of manifestations of a disease or condition," the FDA wrote in its announcement in the Federal Register.

In order to capture that range of disease manifestations, large numbers of patients are enrolled in trials typically over a longer period of time, and trials may be repeated to rule out risks and resolve safety signals.

The FDA has an accelerated approval pathway under 21 CFR part 314, subpart H, and 21 CFR part 601, subpart E. It also has flexibility in its existing statutory requirements to facilitate approval for patient populations with serious unmet needs.

However, the agency has recognized that those measures have not been sufficient to encourage adequate progress in some areas of high unmet need, particularly in the area of antibiotic-resistant bacterial infections.

The move was widely supported by speakers from pharma and biotech companies.

"GSK applauds the FDA's efforts in creating an alternative approval pathway," said Paul Huckle, chief regulatory officer for GlaxoSmithKline plc. "If properly designed and implemented, such a new pathway might help rapid delivery of antibiotics to patients."

Huckle noted that carrying out one more large clinical study for those subpopulations of severely ill patients is challenging because of the limited numbers of patients available.

In addition to bacterial infection, GSK saw potential for use of the alternate approval pathway in other areas, like oncology and rare disease. "We further believe the proposed pathway could address other infectious diseases with high unmet medical need such as influenza," Huckle said.

Industry voices were united in placing responsibility for correct use of the drugs approved through the new pathway on physicians. When asked to whom stewardship of the more restricted labeling belongs, Jennifer Jackson, senior vice president of regulatory affairs for Cubist Pharmaceuticals Inc., of Lexington, Mass., said "It is the purview of treating physicians and the hospital where these patients are being treated."

Addressing the same question, Huckle said, "GSK believes the accountability for monitoring prescribing practices should reside at the community level."

Huckle advocated clear labeling with a distinctive logo to alert providers that the drug was approved under a specially restricted label, and said that label could come with a training program from the manufacturer. He recommended against "REMS-type requirements," however, saying that it would "needlessly burden an overburdened health care system."

A dissenting opinion came from John H. Powers, of the George Washington University School of Medicine and the University of Maryland School of Medicine, cutting through the chorus of assent from industry representatives.

"It is unclear what defines unmet medical need. The proposal lacks specifics about how it interacts with other FDA programs," Power said. He raised the question of what legal or regulatory options the agency would have if companies promoted their specially approved drugs for unstudied indications.

"It is unclear if this pathway would increase therapeutic options," Powers added. "The recent history of antibiotics shows that many drugs have not met unmet medical needs."

Powers urged the FDA to adhere to its own guidance. "First do no harm. The food and cosmetic act intended no lower standard."

While acknowledging that a drug that decreases "irreversible morbidity and mortality" would be worth having, he warned "Doctors don't read labels."

Andrew J. Emmett, a representative of the Biotechnology Industry Organization (BIO), raised logistical questions about the proposal. "Would the pathway be granted early in the drug development process, or at the time of FDA review, like priority review? We suggest it should be available early in clinical development," Emmett said.

Emmett also advocated for development of "greater clarity" around how subpopulations are characterized. "How will the FDA and sponsors achieve common understanding of this criteria?" Emmett asked.

Integrating the new pathway with existing incentive structures was another potentially problematic item on BIO's agenda. "It's unclear how the [new designation] will interact with the orphan drug designation."