Published Online:December 10, 2013
With the rise of targeted therapies, the days of letting doctors report informally on unexpected reactions to new cancer drugs are long gone. The change signals a larger role for phase IV, the post-marketing research step in the approval process.
Accelerated approvals can take months, if not years, off the time it take to get a life-saving drug to a cancer patient, but they may occur without sufficient efficacy data. So, today those approvals typically come with a catch: Pharmaceutical companies must closely monitor patients and report reactions to toxicity. The US Food and Drug Administration has created the REMS program – for “Risk Evaluation and Mitigation Strategies” – for drugs approved where the risk-to-benefit ratio “may not be apparent in all clinically relevant scenarios,”1
according to Mark Crowther, MD, of St. Joseph’s Hospital in Hamilton, Ontario.
Dr Crowther was part of the education session, “A Fresh Look at Drug Approval: Moving Away from Tradition,” offered at the 55th
American Society of Hematology Annual Meeting and Exposition in New Orleans.
The “post-licensure” monitoring programs represent the balancing act the FDA faces in trying to hasten the time it takes to get new therapies into the market. Long approval periods not only keep beneficial drugs away from patients; they also drive up costs. Thus, the FDA awards “breakthrough” designations when it can be shown that a drug “may [provide] substantial improvement on at least one clinically significant end point over available therapy.”1
Such research is obviously beneficial to patients. Sometimes the size of a clinical trial, or its design, prevents researchers from detecting reactions that become apparent once a drug reaches the general population. Dr Crowther cited the case of Cervistatin, a cholesterol-lowering agent, which was taken of the market after reports of deaths from rhabdomyolysis, especially among patients also taking gembfiborzil.
But data collection benefits drug developers, too. Not only does the combination of accelerated approval with post-marketing research get drugs to market quickly for their original purpose, but phase IV research “may lead to new indications,” Crowther said.
Compared to phase IV research of earlier eras, today’s studies are robust and systematic. Self-reports, which Dr Crowther dismissed as useless, have been replaced with large data sets and obligatory, uniform reporting. The “real time” aspect of these methods allow regulators to closely monitor new therapies and act quickly if there’s a problem.
Another game-changer has been the FDA’s Sentinel project, launched in 2008. This national system, which will become more powerful as electronic record-keeping takes hold, lets the FDA track not only toxicity reactions, but also drug and dosing changes made in response to its warnings. What’s more, unlike post-market research done by pharmaceutical companies, this project offers the independence of a third party.
Crowther M. Phase 4 research: what happens when the rubber meets the road? Hematology Am Soc Hematol Edu Program, 2013; 2013:15-18.