GxP Lifeline Feature Article

Gems on REMS
by Peter Pitts

I recently chaired the "Risk Management and Drug Safety Summit" (co-sponsored by the Center for Medicine in the Public Interest, FDA News, and United BioSource Corporation). It was a content-rich experience.

When I told my wife -- who is not in this line of work -- that I was chairing a conference on REMS (Risk Evaluation and Mitigation Strategies), she asked me what I was doing at an event about rapid eye movement. I can assure you that there was no REMS sleep allowed during this event.

When I told my wife -- who is not in this line of work -- that I was chairing a conference on REMS (Risk Evaluation and Mitigation Strategies), she asked me what I was doing at an event about rapid eye movement. I can assure you that there was no REMS sleep allowed during this event.

A common question I get about REMS is - how is it different from what we used to call RiskMAPS? I see two main differences. The first, obviously and importantly, is that REMS has actual legislative language. And that's an important detail - but it's one-dimensional.

The second, more important and contentious difference is the environment into which REMS was birthed - an environment in which there is growing realization that the 21st century FDA must add a third leg to its mission of safety and efficacy - and that third leg is safe use. The safe use of drugs. And the formulation, implementation and communication of plans - REMS plans - that will assist physicians and patients in achieving better outcomes through the strategies and tactics devised therein.

According to CDER Director Dr. Janet Woodcock, "FDA does not control the health care system, so our improving the use of marketed drugs, to a great extent, is going to involve influence rather than control."

"Influence rather than control" is a savvy and sophisticated concept -- one that many of our elected members of Congress could learn from, and one in which REMS plays an important role.

The FDA's new "Safe Use" initiative is the patient-facing sibling of the agency's "Safety First" pharmacovigilance program. But it's more than that -- it's the FDA reasserting ownership of safety from those who would use it only as a mallet of fear. I will not mention names.

That being said, there are those in industry and in the broader healthcare policy arena who look at REMS and don't see GEMS.

Many have looked at the FDAAA language on REMS and see it as an ill-advised green light for the FDA to inject itself into the practice of medicine.

While I agree that REMS does indeed represent an expansion of the FDA's authority, I do not agree that it is either ill advised or an over-extension of the agency's purview. REMS is the responsible extension of the FDA's mission of safety and efficacy into the new realm of safe use. The first real move into this space, if you think about it, was the FDA's change to the warfarin label. Warfarin is complicated to use because the optimal dose varies greatly among patients. With warfarin, if the dose is too strong the risk of serious bleeding increases and if the dose is too weak, the risk of stroke increases.

Via molecular diagnostics specifically called out in the amended FDA label, the health benefits and the resulting savings in health care costs generated by using personalized warfarin dosing decisions are estimated to prevent 85,000 serious bleeding events and 17,000 strokes annually - and that's just in the United States. And estimates predict the reduced health care spending from integrating genetic testing into warfarin therapy to be $1.1 billion annually. And that's the mid-range.

It's important to note that when the FDA announced the warfarin label change the agency (and Larry Lesko in particular) came under attack from critics who asserted that this was the FDA, inappropriately, telling doctors how to practice medicine.

In a recent paper, FDA Deputy Commissioner Randy Lutter said, "The Food and Drug Administration has a key role to play in facilitating the use of genetic information in drug therapies because it approves labels, and labels influence how doctors use drugs." It does not take even a small leap of faith to apply the philosophy of REMS to this trend of thought.

The concepts of "safe use" as an integral part of the FDA's 21st century mission and REMS as one of many tactics to achieve better patient care are contentious and crucial. And it is that debate which brings us together today.

Here's what Jane Axelrad, the associate director for policy at CDER, had to say recently about REMS: "These safety plans allow patients to have continued access to certain medicines for which there are safety concerns that can be managed through appropriate use."

Whether you say "appropriate" use or "safe" use - the principle is the same - making sure that the risk/benefit analysis of any given therapy is communicated in a lucid and (when required) strident manner.

Sometimes that requires a label change. Sometimes it requires a REMS plan. But it will always require the active participation and leadership of the FDA in partnership with the pharmaceutical industry, physicians, and yes - even patients. Because no safe use program will succeed without the secret ingredient of patient responsibility.

While some see REMS as mission creep, others see it as the natural and logical extension of FDA responsibility in our new age of more precise diagnostics and personalized medicine.

That's how I see it and why the Center for Medicine in the Public Interest was pleased to be a co-sponsor of this conference.

Here are some of the more memorable comments, questions, clarifications - and challenges from the recent Risk Management and Drug Safety:

Janet Woodcock, MD, Director, CDER, FDA

"Safety means doing the right things for patients."

"FDA must consider post-approval issues as part of a drug's lifecycle."

Dr. Woodcock also addressed the environment in which REMS exists. She pointed out that there is a real difference between "headlines and help." In other words, REMS and other safety mechanisms can be viewed as either "headlines" about "unsafe" drugs or in a more appropriate context of "safe use."

To this point she specifically discussed warfarin and abacavir - are these "dangerous drugs" or medicines that, with the appropriate diagnostic tools, can be used safely? Two sides of the same coin. Janet opts for "safe use," while others (in the media and elsewhere) seem more predisposed to the other.

