The FDA appointed advisory committee on whether to recommend approval for Dendreon’s Provenge (sipuleucel-T) met in Washington, D. C. on March 29th. After voting unanimously to recommend Provenge as “reasonably safe,” the 17-member panel fell short of unanimity on whether the drug is effective. The first 4 votes were against. Following intervention by an FDA official, 13 members voted in favor. Accounts vary as to how and why the FDA official intervened during the vote.

According to Kirsten Orsini-Meinhard reporting for The Seattle Times: “The original question posed to the panel was, ‘Does the submitted data establish the efficacy’ of Provenge? But during the voting, several members said they were having trouble with the meaning of ‘establish.’ That may have been a reflection of the mixed results Provenge showed in clinical trials. So the question was changed to ask whether the data showed the drug was ‘substantially effective.’ That weaker formulation won a strong majority.”

Joel Nowak, a prostate cancer patient, emphasizes the impact of 15 oral submissions by prostate cancer advocates before the vote. Joel writes:

When they came to the final question, “Does the submitted data establish the efficacy of Sipuleucel-T (Provenge)?”. . . . The first three committee members all voted no, but all of them went on to qualify their votes. The members struggled, as it was very clear they wanted very much to vote yes. Their explanations for how they voted [sic] more like an apology to those of us who had testified and as an expression of their feelings of concern that there isn’t any good alternatives to treat patients with advanced prostate cancer. Many of their comments reflected the concerns and thoughts that had been raised by the patient advocates. In some cases, we actually heard parts of our stories repeated back to us.

After the third committee member went through his very uncomfortable explanation, the committee chair, Dr. James J. Mulé, stopped the voting process and addressed the members of the FDA who were present. He requested that they reconsider the wording of the question, as all of the committee members who had spoken indicated they did feel that there was a strong suggestion that Provenge did in fact extend life.

The FDA responded that they could not change the question, as this was a standard in all evaluations.

The next committee member again voted no, but with all the twists and turns that had already been expressed by the prior members. After this vote, the FDA stopped the process and changed the question for the committee to evaluate. The question was modified to whether or not the data submitted demonstrated substantial evidence that Provenge contributed to the extension of life (as opposed to establish the efficacy of the treatment).

The voting recommenced with the final vote of 13 to 4 in support of affirming the changed question! This was a historic vote that took a tremendous amount of courage from the individual committee members. (Provenge: Why the Fuss?)

What, though, stood in the way of panel members deciding for themselves (if they wished) that the company’s data on a gain in median overall survival constituted (did establish) substantial evidence of efficacy? Nothing, really, except for countervailing data showing that gain in median time to progression for men who took Provenge amounted to less than two weeks.

The question was (or should have been) how to analyze those two contrasting sets of data to obtain a clearer picture of whether the vaccine works or does not.

Efficacy has been a core criteria of the FDA’s democratically mandated drug review process since the Kefauver-Harris Amendments (Drug Amendments of 1962) in response to the Thalidomide catastrophe. Manufacturers are required to “demonstrate the effectiveness of their products through the conduct of adequate and well-controlled studies.” Offering guidance to industry under the Food and Drug Administration Modernization Act (the Modernization Act) of 1997 for human drug and biological products (P.L. 105-115), the agency said: “The public health is best served by the development of sound evidence of effectiveness in an efficient manner.”

For FDA officials to offer an ad hoc rewording of this core standard — if this is what actually happened — is more significant than the four votes against this immunotherapy.

There’s a difference between wanting to vote yes and wanting to be able to vote yes.

“Substantially effective” means maybe we can set aside the part that wasn’t/isn’t effective, given that so much is. And that’s what Dendreon wants patients to hear, because trials of this drug failed to meet the goal which the company set by choosing Time To [disease] Progression (TTP) as the primary endpoint.

“We found that the [median] time to disease progression for sipuleucel-T was 11.7 weeks compared to 10.0 weeks for placebo,” Eric Small M. D. said in June 2006. “This shows the difficulties in using the worsening of the disease as an intermediate marker for overall survival of patients treated with immunotherapy,” he said. “The study however, suggests that sipuleucel-T may provide a survival advantage to asymptomatic HRPC patients.”(Provenge prostate cancer vaccine linked to longer survival …. June 28, 2006).

A remarkable statement. They never selected worsening of disease as an intermediate marker, they chose Time to Progression as a primary endpoint, i.e. as primary evidence of the therapy’s effectiveness. This immune therapy failed to work the way it was expected to do; it did not stop or slow down progression of the disease. Nonetheless, median survival for men who received Provenge was 4.5 months longer than for those who received placebo (dummy vaccination). Why? How?

Dr. Mario Eisenberger at Hopkins, discussing Provenge in 2005, said: “There was no significant difference in the time it took cancer to progress — which means that the primary end point of the study was negative.”

Dr. Howard Scher, at the meeting March 29, put even that in doubt: “Does this drug prolong life? I just don’t know at this point in time.”

When a new cancer drug is approved, its use may become more targeted, sophisticated, refined and more effective than was possible in the clinical trials that brought about its approval. Sometimes, of course, new side effects turn up (like osteonecrosis of the jaw with Zometa and cardiovascular events with Vioxx). If Provenge is approved, some doctors will prescribe it off-label. Patients with less advanced cancer than those in Dendreon’s trials will want to try it. It’s already been shown that combining a vaccine with hormonal therapy extends time to disease progression in men with non-metastatic prostate cancer. This might be one way Provenge could be used.

But this is just the type of evidence that Dendreon’s clinical trials failed to provide.

Since there’s no cure yet in sight for hormonally-refractive advanced prostate cancer, men living with this stage of the disease learn to experiment. On the face of it they don’t play strictly by FDA rules. For one thing, the number of prostate cancer patients who enter clinical trials is negligible, although all depend on the few who do enter to help establish — yes, establish, by putting their bodies to the test — the safety and efficacy of drugs to be used by all.

Most patients with advanced prostate cancer actually employ FDA rules all the time. These are men who, if they “push the envelope,” search for peer-reviewed evidence and keep good records. These are men who believe that odds can be beaten and know that the median isn’t the message, yet who have nothing to gain from poorly designed experiments yielding questionable data. These are men who are capable of deciding what “establish the efficacy” means for themselves. If it’s working, and tests and scans show it’s working, keep on taking it. If it mostly works — if it’s “substantially effective” — well, that depends. If it delays disease progression in any meaningful way — via a period of stable disease, slower tumor doubling time, slower metastatic spread or even just a palliative reduction in pain or discomfort — to that extent it’s working.

Where are any such effects shown for Provenge? If it didn’t stop the cancer from progressing in any such ways, that’s a funny type of “substantial evidence” that it works.