The REMS Pioneers: Amgen’s Nplate Sets Another New Standard

Hymen Phelps & McNamara attorney Frank Sasinowski has a prop he likes to use when he calls on Food & Drug Administration reviewers to talk about a regulatory issue.

It is a new drug application filed by Wyeth 50 years ago. It includes, he says, everything you get in a modern NDA. Evidence of safety and efficacy. A chemistry, manufacturing and controls section. Proposed labeling. Everything.

And you can hold it in one hand, a thin stack of paper, organized by a single binder clip.

It sure is eye-catching. Today’s NDAs are so large and complex it is now silly to imagine them in printed form, except for colorful analogies like Eli Lilly & Co. saying the prasugrel (Effient) NDA would be as tall as the Empire State building if it was reduced to stack of paper.

Sasinowski’s message?

The vast increase in complexity of NDAs is not related to a change in the standard for approvals per se. Rather, it is a result of decisions made by individual FDA reviewers about how much evidence they need to be convinced to allow a drug to be approved.

Well, it looks to us like history is repeating itself in the form of rapidly expanding stacks of paper necessary to comply with the FDA's new Risk Evaluation & Mitigation Strategy authorities. The REMS were created by the FDA Amendments Act of 2007, and we are living through history as FDA and the pharmaceutical industry create a new regulatory framework on the fly.

FDA has now used the REMS authorities about half-a-dozen times for new approvals, and the level of complexity is leaping exponentially—at least as measured by page count.

The first handful of REMS were dealt with in the context of the approval letter FDA sends to sponsors of all new drug applications: less than a page of text invoking the legal authority for a REMS, informing the sponsor of the need for a mandatory medication guide, and setting a bare bones assessment schedule. (You can read The RPM Report's coverage of the “REMS 1.0” group here.)

Then came Entereg. The GSK/Adolor post-operative ileus therapy had the first REMS that included restrictions on access (limiting distribution to hospitals who register with the sponsor) and use (no more than 15 doses in the in-patient setting). In addition to an overview of the REMS in the approval letter, FDA released a 24-page summary of the program, including copies of the packaging and registration materials. (You can read The RPM Report's coverage of the Entereg REMS here.)

Now comes Nplate. Amgen’s new platelet boosting therapy to has a still more restrictive REMS, involving registration of institutions, prescribers and patients. (The first in-depth look at that program appears in “The Pink Sheet.”)

The page count? Ninety-four.

So, in the six months since the REMS authority took effect, we have already seen the approved versions of the program expand about 100-fold.

If that trend continues, maybe the Effient REMS will also be as tall as the Empire State Building?