Mary Jo Laffler, FDA Office of Oncology Drug Products Director Richard Pazdur plans to convene an advisory committee meeting to clarify standards  for use of progression-free survival data  , a move prompted by industry's aggressive adoption of the surrogate endpoint and, more broadly, the gradual decline in the level of drug benefit that sponsors seek to use in support of a cancer drug approval.

Though Pazdur wouldn't predict the timing of a meeting - beyond "soon" - he confirmed that it is an important issue that should be the topic of an upcoming meeting of the Oncologic Drugs Advisory Committee.

In the last decade, there has been an extensive shift in oncology trials, with sponsors embracing the opportunity for earlier, arguably easier approval. The trend arose after FDA started accepting PFS as an early marker thought to be predictive of an eventual survival advantage - prompted by the urgent need for treatment options and availability of the accelerated approval pathway.

Allowing PFS to support accelerated approvals and eventually to support full approval did result in some impressive advances in medical oncology reaching patients years sooner than would have otherwise been possible. FDA has been careful to require trials to continue on in the post-market setting to demonstrate an overall survival finding, and the agency has upheld overall survival as the gold standard of efficacy evidence.

But the widespread reliance on PFS endpoints also created some sticky regulatory issues.

Chief among those is the issue of the clinical meaningfulness of the PFS finding. "We've been questioned repeatedly about what is the clinical meaningfulness of just simply delaying an X-ray finding," the oncology office director commented.

"If a median difference is five or six months, one would think that is a large effect, and I think most of us would agree," Pazdur said. "But what is disheartening," he continued, is that as FDA meets with sponsors, it is detecting "a progressive decrement in what one considers a large effect. Some people think six weeks is a large effect."

The problem is compounded because FDA calls for PFS trials to be powered for overall survival (as that could be the only opportunity to get that sort of assessment). But with trials sized for survival, "relatively questionable" effects on PFS can yield highly statistical significance just due to the large number of events and patients in the trial, Pazdur noted.

The need to show a clinically meaningful benefit, not just a statistically significant finding, came up at the recent ODAC review of Centocor Ortho Biotech's applications for Yondelis and Doxil .

Other issues related that would be good fodder for an ODAC discussion include how to handle situations where a drug is approved based on a PFS benefit and then fails to demonstrate a survival advantage (as happened with AstraZeneca's lung cancer therapy Iressa , without a clear cut resolution). Statistical and methodological issues have also developed with PFS assessments, and bear the consideration of a dedicated advisory committee.

The Engelberg/Friends of Cancer Research conference addressed one such PFS-related issue where FDA is willing to amend and clarify policy: the use of blinded independent central review of PFS endpoints. A conference panel presented a proposal to move away from the 100 percent audit of locally evaluated assessments (developed in conjunction with a Pharmaceutical Research and Manufacturers of America working group).

Over time, the default position has been to proceed with 100 percent auditing of reader evaluations, because of discrepancy in the measurements and concerns about potential bias. Pazdur ascribes that more to industry being careful than an agency edict, but acknowledged that no one really knew what to do with the discrepancy rates being reported between investigators and X-ray readers, if there was any clinical or regulatory implication. Now, that practice is recognized as inefficient.

FDA real interest, in terms of evaluating the methodology of PFS measurement, is whether there is bias, Pazdur explained. Measurement errors are "inherent in the subjective nature of interpreting" the PFS findings. "It seems to me that throughout these trials there's pretty much a 30-40 percent discordance rate on reading these X-rays, period. When one hears that for the first time, one is taken aback - and says oh my god, these people don't know what they're doing - but it's just the cost of doing business in these X-rays."

"We are interested in looking at other ways of managing bias and assessing bias, and that's our underlying principle here. It's not simply to look at discordance rates. I firmly believe that these discordance rates just reflect radiographic misinterpretation or differences of interpretation of X-rays. That's not what's important in our world, our world is to determine a treatment effect."

When it comes to discordance, what FDA is really interested in is differential discordance - which Pazdur noted should be part of the ODAC discussion on general PFS issues. That meeting also would give FDA an opportunity to discuss the potential alternatives to 100 percent audits. Pazdur signaled at the conference that he was willing to pilot the proposals being offered, though he noted that because of the international nature of registrational programs, it should also be discussed with EMEA.

While industry is always looking for more answers and more FDA clarity on clinical development policy, sponsors should be careful. It's possible that the agency will rule out the use of PFS in certain disease areas where it is difficult to radiographically assess tumor progression, or in very refractory disease where it wouldn't take long to study survival. Both were flagged by Pazdur.

There are also still vocal critics of using PFS endpoints. "This is a PFS love-fest. It's the Woodstock of PFS," Pazdur told the conference. "There is an equally loud voice out there in the oncology community," he reminded them, "from patient groups, from the statistical groups and clinical trial groups that really are questioning the use of PFS."

An ODAC devoted to PFS issues would be a perfect setting for those objections to be heard.