The role of pragmatic clinical trials, or trials able to evaluate effectiveness of interventions in real world clinical practice, has been questioned for decades on their utility and value by regulators and policymakers. The 21st Century Cures Act tasked Food and Drug Administration with establishing guidance to industry on how to use real world evidence (RWE) to support new drug indications for currently marketed therapies.

During the 22nd annual meeting by the International Society for Pharmacoeconomics and Outcomes Research, experts debated the clinical utility and need for randomization in controlled trials. On the one hand, randomization provides an extra instrumental variable that can address potential biases due to confounding effects in order to estimate causal effects. “With the knowledge we have, it’s very risky not to have randomization” commented Robert Califf of Duke University, former commissioner of the FDA. Without randomization, treatment switching among study subjects can reduce the magnitude of the treatment effect and make causality difficult to assess. Switching of treatments, a common outcome seen in PCTs, can result in a reduced magnitude of treatment effect – a result that could negatively influence payers and providers.

Despite these challenges, the healthcare community recognizes that RCTs are unable to answer the critical questions that truly help determine value. Will the drug work in the larger population? Does the intervention improve quality of life? What are the long term impacts? PCTs help fill in these evidence gaps. “We are underperforming in areas we can do better due to the ‘legacy’ of just doing normal RCT” commented Sean Tunis of Center for Medical Technology Policy.

Experts outlined ways for PCT use in two areas. First, incorporating more pragmatic elements in study design, such as using a broader inclusion criteria, larger sample sizes, active comparators, and co-primary/secondary outcomes measures of greater relevance to patients, clinicians, and payers. Secondly, conducing a PCT in Phase IIIb prior to drug approval following a “clean” Phase III – one void of serious safety signals.

All eyes are on Europe, where a new EU directive for low intervention clinical trials (among authorized medicines) will be enacted in 2018. This directive includes less stringent adverse event reporting requirements, among others, to help reduce the administrative burden and cost thereby stimulating greater research into the appropriate uses of new medicines. The successful conduct of these low intervention clinical trials and positive reception by regulators and payers may increase PCT use in the United States.

Experts predict that the 21st Century Cures Act will drive increases in PCT use over the next decade, but changes within the next five years remains unlikely. “We’re afraid what Mr. Payer will say,” replied one manufacturer representative. “PCTs can’t answer the questions that manufacturers want answered: is there a different in effectiveness of the two treatments.”


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