She also mentioned that the FDA's Office of Surveillance and Epidemiology needs to hire "real experts" on "REMS issues" who can develop "predictable procedures and best practices."

Per the agency's forthcoming "safe use" program, Dr. Woodcock called for a public/private partnership to make the design and outreach of this important initiative more robust.

Laurent Auclert, MD, Head, Risk Management Plan Unit, Global Pharmacovigilance & Epidemiology, sanofi-aventis

Dr. Auclert began his talk by pointing out that "epidemiologists and statisticians must talk with each other." Everyone seemed to agree that this is both a good idea and an interesting sociological experiment.

He also considered the difference between RMPs in EU ("risk assessment") versus REMS in the US ("risk minimization"). A contentious proposition.

Jane Axelrad, JD, Associate Director for Policy, CDER, FDA

Jane pointed out that of the 15 post FDAAA REMS plans required by the agency, 12 were "MedGuide only." Her point was that the agency is using its REMS authority "judiciously."

They don't call her "Judicious Jane" for nothing.

She also reinforced the point made by Janet Woodcock that the FDA is trying to provide clarity to the process by developing both templates and clarity (per FDAAA) of classifications - and that the agency is preparing official guidance.

Carmen Bozic, MD, Vice President, Drug Safety & Risk Management, Biogen Idec

Dr, Bozic presented the risk management plan for Tysabri (TOUCH -- TYSABRI Outreach: Unified Commitment to Health). Fascinating stuff. She called it "elaborate." A more appropriate adjective is "elegant."

Robert Goldberg, PhD, Vice President and Director of Programs, CMPI

CMPI's very own Bob Goldberg opined that "REMS may very well be a way to revive applications that once looked dead."

I hope so - and so do many others who look at the current "safety jihad" (and jihadists) along with the current parched pipeline and wonder whatever became of the hoped-for miracles of the "biomedical century."

Donald Therasse, MD, Vice President, Global Patient Safety, Lilly Research Laboratories

Don said what everyone was thinking, "The drug label must remain the central tool in risk minimization." And considering the current and heated debate over preemption, this is not only a timely comment - but a core and crucial one. He also opined that, "REMS must complement rather than direct or impede the practice of medicine."

John Ferguson, MD, Vice President & Global Head, Pharmacovigilance and Medical Safety, Novartis Vaccines & Diagnostics

John discussed REMS in the context of "string theory," specifically outcomes, probability, and values (perceptions) - referring not to benefit and risk, but rather "composite benefit and composite risk." He posed a disturbing question, "In an age of risk management - what happened to benefit." Indeed.

Cherif Benattia, MD, Vice President, Pharmacovigilance & Public Health, Vertex Pharmaceuticals

Cherif began by saying that we must shift the conversation "from information to communication and information." Sounds obvious - so why aren't we doing it? He also asked a disturbing question:

"Who should manage drug safety? Lawyers? Doctors? The FDA? State legislators? Federal legislators?"

And that's a good place to stop - but not for too long.

Peter Pitts is President of the Center for Medicine in the Public Interest, a think tank on public health care policy issues and Senior Vice President, Director for Global Health Affairs for MS&L Worldwide. From 2002-2004 Peter was FDA's Associate Commissioner for External Relations, serving as senior communications and policy adviser to the Commissioner. He supervised FDA's Office of Public Affairs, Office of the Ombudsman, Office of Special Health Issues, Office of Executive Secretariat, and Advisory Committee Oversight and Management. He served on the agency's obesity working group and counterfeit drug taskforce and remains a Special Government Employee (SGE) consultant to the FDA.

His comments and commentaries on health care policy issues regularly appear in The New York Times, The Los Angeles Times, The Washington Post, The Wall Street Journal, The Financial Times, Health Affairs, The Boston Globe, The Washington Times, The Chicago Tribune, The Chicago Sun Times, The San Francisco Examiner, Investor's Business Daily, The Baltimore Sun, The Economist, Nature Biotechnology, The Journal of Life Sciences the BBC World Service, Fox News,and The NewsHour with Jim Lehrer, among others.

His book, Become Strategic or Die, is widely recognized as a cutting edge study of how leadership, in order to be successful over the long term, must be combined with strategic vision and ethical practice. He is the editor of the new book, Coincidence or Crisis, a discussion of global prescription medicine counterfeiting.

FDA Link
Questions and Answers on the Federal Register Notice on Drugs and Biological Products Deemed to Have Risk Evaluation and Mitigation Strategies http://www.fda.gov/CDER/regulatory/FDAAA/FR_QA.htm

FDA Identifies First Steps in Requirements for Safety Plans for Certain Drugs and Biologics http://www.fda.gov/bbs/topics/NEWS/2008/NEW01811.html

Additional Article
FDA Expands Risk Evaluation and Mitigation Authority http://ohsonline.com/Articles/2008/03/FDA-Expands-Risk-Evaluation-and-Mitigation-Authority.aspx

MasterControl Video:  Reducing Risk with MasterControl

MasterControl Video:  Gaining a Competitive Edge with MasterControl

Learn More

White Paper:
Risk Management: Best Practices for Medical Device Profitability
Risk Management for Pharmaceutical Companies Under FDA's Q9 Guidance
GAMP 5 - A Risk-Based Approach to Compliant GxP Computerized Systems

Click here to view all available resources.