Glass Ceiling Effect in Clinical Trial Research: Impossible to Overcome?

Prospective randomized, double-blinded clinical trials are often considered the gold standard for clinical evidence. However, in spine surgery, achieving these standards is challenging due to various limitations. This raises the question of whether we need to redefine what constitutes the highest grade of clinical evidence to impact practice effectively.

Different surgical subspecialties use various classifications and levels of evidence reporting. While spine surgery research often focuses on diagnosis, treatment, and economic analysis, other fields, like plastic surgery, may prioritize prognosis-based classifications. Many large-scale spine trials face difficulties with controlled double-blinded randomization, often due to patient cross-over between treatment arms. Moreover, spine surgery trials rarely progress beyond the Phase II single-center stage due to ethical and practical constraints.

Disease Burden of Musculoskeletal Diseases

Orthopedic disorders and musculoskeletal trauma have a significant global economic impact. Acute and chronic conditions contribute heavily to healthcare costs, particularly in Latin America. The lack of comprehensive care programs and resources in developing countries exacerbates this burden. Data from the Institute for Health Metrics Evaluation highlights low back pain as the leading cause of disability in Latin America, followed by osteoarthritis and neck pain. The aging population in the region is expected to increase the demand for orthopedic care, straining already stretched healthcare systems. Efficient resource allocation and high-grade clinical evidence are essential to avoid rationing services and increasing social disparities.

Clinical Trial Standards

The ‘good clinical practice’ (GCP) standards for clinical trials, formulated by the International Conference on Harmonization (ICH) in 1990, aim to protect human subjects and promote good science. GCP guidelines encompass all aspects of clinical trials, from communication with ethics committees to documentation and reporting, ensuring ethical and scientific rigor.

The Level of Evidence

Various classifications for clinical evidence levels exist across medical societies. In orthopedic and musculoskeletal trauma care, evidence can be directed at diagnosis, treatment, prognosis, and economic analysis. Observational cohort studies or systematic reviews of multiple cohorts often provide the highest grade of evidence when RCTs are impractical or unethical. The Spine Outcomes Research Trial (SPORT) faced cross-over issues, highlighting the challenges of achieving high-quality data in orthopedic RCTs.

Practice Recommendations

Modern clinical decision-making is guided by evidence-based practice guidelines from various orthopedic societies. Strong recommendations are based on consistent evidence from multiple studies, even if they are not all Level I. In surgical subspecialties, Level II, III, and IV studies often form the majority of evidence supporting clinical guidelines.

The Ceiling Effect

Many surgical innovations, including in orthopedics, have been implemented without high-grade clinical evidence. Examples like arthroscopic knee surgery and vertebroplasty show that lower-grade evidence, if consistent, can still guide practice. Poorly designed RCTs may not provide better evidence than well-conducted cohort studies. Tools like the Jadad score and CONSORT guidelines help assess the quality of RCTs, but the limitations of randomization in surgical trials often necessitate alternative approaches.

Randomization Challenges

Orthopedic RCTs face unique challenges, such as evolving techniques, unequal surgeon skill levels, and the inability to blind procedures. Unlike drug trials, surgical RCTs rarely progress beyond Phase II single-site studies. Ethical concerns, patient reluctance, and logistical issues further complicate these trials. Propensity scoring can help reduce bias in observational studies by balancing covariates between treated and control groups.

Potential Solutions

Given the limitations of randomized trials in orthopedics, alternative methods like propensity scoring, concurrent prospective data collection, and durability analysis can provide meaningful clinical evidence. Durability analysis, illustrated through Kaplan-Meier survival curves, helps communicate treatment benefits and manage patient expectations.

Example: Spinal Endoscopy

Endoscopic spine surgery has faced skepticism due to limited high-grade evidence. However, survival analysis has shown its benefits in certain indications. Traditional outcome tools may not fully capture patient satisfaction with endoscopic procedures. Analyzing the durability of treatment benefits provides a more comprehensive assessment of its effectiveness.

Summary

Outcome research in orthopedic and trauma surgery is limited by randomization challenges and a glass ceiling effect. Well-designed observational studies can offer higher quality evidence than poorly executed RCTs. This is particularly relevant in Latin America, where resource constraints necessitate efficient research methods. Durability analysis offers a clear, visual way to communicate treatment benefits and improve patient care.

Authors:

Kai-Uwe Lewandrowski, MD, Morgan P Lorio, MD, Albert E. Telfeian, MD, PhD, Huilin Yang MD, Ph.D.

Reference:

Breaking through the glass ceiling effect of high-grade clinical evidence creation in orthopaedics & trauma. K.-U. Lewandrowski, J. F. R. León, Á. Dowling, M. R. Garcia, J. G. Rugeles, C. Ramirez, et al. Revista Colombiana de Ortopedia y Traumatología 2022 Vol. 36 Issue 4 Pages 215-228. DOI: https://doi.org/10.1016/j.rccot.2022.10.003