Intended for healthcare professionals


Trials that say “maybe”: the disconnect between exploratory and confirmatory testing after drug approval

BMJ 2018; 360 doi: (Published 20 March 2018) Cite this as: BMJ 2018;360:k959
  1. Benjamin Carlisle, PhD student,
  2. Carole A Federico, PhD student,
  3. Jonathan Kimmelman, associate professor
  1. Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, 3647 rue Peel, Montreal QC H3A 1X1, Canada
  1. Correspondence to: J Kimmelman jonathan.kimmelman{at}

Clinical trials that explore the repurposing of drugs for off-label uses are common. But without a commitment to rigorously testing the hypotheses generated by these exploratory trials, patients are put in harm’s way, argue Benjamin Carlisle and colleagues

Key messages

  • After a new drug receives approval, companies and public sponsors often run numerous small trials exploring the drug’s activity in different indications

  • The level of evidence produced in such trials is usually low, and drug companies and public sponsors often fail to follow up on promising exploratory findings by running large, confirmatory trials

  • The poor uptake of confirmatory testing often results in prolonged periods where ineffective and costly drugs are used off-label; the sacrifice of patients who participated in the original small trials goes unrealised

  • Ethics committees and policy makers should devise measures that encourage better coordination between exploratory and confirmatory trials after drugs are approved

Most clinical trials are directed not towards getting new drugs approved but at repurposing already licensed drugs for new applications.1 When drugs are first licensed, companies, public funders, and medical centres often mount vigorous trial programmes exploring a drug’s activity in other indications or in combination with other treatments. These studies generate myriad hypotheses about possible treatment options for patients.

This uncertainty about clinical value, which we call “clinical agnosticism,”2 provides grounds for rigorous, hypothesis testing trials. But, as we describe below, confirmatory trials are often not swiftly performed. This delay has ethical implications: the sacrifice of research volunteers in exploratory studies goes unappreciated, and other patients and healthcare systems are at risk of using ineffective and unsafe treatments for many years.

How post-license trials create clinical agnosticism

The primary aim of exploratory trials (typically phase I and II trials) is to produce evidence that a new treatment might be effective and might compete with standard of care. Favourable results …

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