Practical Clinical Trials: from Medicine to Psychiatry
John S. March, MD, MPH1, 2 and Mark Shapiro, MA2
1Department of Psychiatry and Behavioral Sciences
2Duke Clinical Research Institute
Duke University Medical Center
Durham, North Carolina
Over the past several decades, clinicians have recognized a pressing need to understand the impact of widely practiced treatments on the major outcomes for common illnesses, like heart attack, stroke, and cancer. This recognition has given rise to large and sophisticated cardiology and oncology research networks devoted to conducting practical clinical trials (PCTs) to investigate these treatment effects. The National Institutes of Health (NIH) were instrumental in supporting these networks, with the stated aim of speeding the translation of clinical research into medical practice. Indeed, the Director of the NIH, Elias Zerhouni, MD, recently emphasized the need for PCTs that are explicitly designed to aid decision makers making decisions about patient care at the doctor-patient and policy levels. Although, the practical clinical trials model is now being adopted by psychiatry, challenges remain before PCTs can fulfill their promise to have a positive public health impact on the care of mentally ill children, adolescents, and adults
Over a decade ago, Sir Richard Peto coined the term “large, simple trial” to describe what is now more commonly know as a practical clinical trial. In doing so, he emphasized that treatment outcome studies should have sufficient power to identify modest clinically relevant effects, employ randomization to protect against bias, and be simple enough to make participation by patients and providers reasonable. More recently, certain defining features, such as comparing clinically important interventions, examining a diverse population representative of clinical practice, and testing a broad range of clinically relevant health outcomes, have been used to characterize PCTs. In psychiatry, for example, a PCT end-of-treatment assessment might use a DSM-IV diagnostic checklist, one or two short self-report scales, a checklist of functional outcomes, and a summary clinician measure, such as a Clinical Global Impressions (CGI) score. Together these might take 30 minutes to complete in the context of a routine office visit. For PCTs, the central question is whether these simplified assessments, which by definition should transfer readily to clinical practice, yield reliable and valid inferences regarding the outcomes of treatment.
In fact, PCTs sometimes reveal that widely used, seemingly sensible clinical strategies that have been shown to work in small industry-funded registration trials can, in fact, be harmful when applied in real clinical settings. In a sobering example, the Cardiac Arrhythmia Suppression Trial (CAST) examined Class I anti-arrhythmic drugs that had been shown in small efficacy trials to suppress extrasystolic ventricular contractions in patients at increased risk of death following a heart attack. Intuitively, it seemed reasonable that a reduction in irregular heartbeats should result in reduced mortality. However, CAST revealed that these drugs were associated with a 250% increase in short-term mortality whereas Class III agents appeared to reduce mortality. The CAST trials nicely illustrate how PCTs can be very useful in confirming that the results of small efficacy trials will translate (or not, as the case may be) to real-world practice.
Another area where PCTs have been extremely successful at improving patient care is in the field of pediatric oncology. The Children’s Oncology Group (COG) network has revolutionized the care of children with cancer. Currently, over 95% of children with cancer are treated at approximately 500 participating centers on the COG network, which is funded by the National Cancer Institute. Besides serving as a national registry of nearly all childhood cancers in the United States, COG provides a national communications network for researchers, care providers, and families of pediatric patients with malignant disease. In addition, COG conducts laboratory investigations and clinical trials of new treatments for cancers in infants, children, adolescents, and young adults. More than half of American children with cancer are entered into at least one randomized COG trial, which in turn has led to dramatic improvement in pediatric cancer outcomes.
Following the example of COG, researchers at Duke University, in partnership with the American Academy of Child and Adolescent Psychiatry (AACAP), created the Child and Adolescent Psychiatry Trials Network. CAPTN is an NIHM-funded, investigator-initiated proof-of-concept effort to establish a PCT network in pediatric psychiatry. Guided in the selection of specific questions by CAPTN members and expert advisory panels, CAPTN focuses on two critically important clinical issues: (a) obtaining randomized evidence regarding the effectiveness of widely used but understudied combined drug treatments; and (b) the short- and long-term safety of pharmacotherapy. CAPTN is now in the early stages of a testing a psychometric tool for reporting adverse events in psychiatric PCTs. While this trial involves about 100 research sites, by next year, CAPTN aims to have several hundred child and adolescent psychiatrists from all practice settings, participating in one to two practical clinical trials annually. This effort promises to advance both the evidence base and research capacity within child and adolescent psychiatry, yet challenges remain.
Clinical research in psychiatry has been hobbled by high costs, lack of funding, regulatory burdens, fragmented infrastructure, slow results, and a shortage of both qualified investigators and willing participants. Consequently, clinical practice in psychiatry remains far from evidence-based, with heterogeneity in practice leading to heterogeneity in the quality of care delivered. In children, for example, there has been a rapid shift from a single-drug standard toward complex multidrug treatment regimens, for which scientific support is lacking. Indeed, researchers have been successful developing new psychiatric treatments, but for the most part, have failed to design trials that maximize clinical utility for practicing psychiatrists, leading to gaps in the research literature. In addition to CAPTN, other projects have recently been initiated to address these gaps, such as the British BALANCE trial in bipolar adults and the industry-funded InterSePT trial in suicide in schizophrenia.
PCTs in psychiatry have been criticized because, unlike cancer and cardiovascular trials, which use “hard,” dramatic and unmistakable events (such as mortality), they rely on “soft” behavioral/symptomatic outcomes. While it is true that psychiatric outcomes are subject to greater measurement error relative to mortality, hard endpoints are readily available in psychiatric research, such as rescue procedures, suicide attempts, treatment switching, hospitalization, school failure or truancy, job loss, or even dropping out from the trial itself. Furthermore, it is possible to over estimate the “hardness” of both medical and psychiatric endpoints—namely, misclassification of myocardial infarction in cardiology trials and suicide adjudication in the InterSePT trial—and to underestimate the proven utility of “softer” endpoints, such as quality of life, global outcomes, or psychometrically robust rating scales.
After decades of industry-sponsored efficacy studies, psychiatry appears primed to follow the rest of medicine in moving toward practical clinical trials that seek to identify moderate, clinically relevant treatment outcomes of substantial public health importance. Such trials are necessary to evaluate clinically important interventions in a diverse population of study participants recruited from heterogeneous practice settings using outcome data covering a broad range of ecologically valid health indicators. In response, psychiatry research networks, like CAPTN, are taking charge of developing evidence to improve clinical decision-making and accelerate the transfer of information from research into clinical practice. To find out more or join CAPTN, visit www.captn.org.