Developments in Post-marketing Comparative Effectiveness Research

Abstract

Physicians and insurers need to weigh the effectiveness of new drugs against existing therapeutics in routine care to make decisions about treatment and formularies. Because Food and Drug Administration (FDA) approval of most new drugs requires demonstrating efficacy and safety against placebo, there is limited interest by manufacturers in conducting such head-to-head trials. Comparative effectiveness research seeks to provide head-to-head comparisons of treatment outcomes in routine care. Health-care utilization databases record drug use and selected health outcomes for large populations in a timely way and reflect routine care, and therefore may be the preferred data source for comparative effectiveness research. Confounding caused by selective prescribing based on indication, severity, and prognosis threatens the validity of non-randomized database studies that often have limited details on clinical information. Several recent developments may bring the field closer to acceptable validity, including approaches that exploit the concepts of proxy variables using high-dimensional propensity scores, within-patient variation of drug exposure using crossover designs, and between-provider variation in prescribing preference using instrumental variable (IV) analyses. POST-MARKETING COMPARATIVE EFFECTIVENESS RESEARCH Lack of evidence on the effectiveness of drugs in routine careClinicians balance benefits and risks of medicines every day. They are taught that randomized controlled trials (RCTs) provide the most robust evidence, and so they go to work happily extrapolating evidence from RCTs to their own patient population, believing that their patients will benefit from an equally large effect. Cochrane 1 pointed out some 35 years ago that RCTs on the efficacy of drugs for their regulatory approval study the extent to which an intervention does more good than harm under ideal circumstances ("Can it work?"). Effectiveness, however, assesses whether an intervention does more good than harm when provided under usual circumstances of health-care practice ("Does it work in practice?").Although there is no doubt about the scientific value of RCTs, their findings have often limited utility in daily practice: they may have sample sizes too small or drug doses too low to fully assess the safety of drugs; follow-up may be too short to show long-term benefits; they may under represent or exclude vulnerable patient groups, including elderly patients with multiple comorbidities, children, and young women, and operate in a highly controlled environment that is far from routine clinical practice. These issues are particularly relevant for preapproval trials. As drugs are on the market for a long time, more RCT evidence becomes available that NIH Public Access Author ManuscriptClin Pharmacol Ther. Author manuscript; available in PMC 2010 July 18. Published in final edited form as:Clin Pharmacol Ther. Few randomized effectiveness studies compare alternative treatment strategies in large heterogeneous populations, but they oft...

The First Decade with the Swedish Prescribed Drug Register – A Systematic Review of the Output in the Scientific Literature

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The risk of infection associated with tumor necrosis factor α antagonists: Making sense of epidemiologic evidence

“…In the example of TNF␣ antagonists, most analyses use methotrexate or nonbiologic disease-modifying antirheumatic drugs (DMARDs) as the comparator drugs. Ideal comparator drugs are those that have the same indication as the study drug and that might be used interchangeably, so that the physician's choice of drugs is almost random (11). If the population receiving the drug of interest (i.e., TNF␣ antagonists) and the population with the comparator exposure (i.e., nonbiologic DMARDs) differ in clinical characteristics that could be predictive of the study outcome, then confounding will bias the results.…”

Generating Evidence From Computerized Healthcare Utilization Databases

“…Four, because they are recorded independently of patient agreement, data are immune from the bias related to the selection of patients by their willingness to participate, an often forgotten limitation impossible to exclude in conventional research studies. 28 Finally, and most importantly, HCU databases guarantee that the information reflects the state of clinical practice in the general population, this being particularly the case where healthcare is assured by a system covering the whole citizenship. The above advantages are listed in Table 2.…”

“…64 In general, it is thought that a set of 3 restrictions can be adopted in comparative effectiveness research with no major impairment of data generalizability. 28 Restricting the investigated cohort only to patients who experience the in-study outcome (case-only design) is another possibility, its use in pharmacoepidemiology and healthcare research via methods such as the case-crossover 66 and the self-controlled case series design 67 being regarded as attractive (particularly in patients with transient exposure to or acute outcomes from drug use) because of the ability to evaluate time-invariant confounders. For antihypertensive therapy, an example has recently been provided by a study that compared the risk of discontinuing antihypertensive therapy in patients under generic versus brand-name drugs.…”