Obey the Signals
by Leslie Whitaker
June 2007
As the call for heightened pharmacovigilance grows more urgent, industry stakeholders are developing new tools to identify potential safety hazards and communicate risk.
Pharmacovigilance is a discipline central to the optimal functioning of the biopharmaceutical field and the protection of the health of millions of patients. Because the very nature of clinical trials usually limits the test populations to a minimal number of patients, many adverse side effects often do not show up until after the drug has been approved and is being distributed to a far larger population. Even at the intended and approved doses, every drug presents a risk of side effects. As a result, scientists, regulators, manufacturers, politicians, physicians and patients are facing the increasingly complex challenge of accurately assessing the benefit versus risk profile. Given the continuous advent of scientific advances and more complicated medical treatments, the negative publicity that accompanies adverse events, and the heightened activism on the part of patients, the need to address this challenge has never been more pressing.
Merck’s 2004 decision to voluntarily withdraw Vioxx (rofecoxib) five years after its approval was a watershed event in terms of how companies and consumers viewed the acceptable risk of medicines. “Recent high-profile incidents, epitomized by the withdrawal of Vioxx, changed the playing field,” says Dr. John Ferguson, vice president of pharmacovigilance at Millennium Pharmaceuticals, in Cambridge, Mass., USA.
Vioxx had been approved in 1999 by the U.S. Food and Drug Administration (FDA) for the relief of osteoarthritis and rheumatoid arthritis, and the management of acute pain. Merck voluntarily withdrew the drug from the market when researchers conducting a post-marketing study of patients at risk for developing recurrent colon polyps found a relative increase in the incidence of cardiovascular events, including heart attack and stroke, in patients taking Vioxx. Although the number of events was arguably small, and the rate of events could be reasonably characterized as uncommon in absolute terms, Merck stopped selling the drug. “This decision was undoubtedly due in part to the non-lethal nature of approved indications for Vioxx and the pattern of Vioxx use in the marketplace,” Ferguson says.
Accounting for patient values makes defining an acceptable benefit-risk balance especially challenging for medications that improve quality of life, Ferguson says. When a post-marketing study identifies a side effect, the acceptability of the potential for harm may vary widely among individuals. For example, a television actor may find the consequences of a facial rash much more troubling than an elderly patient living in a nursing home. In a case such as this one, the elderly patient may accept the risk, but the actor may not. Recognition of the need to account for patient preference “has forced everybody to rethink how we look at benefit and risks,” Ferguson says.
Mapping Out Risk
The best-practice approach to assess and communicate the potential risks and benefits of a drug is to draw up a Pharmacovigilance Plan, which typically includes the following steps:
1. Identify known risks of the drug in the patient population, determine whether the benefits are worth proceeding, and if they are, develop a plan to minimize those risks.
2. Recognize suspected risks and develop a plan to further evaluate them, which may include conducting follow-up safety studies.
3. Maintain a surveillance system to monitor for possible unknown risks.
Depending on the specific safety issue, risk minimization may require no action beyond routine pharmacovigilance monitoring of incoming safety information. However, in some cases, labeling changes, letters to physicians or the development of a Risk Minimization Action Plan (RiskMAP) may be required.
A state-of-the-art RiskMAP enabled the 2006 return to market of Tysabri (natalizumab), a highly effective treatment for Multiple Sclerosis (MS), says Dr. Ned Kelly, vice president, global pharmacovigilance, strategic research and safety at Quintiles Transnational, in Durham, N.C., USA. Developed by Biogen Idec and Elan Corp. and given intravenously, Tysabri had been shown to be among the most effective drugs on the market in relieving MS’s debilitating symptoms and reducing relapses.
But in February 2005, just months after Tysabri’s approval, two patients in a long-term clinical trial developed progressive multifocal leukoencephalopathy (PML), a viral infection of the brain. Biogen Idec and Elan Corp. immediately withdrew the drug from the market, but because Tysabri had produced unmatched effectiveness, many patients were distraught by its disappearance, Kelly says. “Many patients received benefits from the drug and were devastated not to have access to it.” Soon thereafter a third patient, this one with Crohn’s disease, developed PML. In all, a total of three patients out of approximately 2,900 patients exposed to Tysabri developed the disease.
A Safe Course
Closer inspection of the infected MS patients showed that all three had been taking an additional immunosuppressant drug at the time of the trial or in the recent past, Kelly says. After careful study of the benefits of Tysabri versus the risks, regulators approved its return to the market based on a RiskMAP submitted by Biogen Idec.
Also in June 2006, Tysabri was given approval for marketing throughout the European Union (EU), where a reconsideration of pharmacovigilance is a key industry concern. The European Commission “is taking a much harder look at the pharmacovigilance legislation and acknowledging the need for reform,” says Dr. Brian Edwards, the London, U.K.-based treasurer of the International Society of Pharmacovigilance. In February 2007, the commission announced a strengthening of the EU pharmacovigilance system based on public consultation held throughout 2006. The commission plans to collaborate with the European Medicines Agency and representatives from member states to establish one set of pharmacovigilance regulations; strengthen the rules of transparency related to pharmacovigilance data, assessment and decision making; and establish a clear legal requirement for conducting post-authorization safety studies.
To some extent, pharmacovigilance—like the practice of medicine itself—is part art and part science, Kelly says. And to meet the current challenge of measuring benefits and risks, more stakeholders than ever before must be brought into the process.
“We must develop a structured approach to determining benefit-risk balance. To use the structure effectively, we need new tools to characterize benefits and risks, and we need to apply the full range of tools earlier in drug development and throughout the life-cycle of products,” Ferguson says. “As for marketed products, spontaneous reporting is invaluable, but we’ve squeezed just about everything we can from it. There is no circumventing the need to lower our threshold for using studies that provide more robust levels of evidence concerning risk. The world has changed. There is no going back.”
Send us Your Comments
Web Exclusives
- An Unbalanced Burden
-
A Q&A with Dr. Kathleen Squires, director of the infectious disease department at Jefferson Medical College in Philadelphia, illuminates the gender differences in the diagnosis and treatment of HIV.
- Turning the Corner
-
After decades of neglect, leading to a rapid increase in incidence, tuberculosis started gaining attention from industrialized nations over the past 10 years. With this new focus, TB’s incidence has started to decrease—but barely.