‘Are we there yet?’ / The utility of alternative clinical trial designs in surgical research

In research assessing new surgical interventions, the standard method of randomized controlled trials is hampered by many difficulties, including poor recruitment, high patient dropout in the control group, and high costs. In a review published in Annals of Surgery, researchers from Cancer Center Amsterdam and UMC Utrecht weigh the pros and cons of new alternative clinical trial designs that attempt to overcome these difficulties.

Clinical trials that compare the use of different surgical techniques are classically structured as randomized trials (RCTs). In this study design, patients are chosen at random to either receive the new method under investigation (experimental group) or the standard treatment (control group). Because all patients are different, randomization serves to minimize bias and maximize statistical power.

“RCTs typically yield the highest level of evidence, but in surgical research RCTs are notoriously difficult to perform,” explains MD-PhD candidate Simone Augustinus. “Surgical RCTs can be hampered by poor recruitment, high patient dropout in the control group, the surgical learning curve, lack of blinding, and lack of financial support.”

New study designs for more efficient research

Alternative RCT designs that may overcome several of these difficulties include:

Stepped-wedge RCTs (SW-RCTs), in which groups or ‘clusters’ of participants receive the intervention at different time points in a random order;
Registry-based RCTs (RB-RCTs) uses data from existing nationwide clinical registries for treatment and outcome data; and
Trials-within-cohorts (TwiCs) where participants sign a broad informed consent for studies using this design before enrollment to the registry, and are consequently randomized assigned to the treatment or intervention group when meeting the inclusion criteria. Only patients who are randomized to the intervention arm sign an additional informed consent.

In the first systematic review of alternative RCT designs in surgical research, Simone and her collaborators found the use of these new designs exponentially increased over the last seven years. The work was published in Annals of Surgery, the world’s most highly referenced surgery journal.

Opportunities and guidelines

“If adequately used, these alternative and innovative trial designs provide the opportunity to overcome specific difficulties associated with surgical research,” says Simone. “This can make sure more efficient research can be done for patients with cancer.”

The authors discuss the advantages and limitations of the new experimental designs and call for the development of guidelines to help researchers assess the suitability of the alternative trial designs on a case-by-case basis.

“Researchers need to consider the specific challenges relevant for their study,” says Simone. She also notes that the new methods do not address all of the difficulties involved, such as the surgical learning curve.

The review is the first to provide an overview of the use, value, and suitability of alternative RCT designs in surgical research.

For more information contact Simone Augustinus, or read the scientific publication: Augustinus, S.M.D., et al. (2022) Alternative Randomized Trial Designs in Surgery: A Systematic Review. Annals of Surgery 276, p. 753-760. Doi: 10.1097/SLA.0000000000005620

People involved at Amsterdam UMC:

Simone Augustinus

Johannes Berkhof

Tara Mackay

Peter van de Ven (UMC Utrecht & Amsterdam UMC)

Marc Besselink

Text by Laura Roy.