At least for the first half of Wednesday's meeting the Oncologic Drugs Advisory Committee began where it left off the previous day - underscoring the importance of randomized controlled trials.

This time around, however, committee members weren't quite as ardent, voting 6 yes, 3 no and 1 abstain that FDA require randomized controlled trials for cutaneous t-cell lymphoma drugs, and almost unanimously supporting approval of Gloucster's Istodax (romidepsin) without an randomized controlled trial.

The day before, the committee had voted that Genzyme's Clolar and Vion's Onrigin , both pending to treat elderly acute myeloid leukemia patients, should conduct randomized controlled trials, despite the apparent impracticality (Also see "ODAC Sides With FDA: Evidence For Elderly AML Drugs Can't Stand On Single-Arm Trials" - Pink Sheet, 1 September, 2009.).

The development of Istodax was agreed upon with FDA through a special protocol assessment, whereby two single-arm studies were accepted for supporting the drug's NDA. When voting on whether the results of the single-arm studies represent a favorable risk/benefit profile, FDA's Office of Oncology Drug Products Director Richard Pazdur asked committee members to answer the question independent of the randomized controlled trial due to the previous agreement.

Urging "Common Sense" From FDA

While members in favor of requiring randomized controlled trials for the approval of CTCL therapies outnumbered those who did not, they all stressed that every situation is unique and that although randomized controlled trials provide more robust information with ability to compare across therapies, they are not feasible in every situation.

"I'm assuming the agency will take this recommendation and apply common sense," said Michael Link, Stanford University School of Medicine. Other committee members cited the increased costs of a randomized controlled trial as compared to single-arm studies and pointed to the limited number of patients available for clinical trials since CTCL is a relatively rare disease.

Pazdur noted that the EMEA requires randomized trials for approval, and that generally regulatory bureaus around the world try to have the same requirements for approval. EMEA Scientific Advice Working Party Vice-Chair Mira Pavlovic was a guest speaker at the meeting to provide the agency's viewpoints.

While a vote requiring randomized controlled trials for CTCL drug development may be bad news for the rest of industry, Gloucester capitalized on its review, with members voting 10 yes and 1 abstention that Istodax has a favorable risk/benefit ratio. Members cited the duration of response across all stages of lymphoma and the consistency of response assessment between the investigators and the independent reviewers. The one reservation members had was that the true level of toxicity has not yet been evaluated.

" I remain somewhat uncomfortable that we have yet not seen the true level of benefit in toxicity," said Gary Lyman, Duke University Medical Center. "I think the FDA and sponsor should ensure some type of long-term safety monitoring. That needs to be kept in mind for future approval."

Allos' Folotyn "Reasonably Likely" To Succeed

During the second half of the day, ODAC took on Allos' peripheral t-cell lymphoma agent Folotyn (pralatrexate) for relapsed or refractory patients. The ultra-orphan indication - for which no therapy is currently approved - was supported by only one single-arm trial.

After much back and forth between members about the drug's limited duration of response (most of which lasted 14 weeks at the most) and the discrepancies that existed between the investigators (more than half the responses were adjudicated), the committee voted 10 yes, 4 no that the response rate and duration of response results are "reasonably likely" to predict for clinical benefit.

This was an important vote to Allos, as it may pave the way for accelerated approval from FDA.

All members agreed that additional studies should be conducted, regardless of approval. "I think we need additional studies," said Pazdur. "It would be a tragedy if this drug was never studied further. We want to see survival data here, not just a response signal."

Pazdur also noted that if the drug is not approved, and the agency requires additional trials from Allos, the drug would still be accessible through the newly refined expanded access program. However, some committee members commented that allowing access through that program could discourage patients from entering a trial since they would be able to acquire the drug hassle-free and that it may also discourage the sponsor from capitalizing on the momentum from their first trial.

-Lauren Smith (lauren.smith@elsevier.com)

Allos' Folotyn and Gloucster's Istodax: Exceptions That Prove The Rule?

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