In 2000, FDA pulled Glaxo's Lotronex (alosetron) from the market. Lotronex, indicated for diarrhea-predominant irritable bowel syndrome (IBS), seemed to cause ischemic colitis in some patients. It was subsequently re-released.
It was in this environment that Novartis took Zelnorm (tegaserod) before FDA for approval for use in constipation-predominant IBS patients. The drug's approval was complicated by the fact that clinical trials of 2,965 Zelnorm-treated patients and 1,740 placebo-treated patients showed a slight increase in abdominal surgeries and gall bladder removals for patients receiving Zelnorm. While the imbalance was not high enough to block FDA approval, the agency required a post-marketing study to ensure that Zelnorm did not increase the risk of abdominal surgery and gall bladder removal.
Needing sound scientific answers quickly, Novartis opted to conduct an observational study using real-world data. Based on health insurance data, epidemiologists matched patients who initiated treatment with Zelnorm with similar patients who did not. They followed health insurance claims for the group for six months to assess incidence of abdominal surgery. They obtained medical records to verify surgical outcomes; additionally, a physician survey and a case control study were performed to ensure the validity of the matching.The two cohorts included 5,524 patients, more than were enrolled in all pre-marketing trials combined. Across both cohorts, 456 potential abdominal surgeries were identified, and medical records were obtained for approximately 85 percent of these. Overall, the study addressed FDA's safety concerns, showing no increased risk of abdominal surgery for Zelnorm-treated patients. Moreover, the study was conducted for less than $1,000 per patient, a fraction of the price of a traditional clinical trial, where per-patient costs can range from $10,000 to $30,000.
With the ability to quickly answer critical safety questions at a fraction of the expense of traditional clinical trials, is there a place in the drug safety arsenal for studies based on automated claims data?
The Evolving Safety Environment
Drug safety assessment occurs both pre-marketing and post-marketing. In the pre-marketing phase, the key tool is the clinical trial, but pre-marketing trials have limitations. Small trials, for example, cannot detect undesirable side effects that occur rarely—say, at a rate of less than one per thousand. In addition, trials are generally performed on people who don't have other diseases and aren't taking additional medications. As a result, when a product launches, adverse reactions occurring at high frequencies are typically well-described. But less-frequent and serious adverse events (AEs) are not, and companies and regulators lack data on the real-world experience of patients with multiple co-morbidities or those using multiple products.
In March 2005, FDA released three guidance documents (Premarketing Risk Assessment; Development and Use of Risk Minimization Action Plans; and Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment), which established pharmacovigilance and pharmacoepidemiology as the key methods in post-marketing drug safety assessment.
Pharmacovigilance (PV) derives from the concept of public health surveillance. Drug companies are required by law to conduct PV, either in-house or through a contract research organization. Drug companies, of course, do not have direct interaction with patients and rely on spontaneous reporting of adverse events by healthcare providers. PV is the first line of defense to identify serious adverse drug reactions during the early post-marketing phase.