As pressure increases on the pharmaceutical industry and its regulators to speed up the drug development and approvals process without compromising on safety, seamless clinical trials are garnering attention.
Instead of the conventional phases I, II and III, seamless trials are combined studies, which can be adapted based on interim results, and have the flexibility to expand rapidly with multiple cohorts, saving time in the drug development process.
US Food and Drug Administration (FDA) commissioner Scott Gottlieb has spoken encouragingly about the approach, and the number of seamless trials in the oncology space has spiked over recent years. A total of 51 studies have been presented at the American Society of Clinical Oncology (ASCO) since 2010, two thirds of those after 2014.
Research has also shown that this increase in seamless trials, defined as early phase studies with more than 100 enrolled patients, has corresponded with a higher rate of drug approvals.
According to a multi-institutional study designed to evaluate the prevalence of seamless clinical trials in oncology, describe their characteristics and determine their success rate, accelerated approval was granted by the FDA for 16% of seamless trials, a big improvement on the estimated overall approval rates for oncology drugs. Only 5% that enter human testing are ultimately approved by the FDA.
“One, if not the utmost advantage of the seamless approach is the compressed development timeline from first-in-human testing to approval of the drug, potentially saving several years and thus allowing highly effective therapies to become available to patients much faster,” says study leader Dr Pedro Barata, an experimental therapeutics fellow at the Cleveland Clinic in Ohio.
Additional benefits include longer-term safety data being accumulated earlier in the development process and stronger data on dose selection and efficacy earlier in the trial.
While the focus of Barata’s study was oncology, there is also scope for the seamless approach to be used beyond cancer drug development.
“In diseases lacking effective treatments, and where patient outcomes are still poor – for example, some neurodegenerative conditions, progressive auto-immune disorders and genetic conditions – seamless designs may help to expedite drug development and potentially allow patients to have access to these therapies sooner,” Barata says.
Speaking at a regulatory conference in September last year, Gottlieb also noted that seamless trials could be expanded beyond oncology as part of a broader plan for the agency to reduce drug development costs in the clinical phase.
“Seamless designs are particularly advantageous for drugs that work in a variety of diseases, allowing rapid evaluation of the drug and potential approval under our accelerated approval pathway,” Gottlieb said. “These new approaches are also highly consistent with the goals of the 21st Century Cures Act and the recently passed FDA Reauthorization Act.”
He also announced that the agency would “begin work” on at least ten new disease-specific development guidance documents over the next year. These will include areas of unmet medical need, such as amyotrophic lateral sclerosis.
Use with caution
While the study carried out by Barata and his colleagues clearly showed high approval rates for oncology drugs studied in seamless clinical trials, it also identified a number of concerns with the approach.
One noteworthy finding was the fact that the design of these studies includes multiple expansion cohorts and that a planned statistical analysis for the calculation of the sample size was frequently absent.
“Whenever a pre-planned statistical plan is missing, the value of data is limited, being simply descriptive and demanding further validation,” Barata says. “The multiple non-randomised cohorts in each trial and modifying the study design with multiple amendments puts the study at a higher rate of false positive or false negative errors compared with later-phase trials, thus affecting the validity and interpretation of the data.”
Other concerns included the potential exposure of patients and drug developers to avoidable risks due to the lack of a safety monitoring system and communication challenges between pharma companies and regulators when protocols are being frequently modified.
“I think these designs must be used with caution while some of the potential risks and limitations are addressed,” Barata advises. “There is a multi-institutional effort working on ways to address the challenges of these studies and come up with solutions to improve the design and conduction of clinical trials. Hopefully, these recommendations will be published soon and universally adopted by the key players in this field.”
Are traditional trials on their way out?
There’s no danger of traditional trials becoming obsolete any time soon, according to Barata. “I think there will be still a role for traditional trials and we will learn how to use the right trial design for the right drug,” he says.
“Maybe for areas/diseases that lack effective agents and outcomes of those patients are still poor, there is a greater pressure to come up with effective therapies in a faster way – in those diseases, programmes to expedite drug development will continue to support the use of these type of designs.
“I predict that the seamless designs will continue to be increasingly used in drug development, hopefully with better ‘rules of conduct’ to avoid unnecessary risks for patients while we allow very effective novel anti-cancer therapies to become available to patients much faster.”