Given the small dataset supporting the Arzerra BLA, FDA made up for the lack of solid data with exhaustive analysis and plentiful expert consultation.

"In the end, in the absence of rigorous data excluding the possibility of benefit, the decision rests on an informed speculation by clinical experts in the field, with the clear knowledge that not every 'reasonably likely to predict' conclusion will in fact be confirmed with a demonstration of clinical benefit," Cross-Disciplinary Team Leader Joseph Gootenberg said in a Sept. 21, 2009, review. Indeed, he added, "in the final analysis, one might expect that a significant proportion would not."

"In this case we have a number of independent opinions from clinical experts in the field," Gootenberg observed, including the Special Government Expert in leukemia who advised in the IND stage on setting the level of proof (response rate and confidence interval) needed to predict clinical benefit and the Oncologic Drugs Advisory Committee, which was asked if the results of the pivotal Phase II study Hx-CD20-406 were "reasonably likely to predict clinical benefit" in the DR population (they said yes, on a 10-3 vote).

FDA also looked outside the agency to assess contemporary CLL treatment patterns, asking its outside consultant "what constituted current medical practice for this U.S. patient population," according to minutes of a Nov. 30, 2005, pre-Phase II meeting. FDA also "recommended that Genmab also consult oncologists to determine current U.S. medical practice."

FDA's search for outside expert opinion on complex and difficult oncology reviews reflects the specialized expertise needed for a disease with so many, and such poorly understood, manifestations. FDA's oncology review team, which must of necessity have a generalist perspective to be ready to review applications for any type of cancer, would be very hard-pressed to stay atop the ever-changing, often off-label prescribing patterns of specialists.

For example, in the review of Bristol-Myers Squibb's Ixempra (ixabepilone) in extensively treated breast cancer patients, FDA turned to a breast cancer expert and Oncologic Drugs Advisory Committee member, Joanne Mortimer of the City of Hope Cancer Center in Duarte, Calif. Her wide-ranging consult, which ranged from the specifics of acceptable levels of adverse events to the value of progression-free survival in the face of doubts that overall survival could ultimately be found, helped FDA find its way to approving Ixempra (¹ Also see "FDA Cleared Ixempra Despite Doubts Over Chance Of Showing Survival Benefit" - Pink Sheet, 1 June, 2008.).

- Bridget Silverman ( ² b.silverman@elsevier.com )

When Hard Data Are Sparse, FDA Looks To The Experts

More from Archive

More from Pink Sheet