Is Traditional Trial Design About to Be Replaced?

The “gold standard” of clinical-trial design—randomized, double blind, and placebo controlled—may finally be on its way out. Long the regulatory requirement for pharmaceutical research, the randomized, controlled trial (RCT) is being replaced by the practical clinical trial (PCT).

“There is increasing notice on the federal level—at the Agency for Healthcare Research and Quality and the Centers for Medicare and Medicaid Services—of the need for solid evidence upon which to base policy decisions,” said Sandra Tunis, M.D., a senior research scientist at Eli Lilly and Co. in Indianapolis.

Tunis chaired a workshop at APA's 2005 annual meeting in Atlanta in May titled “Practical Clinical Trials: Comparing Effectiveness of Psychopharmacologic Treatments.”

While the standard RCT has long been used to bolster policy decisions stemming from evidence-based medicine, Tunis continued, “clinical researchers and regulators alike have long recognized that the majority of RCTs have limited generalizability and applicability to how clinicians treat the average patient seen in the medical office on a day-to-day basis.”

Indeed, studies have shown that the patient populations generally found in RCTs are quite different from the general patient populations found in real-world clinical settings.

The problem, Tunis noted—which is at once both the hallmark and the bane of the RCT—is the high degree of carefully controlled patient selection.

Patients who have a comorbid condition in addition to the primary condition being studied are generally excluded from RCTs. For example, an RCT studying the efficacy of an antidepressant medication for major depression would exclude patients with major depression who also have an anxiety disorder. RCTs on antipsychotics regularly exclude patients with psychosis who also have a substance abuse disorder, yet that comorbidity is extremely common in the real world. Also excluded from RCTs are psychiatric patients who have significant comorbidity of other medical disorders, such as cardiovascular disease or diabetes— again, common comorbidities in patients with psychiatric disorders.

“A practical clinical trial aims to max out the generalizability of the study,” Tunis explained. “PCTs commonly have minimal inclusion or exclusion criteria. In contrast, they specifically aim to enroll a wide range of patients from a range of clinical practices.”

While PCTs do have some form of randomization, they are not necessarily double blind and do not include placebo control groups. Rather, a group getting the treatment being studied is compared with a group receiving the“ usual care” for the disorder.