Talk about a rock and a hard place. Once drugs reach the market, or as a condition prior to approval, the industry’s handling of risk is caught between the needs of regulators, shareholders and public. At the 2008 Clinical Trials Congress, held in Orlando, there were signs that the burdens of risk management are daunting but manageable. One theme: the involvement of preclinical teams and data.

Wyeth’s Michael Blum, VP of medical pharmacovigilance, global safety surveillance and epidemiology, said the key concept is a proactive approach to drug safety, not a reactive one. He stressed that the idea is easier said than done. “It requires a mindset change in many organizations,” said Blum. Continuous reassessment of the risk-benefit ratio with a particular compound, he said, may lead to re-deployment of resources to compounds with better odds of making it through the approval process.

Some of the traditional lines of demarcation within any life sciences organization, he said, have to be reconsidered. “You must have sufficient timely proactive and reactive preclinical information,” he said. “We have to dispel the perception that there is a preclinical phase and a clinical phase.”

Rather than a simple linear process in which preclinical studies inform clinical trial design, Blum suggested, signals or safety questions that arise in the clinical or postapproval segment of a product’s life cycle can be reinserted into the preclinical phase for additional study.

Integrate the Data

Blum said electronic data capture (EDC) systems are making the timely receipt of data less of a problem. But still looming large is the difficulty of combining different types of data. Wyeth has been working on the underlying technology to make that happen for a while, but didn’t discuss those efforts in any detail. Blum did say this about the industry as a whole: “There is not an ongoing integration of the data for the purposes of looking for emerging safety signals. This is a new area. It may be more than simple pooling. There may be meta-analysis.”

In the same session, Eleanor Segal of Actelion Pharmaceuticals had a more specific case history. She’s head of global drug safety and global medical information at the firm. In an indication of how serious the risk management plan for pulmonary hypotension drug Tracleer was, 29 Actelion people were involved at a time when the company’s head count was 200.

Segal, too, stressed using the preclinical data and teams as an early warning system for what happens as a product moves into man or wider commercial distribution. “If an issue comes up, we can find out about it very fast,” she said, noting a key Actelion committee with members of both clinical and preclinical members.

Web Registry

The company’s risk management plan was mandated by the European authorities. Actelion expected to have perhaps 1,500 patients in its database. But its web-based tracking system eventually gathered data on more than 5,000 patients. “It was really a postmarketing signal detection system,” she said, describing an extensive effort to help physicians monitor patients for both liver function and pregnancy. There’s a peer-reviewed abstract about the effort here, but the Actelion risk-management system has since captured an even higher percentage of European patients taking the drug.

The system was initially provided by a vendor that changed hands but is now known as etrials, Segal said. It’s rare to hear a sponsor acknowledge the role played by a technology partner.

The system generated a massive weekly report. “We got a whole data printout once a week that we had to compare to the adverse events reports,” she noted. In the end, the company collected an impressive 3,400 years of patient exposure to Tracleer, far more than were reviewed during the trials used to gain market approval. In the end, that data satisfied regulators that the Tracleer risks were being managed and in reassuring alignment with what had been seen during Phase III trials. As it turned out, Segal said, roughly 47 percent of the patients could continue taking the drug.

In short, even a mid-sized firm like Actelion can shoulder the modern financial and technology burden for risk management. “We have shown that the frequency and severity of a known event did not change under real-world prescribing conditions,” said Segal.

A Manageable Plan

Another presenter at the Clinical Trials Congress session was Pfizer‘s Claudia Turner, executive director of safety and risk management. She reviewed some of the recent user fee legislation, known as FDAAA, which mandates a renamed version of risk management plans, called risk evaluation and mitigation strategies (REMS). “REMS is likely to dominate the developing and marketing of pharmaceuticals for decades,” said Turner.

In 2007, Turner said, Pfizer added four standard operating procedures that were related to safety. (She didn’t discuss them in detail.) Significant effort is being pushed in the same direction: the company is running more than 100 studies, each with more than 50,000 patients. “Safety is no accident,” said Turner. “It involves a lot of work and resources.”

Start Early

Showing a complex quadrant of risks, benefits and feasibility for different risk management plans, Turner mapped several Pfizer products into her grid. She discussed not only the aphrodisiac Viagra but also the inhaled insulin Exubera and heart drug Tikosyn. In the case of the latter two products, Turner explained, they are no longer sold, either because of an unfavorable risk-benefit ratio (Exubera) or because the risk-management plan itself was not realistic (Tikosyn). 

“There are a lot of things we can do in the pre-approval arena that enable us to manage risk,” she said, citing Pfizer’s sharing of risk plans with regulatory officials even when such documents may not have every last “i” dotted, and “t” crossed. “The initial plans will not be fully detailed,” Turner explained. That may be greeted with skepticism, she conceded, but is still a better strategy than than being caught behind the curve if problems arise and no plan is at the ready.

Re-Emphasize Preclinical

Starting with a provisional plan at an early date helps a sponsor demonstrate that it is watching the data and the market and responding sensibly. In the case of Viagra, she said, Pfizer was ready for media and regulatory interest when the first safety reports arose.

After inspecting the data, the company’s plan involved extensive advertising and public education about the risks of concomitantly taken nitrates and Viagra. The company marshaled the data to show that there was a manageable association between men with underlying cardiovascular disease and erectile dysfunction.

“The cornerstone was the risk communication,” said Turner. “This is an important balance between your risk-benefit profile and the ability to manage the risks through your plan. Your risk management plan must be realistic and feasible.”

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