Clinical research methodology I: introduction to randomized trials.

With increasing initiatives to improve the effectiveness and safety of patient care, there is a growing emphasis on evidence-based medicine and incorporation of high-quality evidence into clinical practice. The cornerstone of evidence-based medicine is the randomized controlled trial (RCT). The World Health Organization defines a clinical trial as “any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes.”1 Randomization refers to the method of assignment of the intervention or comparison(s). Fewer than 10% of clinical studies reported in surgical journals are RCTs,2–4 and treatments in surgery are only half as likely to be based on RCTs as treatments in internal medicine.5 Multiple factors impede surgeons performing definitive RCTs, including the inability to blind health care providers and patients, small sample sizes, variations in procedural competence, and strong surgeon or patient preferences.5–8 Not all questions can be addressed in an RCT; Solomon and colleagues8 estimated that only 40% of treatment questions involving surgical procedures are amenable to evaluation by an RCT, even in an ideal clinical setting. In surgical oncology, trials evaluating survival after operations for a rare malignancy can require an unreasonably large sample size. Pawlik and colleagues9 estimated that only 0.3% of patients with pancreatic adenocarcinoma could benefit from pancreaticoduodenectomy with extended lymphadenectomy; a randomized trial of 202,000 patients per arm would be necessary to detect a difference in survival. These reasons should not dissuade surgeons from performing RCTs. Even for rare diseases, randomized trials remain the best method to obtain unbiased estimates of treatment effect.10,11 Rigorously conducted RCTs minimize bias by controlling for known and unknown factors (confounders) that affect outcomes and distort the apparent treatment effect. Observational studies, including those with the most sophisticated design and analysis,12,13 can control only for known confounders and might not adequately control for those. Many surgical and medical interventions recommended based on observational studies have later been demonstrated to be ineffective or even harmful. These have included blood transfusions to maintain a hemoglobin >10 mg/dL in critically ill patients,14,15 bone marrow transplantation for breast cancer,16–19 and extracranial-intracranial bypass for carotid artery stenosis.20,21 Another major reason for RCTs to be of interest to surgeons is that patients enrolled in trials can have improved short-term outcomes, even if the intervention is ineffective.22–25 Potential sources of this benefit include enrollment of lower-risk patients, use of standardized protocols and improved supportive care, and greater effort to prevent and address treatment hazards. Different outcomes can also be observed in trial participants because of either the Hawthorne or placebo effect, both of which can distort the apparent treatment effect and threaten the validity of the trial. The Hawthorne effect occurs when changes in clinicians’ or patients’ behavior, because of being observed, results in improved outcomes. For example, a prospective observational study evaluating operating room efficiency after an intervention can demonstrate improvement over historic performance, in part because the staff is aware of being observed rather than as a result of the intervention. The placebo effect occurs when the patient derives benefit not from the treatment itself, but from the patient’s expectations for benefit. In a randomized trial of arthroscopic surgery versus sham surgery for osteoarthritis of the knee, the placebo procedure had equivalent results to debridement and lavage, despite lack of any therapeutic intervention.26 Despite the advantages of well-conducted RCTs, poorly conducted trials or inadequately reported results can yield misleading information.27,28 Recently, Chang and colleagues29 demonstrated the continued paucity of high-level evidence in surgical journals and called for articles on clinical research methodology to educate surgeons. The purpose of this article is to serve as an introduction to RCTs, focusing on procedures for assigning treatment groups that serve to minimize bias and error in estimating treatment effects. Common threats to validity and potential solutions to difficulties in randomizing patients in surgical trials will also be discussed.