ideasIdea
After approval, a pragmatic trial in the patients the pivotal trial excluded
Drugs are approved on trials of fit, younger patients and then given to everyone. A required follow-on trial in older, sicker and more diverse patients would show whether the benefit holds in real life.
As a condition of approval, sponsors fund a pragmatic randomised trial with broad eligibility run in community settings, using routinely collected endpoints (OS, hospitalisation, treatment discontinuation) and minimal extra visits, modelled on the FDA's Project Pragmatica and the Pragmatica-Lung trial. Results feed label updates on dosing and benefit in the broader population.
Hypothesis
Pragmatic confirmatory trials will show a smaller but still positive effect in most cases and will identify at least some approved regimens whose benefit does not extend to the real-world population, leading to label changes.
Rationale
Real-world outcomes are often worse than trial outcomes, and it is unknown how much is due to population differences versus care. Only randomisation in the broad population resolves this.
What would test it
Track Pragmatica-Lung and the next five such trials for enrolment speed, cost per patient and concordance with the pivotal effect size.
Maturity
early clinical
Who has to act
regulator
Cost to try
Large (over $50M)
Years to first evidence
4
Bottlenecks it attacks
- Trial design, endpoints and cost · A phase 3 trial takes years and hundreds of millions of dollars, and often answers a question that has already moved on.
- Weak real-world evidence and registries · We do not reliably know what happens to patients after approval, so we cannot tell which drugs deliver in practice.
- Older and multimorbid patients are excluded and undertreated · Most people with cancer are over 65 but most trial patients are younger and fitter. We guess how to treat the majority.