Threats Made Against Ex-Hedge Fund Manager Who Questions Provenge Efficacy

Threats Made Against Ex-Hedge Fund Manager Who Questions Provenge Efficacy

October 15th, 2012 // 7:46 pm @ jmpickett

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Earlier this year, a former hedge fund manager named Marie Huber co-authored a medical study that questioned the benefit of the Provenge prostate cancer vaccine, prompting yet another debate over the controversial medicine and, in the process, she received threatening remarks on investor message boards.

Now, she is figuring in yet another flap. Documents she obtained through a Freedom of Information Act request indicate Dendreon, which sells the vaccine, analyzed some data in a key clinical trial in a different manner than the FDA had been told would occur. And the disclosure is raising questions about whether Dendreon followed scientific procedures properly.

The disclosure, which was first reported by Reuters, may mark the latest setback for Dendreon, which has been at the center of controversy for years over Provenge, including allegations of conflicts of interest among two members of an FDA advisory panel and patent protests over delays in approval. Most recently, Dendreon laid off workers and changed management amid disappointing sales.

At issue now is a statistical analysis plan that was submitted to the FDA in early 2008, Reuters writes. Dendreon told the FDA its trial would first look at whether patients who received Provenge survived longer than patients given a placebo. The analysis would also look at whether the vaccine affected patients differently depending on age – younger than 65, or 65 and over (here is the SAP).

But when the results of the its IMPACT trial were published in The New England Journal of Medicine in July 2010, the cut-off point for the analysis was 71 years, not 65 (back story and study abstract). Dendreon denied to Reuters that the data was manipulated, but the impression is creating skepticism.

Deviating from pre-specified statistical analyses raises the suspicion “that they didn’t like what they saw and went looking for something better,” Harvard School of Public Health biostatistician Scott Evans, who has no link to the clinical trial or Dendreon, tells Reuters. “If so, it’s data dredging with the possibility of producing a false positive” to reflect well on the vaccine.

The Dendreon chief medical officer tells Reuters the “FDA guidelines require using 65 as a dividing line, but the trial researchers later determined that 71 made more sense biologically, since it represented the median age of patients in the trial.” Meanwhile, an FDA spokeswoman tells the news service that Provenge was approved based on the reported effect for all patients, regardless of age, and the agency stands by its decision.

But in her paper published earlier this year in the Journal of the National Cancer Institute, Huber argued that age matters and that by reporting a different age analysis than the one Dendreon told the FDA would be performed, the vaccine maker hid problems with Provenge. And she accused Dendreon of hiding data (back story).

The IMPACT trial showed that patients on Provenge showed a median 4.1 months survival benefit, compared with men who received placebo, and that men both older and younger than 71 years old benefited, although the younger men benefited slightly less. The findings were used to endorse Provenge, which costs $93,000 and is complicated to administer.

But the JNCI paper argued that the main reason Provenge was deemed to extend survival was that older men who did not receive the treatment died months sooner than other patients in other studies. This is because the placebo they received was harmful and made Provenge appear better by comparison. Huber and her co-authors used unpublished data from Provenge clinical trials to compare the vaccine effects on men older or younger than 65, Reuters notes.

“Their analysis found that the main reason Provenge appeared to extend survival was that older men who received the placebo died surprisingly early, and many months sooner than those who received Provenge,” Reuters writes. The placebo “was particularly dangerous to men over 65,” Huber tells the news service. And she tells us, “this was a big red flag.”

After we published (earlier this year), they dissmissed our paper for relying on a ‘post-hoc’ analysis. Kantoff (Philip Kantoff of the Dana–Farber Cancer Institute and the lead author of the IMPACT trial) and Frolich chided us for this ‘statistical no-no.’ But to substitute a more favorable analysis and then represent it as pre-specified is falsifying,” she tells us.

“Ultimately, it isn’t this lie that matters, but all the questions they can’t answer. This lie was merely their attempt to dismiss the validity of the questions, and to hide the analysis back in 2010 that lead to these questions,” she continues. “The FDA has approved a treatment that has shortened and made more painful the lives of hundreds of men. They are trying to cover this up and are more interested in protecting themselves than in protecting patients.”

As Reuters notes, the FDA’s “Guidance on General Considerations for Clinical Trials” says that trial results should be analyzed according to a pre-specified SAP (read here) An FDA spokeswoman declined to discuss the discrepancies found in the age-specific analysis with Reuters.

But Susan Ellenberg, former director of the FDA Office of Biostatistics and Epidemiology and now a biostatistician at the University of Pennsylvania, tells Reuters that Dendreon should explain why it deviated from its SAP plan. “It’s very easy to find a cut-point to show what you want. They shouldn’t publish something different from the SAP without explaining why or presenting both.”

For its part, Dendreon maintains all data was shared with the FDA. “You have to be really careful about calling into question a finding from a randomized clinical trial,” Frohlich tells Reuters “The less favorable results from changing the cutoff age to 65 from 71 are almost certainly “a chance finding,” he said.

Meanwhile, Provenge supporters – a vocal group that includes patients and investors – are upset over the incident and label the JCNI study as junk science. Some have been complaining on message boards that her work is designed to drive down Dendreon stock. Others are circulating a story about a Provenge patient, who says the vaccine saved his life as proof that Provenge is beneficial, despite the debate over the IMPACT trial