Review
Limitations of randomized clinical trials for evaluating emerging operations: the case of lung volume reduction surgery

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Abstract

Although unanswered questions remain, scores of observational studies and several small randomized clinical trials (RCTs) indicate that lung volume reduction surgery (LVRS) offers safe and effective palliation for a relatively well defined subset of patients with advanced emphysema. Nonetheless, Medicare and other insurers stopped reimbursement for the procedure. Subsequently, two multicenter RCTs on LVRS, the National Emphysema Treatment Trial (NETT) and the Overholt-BlueCross Emphysema Surgery Trial (OBEST), were launched with the stipulation that the procedure would not be paid for outside these trials. Thus access to LVRS has been denied to patients who could benefit but do not wish to participate in an RCT. Emerging operations, unlike new drugs or devices, pass through evolutionary changes and frequently fail to produce data that meet the scientific rigor required by randomized studies. In such a setting, the observational approach is more appropriate. Indeed, almost all operations in the present surgical armamentarium have been evaluated and have evolved through observational studies without the use of RCTs. By the time new operations are standardized and qualify for RCTs, benefits for certain patients may be demonstrated and randomization could involve unacceptable health hazards. Patients from this population should be offered the choice between participating in RCTs and having the operation outside the study. Imposition of financial restrictions that bars access to a therapy with known benefit is a questionable practice.

Section snippets

The LVRS story

Pulmonary emphysema affects approximately 2 million adults in the United States and three to four times that number worldwide. Medical treatment offers only limited palliation and does not slow or halt progression of the disease. Of the many operations introduced during the past century to remedy the consequences of advanced emphysema, almost all failed to achieve the desired objectives and were abandoned [5]. One of the exceptions, lung transplantation, is of limited value because of the

Methods for evaluating new operations

At the time HCFA and the National Institutes of Health began to organize a clinical trial on LVRS, indications for the operation, the basics of operative technique, and details of perioperative management had been moderately well standardized. Operative mortality in different centers varied widely but most surgeons reported figures between 5% and 8%. Observational studies provided impressive evidence about the short-term effectiveness of the operation in a relatively well defined subset of

Choice of studies for advanced evaluation of LVRS

In May of 1996 HCFA and the National Institutes of Health announced joint sponsorship of the National Emphysema Treatment Trial (NETT) on LVRS. The study was designed to randomize 4,700 Medicare patients between LVRS and the best available medical treatment for 5 years at 18 clinical sites throughout the United States. Patient eligibility criteria for NETT resembles the characteristics of the population in which the short-term effectiveness of LVRS had already been established. The duration of

Progress of the clinical trials and utilization of LVRS

Fewer than one third of the anticipated number of patients have entered NETT and OBEST. As there appears to be no prospect for a change in the pace of enrollment in the foreseeable future, the recruitment phase of the two ongoing randomized trials may not be completed for another 6 to 10 years. NETT has already cut back its original enrollment goal from 4,700 to 2,500 patients [38]. OBEST has joined forces with the Canadian Lung Volume Reduction Trial in an attempt to obtain statistically

Comment

In spite of declining LVRS utilization, a steady stream of data from uncontrolled case series have continued to confirm the short and midterm effectiveness of the operation 42, 43. Two RCTs from the United States (37 and 49 patients), and one each from the United Kingdom (48 patients), Sweden (38 patients), and Italy (60 patients) compared LVRS with the best available medical treatment. All five studies reported better outcomes in the surgical arms 39, 44, 45, 46, 47, 48. Observational studies

Acknowledgements

The research component of OBEST is supported by the Thoracic Foundation, United States Surgical Corp and Biovascular Corp.

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