Stepping Up Risk Management Efforts Is Sound Prescription for Pharma

Pharmaceutical companies seeking to expand their risk management programs do not have to look far for justification, considering the recently enacted FDA Amendments Act, which gives the agency more authority to ensure drug safety, and Merck’s recent $4.85 billion settlement for qualifying liability claims related to VIOXX®.

Companies need to take another look at their drug safety policies and procedures to ensure robust risk management strategies – with the goal of transitioning these processes to a more proactive approach.

“Generally, all products have risks; the challenge is to develop and implement strategies that maximize patient benefit while minimizing patient risk,” according to Terri Madison, president, i3 Drug Safety. “The level of tolerance for risk depends on the product’s use; higher risk for a life-saving treatment is more acceptable than even minimal risk for a product that treats cold symptoms. These principles are the foundation of risk management, and the industry must evolve to incorporate these principles into their routine product development and maintenance strategies,” she said.

With stronger requirements for risk management included in both European and U.S. legislation, companies will face new challenges in the coming years. Regulators now have greater authority to ensure safety and can require activities be undertaken to mitigate known risks, despite limited data regarding the effectiveness of different risk minimization activities. Regulators can also require evidence of proactive monitoring to identify unidentified risks, yet consistently reliable tools for this are still in development.

“Pharma companies need to meet these challenges by appropriately funding these programs and by demonstrating leadership in the science and methods to support these programs,” Madison advised. Recent initiatives, such as the Observational Medical Outcomes Partnership (OMOP) and the collaboration led by Mark McClellan from the Brookings Institution who was just named to chair the Reagan-Udall foundation, look promising.

A historically reactive industry

When it comes to regulating drug safety, the tendency has been to maintain the status quo until an event occurs that shines a spotlight on drug safety issues, creating political pressure to call regulatory bodies to action. In the United States, prior to the recently enacted FDA Amendments Act, the last significant regulatory change to address drug safety issues was the 1962 Kefauver-Harris Amendments, issued as a response to the thalidomide disaster, where children exposed in utero were born with phocomelia (flippers instead of limbs).

“Since 1962, when the thalidomide tragedy helped the government raise the safety bar for drugs, significant improvements to safety surveillance and risk management systems have evolved just over the last few years,” Madison said. More recent high-profile events leading to an increased focus on drug safety and risk management include the withdrawal of the diabetes drug Rezulin from the market in 2000 after safety data showed that it had higher liver toxicity than other drugs on the market, and the 2004 withdrawal of VIOXX® due to an increased risk of cardiovascular events, such as heart attacks and strokes.

In 2005, the FDA issued three guidance documents to address risk management activities:

Premarketing Risk Assessment – covering risk assessment during product development;
Development and Use of Risk Minimization Action Plans – covering the development, implementation, and evaluation of risk minimization action plans (RiskMAPs); and
Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment – covering safety signal identification and interpretation, pharmacoepidemiologic assessment of observational data, and pharmacovigilance plan development.

Meanwhile, in Europe, the Guideline on risk management systems for medicinal products for human use, issued in late 2005, established that a European Union risk management plan (EU-RMP) was required for all marketing authorization applications. The FDA’s documents were guidance, not regulation. To date, the FDA has requested a RiskMAP to be submitted on an as-needed basis, similar to EU regulators, who do not routinely require the risk minimization portion of the EU-RMP.

FDA Amendments Act gives agency more options

The FDA Amendments Act, signed into law Sept. 27, includes multiple provisions (in Title IX) for ensuring drug safety, including:

If new safety information becomes available, the FDA can order changes in drug labels and establish time frames for the labeling change.
The FDA can require post-approval studies and/or clinical trials to assess risk or a signal of risk.
The FDA can require the development of a risk evaluation and mitigation strategy (REMS) to ensure that a drug’s benefits outweigh its risks.
The FDA must work with the public, private, and academic entities to create a surveillance or sentinel system that uses electronic patient databases to monitor safety signals for approved drugs.

“Essentially, Title IX gives the FDA the power to actively enforce commitments for increased study of drug safety with a specific deadline,” Madison commented. “It used to be that a company could go to an approvable meeting and the FDA would ask for a postmarket study, but years later, the study may have not even been started.”

She suggested that the FDA and other regulators will continue to look to product labeling to communicate and mitigate risks. However, REMS provisions give the agency enforcement clout when monitoring requirements for risk evaluation and minimization.

“Most global companies are experienced in creating a risk management plan because they have been filing them with the EU,” Madison said. “However, the industry is still relatively new to formulating risk minimization strategies, so the increased authority of the FDA to require REMS documents will definitely challenge us,” she continued. “There is very little data available regarding which risk minimization activities actually work, and even those that do work only deal with known risks. Unknown risks will also need to be rooted out and dealt with.”

Ease transition to proactive paradigm with tools, support

Considering the renewed focus on drug safety issues, most senior executives have realized that it’s not in anyone’s best interest to let safety issues languish. “At a very high level, people understand that safety surveillance needs to be moved from a reactive to a proactive paradigm,” Madison said. However, what is understood at a high level may not be trickling down to the rest of the company, she continued. “Day-to-day pressures to meet goals may make drug safety measures seem like a lesser, or a competing, priority.”

Making risk-benefit assessment an ongoing internal priority, not one that is mandated by regulators, could help change the safety paradigm, she added. “We need to figure out how to get more dollars directed to evaluating the risk-benefit of drugs, especially for recently launched products. Perhaps if the argument was framed in this context, companies would see this as a positive marketing force,” she said. “The current framework, where safety studies have a reputation for putting the brakes on sales, is a barrier to understanding risk-benefit and promotes waiting for a safety problem to develop that can spiral out of control very quickly.”

To help pharmaceutical companies reach their safety goals more efficiently, i3 Drug Safety offers pharmacovigilance, epidemiology and risk management expertise all under a single umbrella, giving the industry “a tremendous synergy between data, science, and methodological expertise,” Madison said. “By supplementing routine pharmacovigilance with our data and scientific assets, we are well-positioned to assess risk in real-time, against robust data sources.”

i3 Aperio™ – a first-in-class signal detection and assessment tool for new drugs – leverages i3’s epidemiological expertise and one of the largest real-world populations to monitor known risks and identify unknown risks.

“We can help companies in any situation,” she said, “whether they have a known safety issue, have gaps in safety information, or are simply looking to be more proactive.” She explained that although i3 has its own rich database, it also works with other databases to conduct global observational epidemiology studies. “The i3 advantage is not just having the data, it’s having the scientists who know how to work with the data and extract from other resources to do elegant research,” she said.

Continually monitoring risk-benefit throughout the product lifecycle is a central theme for improving drug safety systems. This is particularly true post-launch, where ongoing assessment of risk-benefit as new data is available is required. The best risk management strategies involve implementation of this ongoing evaluation, so that key findings about product safety can be identified and addressed as early as possible.

“Companies should not be afraid to be proactive,” Madison concluded. “If a company is focused on ongoing data evaluation to maximize benefit and minimize risk, it is doing the right thing.”