Randomized Controlled Trials (RCTS)

(7/1/07)- We have written many articles on this Web site of the importance of randomized controlled research trials (RCTs) as an efficacy measure of the results of these trials. RCTs represent a gold standard in clinical settings as well as by use of health policy makers. The Guyatt et al article, appearing in JAMA 1999; 281:1836-1843, suggested that these studies also effect changes in medical practice, directly impacting on individual health.

As consumers of medical services become more sophisticated in the use of the Internet search engines, they are encountering sites that are challenging the specificity of research results of RCTs as result of exclusion criteria in these studies. Exclusions involve the selective eligibility criteria of randomized controlled trials and thus the effectiveness of generalizing to the general population. "Appropriate eligibility criteria are, of necessity, essential for the design of internally valid and efficient RCTs that aim to measure the efficacy of an intervention". (JAMA 2007; 297(11): 1234.) By excluding certain populations, the result is that insufficient information is available for these populations to apply the results of the study.

As result of selective publication of clinical test results and avoidance of potential adverse effects in reporting results, pharmaceutical companies have found themselves targets of lawsuits. Careful review of many studies has indicated that certain specific cohort groups are excluded from research studies i. e. minority groups, women, children, older people, individuals with chronic medical conditions, physically disabled etc. In the study described below, the authors cite a study of 20,388 Medicare beneficiaries discharged from acute care hospitals in the US with the principle diagnosis of heart failure. The Medicare study found only 13% to 25% met the enrollment criteria for three landmark RCTs that have influenced the therapies of all patients with congestive heart failure. The results of these studies may not apply to a full three-quarters of the population the study is establishing as the evidence-based treatment standard.

JAMA (2007; 297:1233-1240) featured a systematic sampling review article of issues pertinent to randomized controlled trials (RCTs) entitled "Eligibility Criteria of Randomized Controlled Trials Published in High-Impact General Medical Journals" by Van Spall HGC, Toren A., Kiss A., Fowler RA. The authors of this study searched the MEDLINE database for RCTs published between 1994 and 2006 in the worlds most widely read and quoted medical journals that publish trials pertaining to conditions of a broad interest to physicians and of potential relevance to broad groups of patients.

They found 4827 articles, 283 of which were extracted to be analyzed. "[T]rial characteristics and the details regarding exclusions were extracted independently. All exclusion criteria were graded independently and in duplicate as either strongly justified, potentially justified, or poorly justified according to previously developed and pilot-tested guidelines." The intended goal of this review was to stress the need for transparency in reporting research results and need for specificity in justifying exclusion trials in the research study.

Since this is a Web site interested in issues related to the elderly, we quote below the results specific to age. "Age was a reason for exclusion in 72.1% of the RCTs…those older than 65 years in 38.5% of the RCTs… Restrictions in the inclusion of older adults applied to individuals ranging from 50 to 80 years…Individuals were excluded from trial participation due to medical comorbidities in 81.3% of the RCTs, most commonly for kidney, infectious, cardiac, liver or hematological-oncological disease…Medication-related reasons were the cause of exclusion in 54.1% of trails…and 12.1% of the RCTs excluded patients on the basis of limited life expectancy." (Ibid)

The results suggest that only the very well-aged population would qualify for most RCTs in light of well established descriptions of the older individuals as taking a number of medications (polypharmacy) and subject to a range of chronic disorders. The question that arises is whether the results are applicable to the entire population of elderly individuals.

Benefits for these individuals may prove minimal or more serious in terms of adverse effects. The comment by Van Spill et al seems apropos: "[T]here is evidence that trial participants assigned to either intervention or placebo have fewer undesirable clinical events and lower mortality rates than those of eligible participants. Exclusions may leave future patients with similar characteristics susceptible to unintended harm from an inappropriate generalization of trail results." The authors place part of the controversy over cyclooxygenase-2 inhibitors (Cox-2 inhibitors) as stemming "from narrowly defined patient populations in the original RCTs".

In 1999 a group of professional journal editors met with scientific researchers, statisticians and other professionals to develop a Consolidated Standards of Reporting Trials (CONSORT) statement. This statement has since been revised. (See: and Ann Int Med 2001; 134:663-694)

The statement consists of a checklist and flow diagram that authors use for reporting on RCTs. The goal of CONSORT is to facilitate critical appraisal and interpretation of RCTs. Interestingly, Van Spill et al report a "nonsignificant improvement in the trial quality score…and a significant reduction in the percentage of poorly justified trial criteria" when they divided the RCTs they studied into two periods (1994-1998 and 1999-2005).

Clinicians need clearly evaluate the generalizability of RCTs to a clinical population, designing studies that include all groups of patients. If this is not possible, clinicians are obligated to define their exclusion criteria within their methods section of the study. Use of nonspecific terms as exclusion criteria need more specific definitions.

The strength of any study lies in its generalization to a clinical population. The challenge is to the researcher to be more transparent.


Harold Rubin, MS, ABD, CRC, Guest Lecturer
July 1, 2007

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