Antipsychotics and Comparative Effectiveness: FDA's Temple Explains Vanda "Not Approvable"

Pay attention to Vanda Pharmaceuticals.

The company and it's rejected investigational atypical antipschotic drug iloperidone appear to be a marker in the ongoing debate over whether FDA is increasingly using a comparative efficacy standard when considering new drug approvals.

“We are disappointed by this response, but will meet with the FDA to discuss this decision further,” Vanda Pharmaceuticals CEO Mihael Polymeropoulos said in a statement after receiving a “non-approvable” letter from FDA for the schizophrenia drug iloperidone, July 29.

Based on comments by FDA's dean of the drug review process, Bob Temple, there may not be much to discuss.

The atypical antipsychotic was licensed from Novartis after the Swiss company dropped it from development. Polymeropoulos previously headed up Novartis' global pharmacogenetics group before founding Vanda in 2003.

The FDA maintained that Vanda had demonstrated the effectiveness of iloperidone at 24 mg/day with efficacy similar to the active comparator, Pfizer’s ziprasidone (Geodon), according to the company. Vanda also claims the agency confirmed a prior study’s results that iloperidone was better than placebo in patients with schizophrenia at doses of 12-16 mg/day and 20-24 mg/day.

But FDA turned the drug away due to its lackluster performance versus Johnson & Johnson’s atypical risperidone (Risperdal). The agency, in its letter, said Vanda would have to conduct an additional trial comparing iloperidone to placebo and including an active comparator such as Risperdal or Eli Lilly’s olanzapine (Zyprexa). The company will also have to generate more safety data for the higher dose.

FDA has been assailed recently for going beyond its statutory obligation of approving and rejecting drugs simply based on its mission rooted in a singular question: do the benefits outweigh the risks? Critics say FDA is adopting a comparative effectiveness standard for me-too drugs.

FDA Office of New Drugs director John Jenkins insists that assertion is absolutely incorrect and that FDA always bases approvals on the benefit/risk question. To read more, click here. However, not everyone at the agency has been nearly as insistent on that issue.

Temple, who oversees the office which regulates psychopharmacologic drugs and also serves as director of FDA's Office of Medical Policy, has warned sponsors of the higher bar for approval in the past for classes where there are already multiple therapeutic options. To read about our warning in 2007, click here.

At a July 30 Institute of Medicine meeting on evidence-based medicine and comparative effectiveness, Temple unexpectedly—and briefly—addressed the iloperidone decision—we think.

“It’s getting much harder to develop the third, fourth, fifth, and sixth member of a class of drugs because when there’s a generic, people are inclined to use the cheap one,” Temple said.

Temple tried to frame comparative effectiveness studies—specifically randomized clinical trials and not literature reviews or observational studies—as the best, and maybe only, way to get those drugs through FDA.

“So to get anyone interested in the next member, you almost have to be able to have some sort of advantage. It could be safety, of course, but I see more interest than ever before because the industry regularly didn’t look at this sort of thing in comparative studies for a fair number of drugs.”

Then he weighed in specifically on what we assume was the iloperidone decision.

“We have taken a couple of steps that I think are interesting. We’ve turned down new antipsychotic drugs because they didn’t seem as effective as the available therapy.”

He continued: “I can’t remember if that ever happened before or whether we didn’t have the [courage] but we did. We decided that it wasn’t good if you’re an acute schizophrenic in the middle of an episode to be treated poorly.”

Those sentiments make it extremely unlikely that Vanda will be able to get an approval without conducting a large, expensive, prospective, head-to-head comparative clinical trial outlined in the FDA letter. Temple made it appear that there would be little room for negotiation.

Now it’s up to Vanda whether they want to use the $65 million in cash on hand plus future rounds of raising capital to do the studies FDA wants.

The broader message to drug developers is you can go ahead and add antipsychotics to the list of drugs that will have a higher threshold for FDA approval.