FDA Difference of Opinion Helps Chelsea Therapeutics in Big Way

FDA Difference of Opinion Helps Chelsea Therapeutics in Big Way

February 27th, 2012 // 1:43 pm @

Source: Pharmalot

In an era when an emphasis on safety is increasingly bumping up against calls for more regulatory flexibility for approving drugs for rare disorders, consider the reversal of fortunes involving a medication from Chelsea Therapeutics. Two weeks ago, the drugmaker disclosed trial data that spooked investors. So did an FDA review that was released the other day and pointed out significant safety concerns. But an FDA panel endorsed the drug, anyway.

The trajectory of events appears simple, but the scenario revealed an interesting point, which is that viewing FDA review documents as a good indicator of FDA panel voting may not be wise. This was especially true yesterday, when some FDA officials – notably, Bob Temple, director of the FDA’s Office of Drug Evaluation 1 – unexpectedly attended the panel meeting and disagreed with agency reviewers about a few central points, according to Leerink Swann analyst Jon Eckerd.

“He was quite vocal… And it was a surprise appearance… The company did not know he was going to be there… And he agreed with the sponsor that (the key clinical trial) was a clear win… He provided some insights into what that division views as a statistically meaningful level for a single trial seeking approval,” Eckerd tells us. “The message is that you can’t just take one aspect of what’s out there in the public (such as FDA briefing documents) and assume that’s what everybody at FDA thinks.”

The contrasting postures taken by different FDA staffers was underscored by the fact that the agency medical reviewer used such phrasing as “in my opinion” and “my regulatory recommendation” in the briefing documents that were released earlier this week. As Eckerd points out, such personalized messages generally do not show up in this way, and one FDA official, Norman Stockbridge, also hinted that agency staffers were likely to express differing opinions as the meeting wore on.

Some background: Chelsea hopes to win FDA approval to market a drug called Northera for treating neurogenic orthostatic hypotension, a rare disorder that causes a dangerous drop in blood pressure when someone stands after lying down. Dizziness and fainting ensue. The ailment is associated with Parkinson’s disease and still more serious afflictions, such as primary autonomic failure and multiple system atrophy.

In an unusual bit of transparency, Chelsea execs earlier this month discussed a communication from the FDA about its trial data (see this). Northera was given orphan drug designation, which afforded a fast-track priority review, but agency concerns about the short duration of a key trial, adverse events and patient deaths caused Chelsea stock to plummet 40 percent after a teleconference for investors.

The FDA briefing documents released this week noted the agency agreed to a special protocol assessment, or SPA, which means trial design was sanctioned. And on the plus side, the key trial, which was called 301 and had enrolled 162 patients, showed a statistically significant result based on a patient questionnaire. There was also at least a one-week benefit (here are the briefing documents).

However, the agency reviewer also wrote that there was no “durable effect,” which meant more than four weeks, and that the safety profile was not clear because of the design of the trials. This was a reference to studies 302 and 303, which failed to demonstrate patient improvement, notably an effect on systolic blood pressure. There was more…

“During the longer term open-label experience, there were several deaths, SAEs, discontinuations for adverse events, and events of hypertensive crisis, strokes, and myocardial infarction. There were also several patients with worsening of their movement disorders… Of utmost concern were reports of neuroleptic malignant syndrome from Japan that aren’t clearly explained,” the reviewer wrote. In Japan, the drug was approved for the same indication since 1989, but also marketed at lower doses.

“…The data that the sponsor provided was insufficient to conclude or exclude causal relationships. It is difficult and imprudent to assign causality to (Northera) because of the mostly open-label design of the study and the nature of post-marketing reporting periods. Nevertheless, the specter of serious safety issues related to droxidopa hasbeen raised and should not be ignored… my regulatory recommendation is that we should not grant approval.”

However, the severity of the illness was a central reason why the FDA panel voted 7-to-4, with one abstention, to approve the drug. “If there were other treatments available, the answer would be ‘no.’ But there aren’t,” said Allan Coukell of Pew Charitable Trusts, the consumer representative on the FDA panel. Moreover, there are few treatment options to improve quality of life for patients who life expectancy is shortened by the disease.

The only other drug approved by the FDA was sold by Shire Pharmaceuticals. Called midodrine, the med was approved in 1996, but the agency deemed its trials to be inadequate. Two years ago, Shire stopped making and marketing the pill, although generics are available and the drugmaker remains the New Drug Application holder. Last month, Shire agreed with the FDA to run new, post-marketing studies that are similar in design, by the way, to the trials that Chelsea ran for Northera.

Meanwhile, the betting is now that Northera will be approved by its review, or PDUFA, date on March 28. The stock is up 66 percent today. However, “additional trials are almost a certainty,” Eckerd writes in an investor note this morning. “Nearly all panelists noted the desire for additional clinical trials, preferably in longer durations, to be required in the post-marketing setting.”

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