SAN DIEGO - Industry is hoping an upcoming Risk Evaluation and Mitigation Strategy guidance document will outline a more transparent process regarding the FDA's REMS decisions.

After more than a year of REMS experience the agency should now provide more clarity about the timing, details and context of its risk management decisions, Johnson & Johnson Senior Director of Regulatory Affairs Andrea Masciale said June 22 during the Drug Information Association annual meeting.

Masciale said the letters FDA sends to alert sponsors that a REMS is needed give little insight into the agency's decision-making process regarding the context of the request, the timing of the discovery of the information and the quantity of the information.

"We don't get any of the FDA analyses - we have no transparency into the full understanding of the determination. We don't know who made the initial determination or where they sit at FDA."

Masciale was specifically referring to the agency's scientific determination that there is new safety information for a marketed product that merits use of the FDAAA risk management authorities. The statute allows FDA to require a REMS for an already approved drug, or mandate a post-market trial, if "new safety information" emerges.

"We are not sure how consistency in applying that statutory standard is assured. We know that the REMS themselves are reviewed at very high levels, but we don't know really all the way down to that initial determination about new safety information requiring a REMS. We're sort of in the dark on that."

J&J's experience with REMS includes programs added for already marketed products - for its anti-epileptic drugs Topamax and Levaquin - as well as a REMS for a newly approved drug, for its pain therapy tapentadol. The firm is also working on REMS for ustekinumab and Xarelto (rivaroxaban).

Amgen's Director of Regulatory Affairs Annetta Beauregard has made a similar request for more information on what exactly FDA is defining as new safety information that can trigger a REMS (¹ Also see "The REMS Report Card: FDA Using New Tools For One-Third Of New Drugs In First Six Months" - Pink Sheet, 10 November, 2008., p. 25).

Amgen's request came out of its own experience as an early adopter of REMS - the program for Nplate was one of the first and remains one of the most extensive. FDA review documents, as well as presentations made by Amgen execs, detail the difficulties of the REMS learning process (² Pharmaceutical Approvals Monthly June 2009, p. 38). The lack of a guidance document was explicitly cited as a complicating factor.

FDA is working on a pair of guidance documents relating to REMS, one covering the general topic and one covering the assessments required by REMS.

But along with the overview of expectations for sponsors, the sponsors want to know more about the processes at FDA and the criteria being applied.

To that end, J&J's Masciale said a MaPP (Manual of Policies and Procedures) document would "help sponsors understand what's going on at FDA when these very important decisions are being made."

Ideally the MaPP would outline "the timelines and expectations of both FDA and the sponsors" from the time the decision was made to require the REMS, Masciale said. It would also state the criteria for attendance at product meetings, including "not just the review team and [Office of New Drugs] divisions, but also the partners in the Office of Surveillance and Epidemiology, and partners throughout CDER and even the agency - all of whom might have an impact and a need in the REMS."

Agency officials did weigh in at the DIA annual meeting, addressing industry concerns about the REMS process during the CDER town hall meeting (³ Also see "Sponsors Can Expect REMS Discussions As Early As Phase II, FDA Says" - Pink Sheet, 26 June, 2009.). OND Deputy Director Sandra Kweder and OSE Director Gerald Dal Pan assured sponsors that as everyone gained more experience, the REMS discussions would come earlier in the process and would have less of a delay on the review times.

Sponsors At Center Of REMS Storm

Masciale also said more guidance is needed on how industry can bring the input of hospital, pharmacist and patient stakeholders on REMS to FDA.

"A lot of times we feel like we're at the center of the storm. All of our stakeholders have issues about REMS and we're the ones who ultimately are responsible for implementing it," she said, adding that she "can't stress enough how multi-stakeholder input is important when developing a REMS and when you're carrying it out. We're asking a lot of people to participate in this process, and we need to get their feedback, and we need to get them involved."

She admired the open process FDA has been using to craft the class REMS for opioid products (⁴ Also see "REMS For Opioids Still Has A Long Road Ahead; Advisory Committee Is Likely" - Pink Sheet, 8 June, 2009., p. 15). "But from a practical standpoint we can't do that for every REMS the agency is going to require," she noted.

Other Items On REMS Guidance Wish List

She said industry also needs clarification regarding the REMS dispute resolution procedures. "The statute describes dispute resolution procedures for REMS in particular, and I have to be frank - they're not exactly the most friendly to sponsors," Masciale said.

"It would be interesting to hear the agency's perspective on how the formal dispute resolution procedures will be implemented - whether it will be the exact same as any of the other formal dispute resolution procedures in agency guidance or whether it will be tweaked at all based on statutory procedure."

Other issues Masciale said she hoped would be addressed in the upcoming guidance include how REMS fit into global risk management practices, a streamlined approach to making changes to an existing REMS, timelines for FDA review once a REMS has been submitted, whether voluntary risk management practices could subvert the need for a mandated REMS, and how FDA intends to communicate the need for a REMS to the public.

And In The End, Who Owns The REMS?

"Finally, there is a lot of confusion about who, indeed, owns the REMS," Masciale said.

"Is this an OND document that we work with the review division on? Is it actually an OSE document? We know that they provide significant review of the REMS. We also know there are other partners at CDER and the agency that are involved. Knowing who the owner is will help us to ensure and ask for the appropriate people to attend our meetings or to weigh in on our questions about REMS in general."

- Jamie Hammon (j.hammon@elsevier.com)

Industry Wants More Transparency From Agency On REMS Determinations

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