Number of Seamless Clinical Trials Expands Rapidly

An increase in the number of approved cancer therapeutics has led to an associated increase in early-phase trials that have adopted a seamless approach, according to a new study.

Seamless trials are combined studies in which-instead of conducting the conventional phases I, II, and III-the trial adapts and expands based on the results of interim data, said lead author Pedro Barata, MD, MSc, experimental therapeutics fellow at the Cleveland Clinic. “First-in-human phase I studies adopting a seamless approach have the flexibility to expand rapidly with multiple cohorts, enrolling hundreds of patients in large expansion cohorts, which tends to save time in the drug development process,” he said.

Barata presented the results of the study at a press briefing at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held October 26–30 in Philadelphia.

The discovery of biomarkers, improved patient selection, and development of more effective therapies in the last decade have led to expedited drug development. Barata and colleagues conducted a multi-institutional study to evaluate seamless trials and their success by measuring the number of drugs tested in the trials included in the expedited programs run by the US Food and Drug Administration (FDA).

They reviewed all clinical trial abstracts presented at the American Society of Clinical Oncology annual meetings between 2010 and 2017. Seamless trials were defined as any early-phase studies that enrolled 100 or more patients.

Of the 1,786 phase I/II trials identified that enrolled more than 57,500 patients with malignant neoplasms, 3% (51 trials) were seamless trials, but accounted for 15% of all the patients enrolled. Seamless trials had up to 13 expansion cohorts, and data from about two-thirds of them were presented after 2014.

Some 50 investigational new drugs were tested in early studies using a seamless approach, which included targeted therapies, immunotherapies, antibody-drug conjugates, and chemotherapies, tested as single agents or in combinations.

The FDA granted accelerated approval to eight drugs, and one other agent was given priority review. “Our findings seem to confirm the higher success rate of the drugs studied with the seamless approach,” said Barata.

Of the 29 studies published, 69% of them did not have a plan for statistical analysis to calculate the sample sizes of the expansion cohorts. This limits the value of the data. “The numerous nonrandomized cohorts in each trial and modifications to the study design with multiple amendments put these studies at a higher rate for false-positive or false-negative errors compared with later-phase trials, thus affecting the validity and interpretation of the data,” said Barata.

There are potential concerns about seamless trials, including exposure of patients and drug developers to avoidable risks due to lack of safety monitoring systems; communication challenges between pharmaceutical companies, investigators, and regulators regarding frequent protocol modifications; and potential limitations with maintenance of data quality and statistical integrity.

Limitations of this study include its retrospective nature, the inclusion of studies from a single national meeting, and limited access to trial information (meeting abstracts) and not the complete trial protocols.

James Gulley, MD, PhD, director of the Medical Oncology Service, Office of the Clinical Director at the NCI, commented, “The increase in the number of seamless clinical trials is an example of another tool to help us more efficiently treat patients. We can better select patients to go on to studies and receive effective treatments.”