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
"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
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
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
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
"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.
Tunis was joined on the workshop panel by colleagues at Lilly, as well as
Kurt Kroenke, M.D., a professor of internal medicine at Indiana University.
Wayne Katon, M.D., a professor of psychiatry at the University of Washington
Medical School, served as the discussant.
Kroenke described as an example of a PCT the ARTIST trial (A Randomized
Trial Investigating SSRI Antidepressants). The ARTIST trial, for which Kroenke
was the principal investigator, was published in the December 19, 2001,
Journal of the American Medical Association. The trial enrolled more
than 600 adults referred from 37 primary care clinics. The primary inclusion
criterion was the primary care physician's clinical judgment that the patient
had a new depressive episode that required treatment with an SSRI.
Patients were randomly assigned to receive paroxetine (Paxil), fluoxetine
(Prozac), or sertraline (Zoloft). As a PCT, patients were allowed to switch
medications, based upon their physicians' clinical judgment. By the end of the
nine-month study, Kroenke said, only half of the patients had stayed with
their originally assigned medication. There was progressive switching with a
significant number of patients and some stopped treatment over time.
The ARTIST trial found no statistically significant differences on any of
the trial's multiple outcomes. Depressive symptoms improved significantly in
all three groups. Overall, 74 percent of patients in the three groups met
criteria for major depression at baseline. By the end of the nine months, only
26 percent met those criteria.
"It simply didn't matter which drug they received," Kroenke
said. "All three medications were effective at relieving depressive
symptoms." However, costs differed between the three groups.
Interestingly, residual symptoms were found to indicate a high risk for
relapse and increased cost to the health care system.
In contrast to standard RCTs, which traditionally focus only on efficacy or
adverse effects, PCTs nearly always include measures of drug effectiveness,
cost-effectiveness, and quality-of-life measures.
"In PCTs, the question becomes, Are there patient-level symptoms or
measures of function that allow the clinician to see cost differences, based
upon starting the patient on one drug versus another?" Katon said."
In other words, can we make evidence-based, real-world formulary
decisions based on individual patient characteristics that have an impact not
only on treatment outcomes but also on cost?"
Katon believes the field is headed in the right direction, "but we
are going to have to be creative in deciding which values or measures to
incorporate into these trials in order to be able to collect the data we
Workshop participants agreed that while progress has been made, outcome
measures need to be developed that are disease specific and more sensitive to
change in short-term as well as longer-term studies.
An abstract of "Similar Effectiveness of Paroxetine,
Fluoxetine, and Sertraline in Primary Care" is posted at<http://jama.ama-assn.org/cgi/content/abstract/286/23/2947>.▪