Asclera: A REMS By Any Other Name…

Quick quiz. There’s a new molecular entity pending at FDA, intended for a cosmetic use. There is a clear signal of a risk of anaphylactic reactions, most likely associated with off-label use at high doses. The review team is in agreement: there needs to be some form of communication plan and special monitoring to assure that physicians don’t casually use higher doses.

Will the product have a Risk Evaluation & Mitigation Strategy as a condition of approval?

We don’t know about you, but our guess would certainly have been yes. After all, FDA seems to be using REMS more and more, right?

Well, not this time.

Here is how Cardio-Renal Drug Products Division Director Norman Stockbridge explained the decision, in the summary review of the March 30 approval of BioForm Medical’s varicose vein treatment Asclera (polidocanol):

“All team members concur on approvability.

An issue to be resolved is how to address the risk of anaphylaxis. There are no such cases in the controlled experience, but there are other allergic reactions—urticaria, hives, sneezing, and what sounds like angioedema. Similar cases to these appear in post-marketing use [overseas]. Post-marketing, there appears to be one reasonably clear anaphylaxis case following low-volume administration to treat a leg varicosity….

Overall, the team has the impression that the risk of anaphylaxis may increase with dose, and that seems plausible. A goal of labeling and any additional post-marketing safety-related activities ought to be discourage off-label use for larger varicosities where the volume of drug necessary will be much higher than it is for the indicated uses.

Dr. Southworth recommends a bolded warning, similar to the one sotradecol has. I concur with this. She recommends a communications plan for healthcare providers for the first few years, and annual review of hypersensitivity reactions. (These can be done outside of a REMS.) I concur with these, too.

She is equivocal on a medication guide, citing the closely monitored setting of administration. I do not favor a medication guide; there is ample opportunity for the patient and physician to discuss treatment options, and practitioners are generally familiar with the risks from use of sotradecol. While I agree with Dr. Southworth that the cosmetic use creates a low threshold for taking conservative measures, I do not think the bar should be quite this low.”

Final decision: approval with no REMS.

So is this a sign that REMS mania has crested? Should sponsors celebrate the return of a standard where REMS are the exception rather than the rule?

Well, not so fast.

First, Stockbridge has already voiced his displeasure with some of the accoutrements of the “Safety First” era, declaring in his memo on Effient that “no one associated with this review should feel good about this.” He meant the endless deliberations about the potential safety issues with Lilly/Daichii’s clot-dissolving drug. Stockbridge was clearly ready to approve the drug long before he wrote those words in April 2009. But Effient itself wasn’t approved for another three months after.

In other words, Stockbridge can’t change anything on his own, and its clear that other FDA review managers have different levels of enthusiasm for the new safety tools. For example, FDA’s Endocrine & Metabolic Drugs Division management, for example, seems to have a very different view of the value of REMS tools. (We’ll have more on that in an upcoming issue of The RPM Report.)

And, while Stockbridge’s rejection of a REMS did avoid a last minute delay for Asclera, it didn’t exactly make this a lightning fast approval. Asclera was first submitted in 1999, and got a “complete response” in 2004. Meanwhile, it continued to be marketed overseas, building the safety database that helped reassure FDA that the risk of anaphylaxis is very rare. That puts Asclera in a venerable class of NMEs that always have an easier time at FDA: those with long marketing histories overseas.

More importantly, while there isn’t technically a REMS on Asclera, there might as well be. FDA and the sponsor agreed to a Dear Doctor letter at launch outlining the risk of anaphylaxis. It isn’t required, so it isn’t a REMS—but it was agreed to prior to approval, and we bet the sponsor doesn’t see much difference there.

And then there is a mandatory post-marketing study—a pretty unusual one at that:
The sponsor will provide “a yearly report (containing both interval-based and comprehensive data) analyzing spontaneous adverse event reports received that describes anaphylaxis or death.” Reports are due annually until 2016.

So BioForm doesn’t have to comply with a REMS. But it does have to send a “Dear Doctor” letter warning of a very rare potential adverse event with off-label use, and submit annual analyses of post-marketing reports.

A REMS by any other name still smells as sweet…