Advanced Planning
by Jessica Royer Ocken
July 2008
Although the European and American approaches to pharmaceutical risk management differ slightly, both share the common objective of ensuring patient safety for marketed products.
As science and technology advance the field of medicine, the ability to treat a condition or illness must be balanced with the treatment’s risk. And in today’s hyper-litigious environment, communicating risk in a transparent manner is critical for biopharmaceutical manufacturers when launching a new drug or rebranding an existing one for an alternate indication. To that end, regulators and companies are jointly developing numerous processes and strategies designed to illuminate the risk/benefit balance of pharmaceutical products.
In May 1999, a U.S. Food and Drug Administration (FDA) task force published a landmark report on strategies for managing risk related to medical product use, says Dr. Stephen Goldman, managing member of Stephen A. Goldman Consulting Services, LLC, in Morris Plains, N.J., USA, and a member of the 1999 task force. The task force proposed a new systems framework to improve risk management within existing structures and stressed that risk assessment is performed on an ongoing basis, with attention to benefit/risk balance, throughout a medical product’s lifecycle.
In 2004, a more global perspective was established as the pharmaceutical industry and regulators from the United States, Europe and Japan finalized the International Conference on Harmonization (ICH) E2E. The resulting document, ICH Harmonized Tripartite Guideline: Pharmacovigilance Planning E2E, outlined the proposed structure of safety specifications and pharmacovigilance plans to be submitted to regulators when applying for marketing authorization for new pharmaceuticals. The guideline also stated that safety specifications and pharmacovigilance plans also would be appropriate when applying for a new indication, significant change in established products (e.g., new dosage form; route of administration; new manufacturing process for biotechnology-derived product), use in a new population, or when a new safety concern arises with an approved pharmaceutical.
Although this guideline was finalized as an FDA guidance in 2005, the agency was only granted the authority to request a Risk Evaluation and Mitigation Strategy (REMS) from a manufacturer upon passage of the Food and Drug Administration Amendments Act in September 2007. Under the Act, the FDA can request that a REMS be submitted if the agency “determines that a REMS is necessary to ensure that the benefits of a drug outweigh the risks.”
In Europe, however, the 2005 European Medicines Agency (EMEA) CHMP Guideline on Risk Management Systems for Medicinal Products for Human Use mandates the submission of an EU Risk Management Plan (EU-RMP), which contains both a safety specification and pharmacovigilance plan incorporating E2E concepts, along with evaluation of the need for risk minimization activities.
Risk/Benefit Balance
Required with the submission materials for any new drug, the EU-RMP “looks at what is known about the safety profile of the drug, what is needed to investigate safety concerns further, and also what is needed in the form of risk minimization activities to make use of the medicine as safe as possible,” says Dr. Stella Blackburn, risk management coordinator for the EMEA in London.
“In the past, pharmacovigilance has been largely reactive, with actions taken in response to arising safety signals. The EU-RMP aims to make pharmacovigilance proactive by detailing what is known and, very importantly, not known about the safety profile of a medicine at a particular point in time.”
The EU-RMP is a synopsis of all the data submitted as part of the application. “Because the EU-RMP is a living document, it is continually updated throughout the lifetime of the product. New safety issues, the results of studies and any other important safety-related information is incorporated within this one document, which is therefore always current,” Blackburn says.
“The EU-RMP is the model,” Goldman says. But the U.S. risk management strategy takes a slightly different approach. The FDA released Guidance for Industry: Development and Use of Risk Minimization Action Plans in 2005, and at a 2007 public workshop on the implementation of Risk Minimization Action Plans (RiskMAPs), the FDA defined it as “an iterative process of assessing a product’s benefit-risk balance, developing and implementing tools to minimize its risks while preserving its benefits, evaluating tool effectiveness and reassessing the benefit-risk balance, and making adjustments, as appropriate, to the risk minimization tools to further improve the benefit-risk balance.”
Rather than being required by the FDA for particular drugs or drug categories, “it’s a judgment call by the agency,” says Dr. Sean Hennessy, assistant professor at University of Pennsylvania School of Medicine, in Philadelphia, Pa., USA, and member of the FDA Drug Safety and Risk Management Advisory Committee. “Before RiskMAPs, the FDA could approve a drug, and then any doctor could prescribe it for any indication. Or they could disapprove a drug, and then no doctor could prescribe it for any indication. It was sort of a blunt-object approach,” he says. “RiskMAPs give us the ability to have a drug used in the right patients, by the right doctors, under the right circumstances to reduce the opportunity for misuse. It takes drugs that would otherwise be too risky and makes them available for some patients in circumstances when the risk/benefit balance would be ideal.”
As in the EU, RiskMAPs can become critical at any time during a drug’s life cycle. “If at any point new safety information becomes available, it may be that the overall risk/benefit balance [of the drug] is no longer favorable in the absence of a risk management plan,” Hennessy says. “So you withdraw the drug or come up with a plan.”
Between October 2002 and December 2006, 130 RiskMAPs were submitted to the FDA for review, and as of February 2007, 30 drugs had active RiskMAPs. Nine of these were put in place after the drug was on the market.
Strategic Risk Mitigation
At its most basic, pharmaceutical risk management identifies hazards and gives an estimate of the level of risk associated with the product as it will be used in a clinical practice. “That level of risk will be the basis of your risk assessment,” says Lincoln Tsang, Ph.D., a partner in the London office of Arnold & Porter, LLP, a legal firm that deals with pharmaceutical regulatory approval and post-approval risk management strategy. “That assessment will be the basis for you to identify the most appropriate risk management plan for a given product.”
Depending on the proposed indication of the drug, its intended population and the severity of the risk, the approach will differ. Potential risks include drug interactions, birth defects, drugs that require ongoing patient monitoring and risks associated with off-label use, Goldman notes. “You would use different techniques in some cases versus another,” he says. “One size does not fit all.”
Indeed, techniques to communicate risk vary widely. Suggestions from the FDA, for example, include education and outreach (i.e., medication guides, letters sent to clinicians, continuing-education units), reminder and/or prompting systems (doctor-patient agreements in which the patient acknowledges awareness of the drug risk and the behaviors to minimize it, a physician’s agreement to obtain tests or follow certain procedures before prescribing the drug, a verification sticker that indicates to the pharmacist that risk-minimization procedures have been followed), and restricted distribution systems, also known as performance-linked access (registry enrollment for patients taking the drug, mandatory patient monitoring, restrictions on who may prescribe, distribute and dispense certain drugs).
At the public workshop, the FDA reported each of the 30 current RiskMAPs’ uses in effect in February 2007 targeted education and outreach to notify doctors and patients about the drug’s risks, and an additional 10 include performance-linked access, Goldman reports.
What’s Next?
Pharmaceutical risk management is not without its challenges—for manufacturers, for clinicians and for patients—but it is also an inevitable reality of the industry’s future. “Risk-management planning is here to stay,” Goldman says. “It should be incumbent upon any company with a product coming out to follow the E2E guidelines: State what you do and don’t know, what you want to know, the evaluations you’re considering,” he says.
Increased discussion and transparency also will be key. “The likely future paradigm is increasing cooperation and collaboration between all the stakeholders—regulators, manufacturers, medical, pharmaceutical and nursing professionals, as well as the patients,” Tsang says. “Drug safety is no longer the purview of one body. Technology is increasingly complex, and we need to communicate with everyone who is engaged in the process.”
Finally, the purpose of risk management must remain at the forefront of this communication. “The bottom line on all of this is public health … and to keep a product on the market, if possible” Goldman says. “Sometimes that’s lost in discussions on this. When an effective product comes off the market, nobody wins.”
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