Georgia Richards, Nick Devito, and Ben Goldacre

Background

The US FDA Amendments Act (FDAAA 2007) requires certain clinical trials to report their results onto ClinicalTrials.gov within one year of completion. European Union (EU) guidelines are broader: they require all trials of medicinal products registered on their EU Clinical Trials Registry (EUCTR) since 2004 to report results within one year of completion. Our FDAAA TrialsTracker and EU TrialsTracker show all individual trials that breach these legal requirements. In each episode from this series we write about one unreported clinical trial: you can read more background here, and past entries are here.

Trial NCT02633969

This week’s unreported trial is titled: “Study of Indomethacin Capsules to Treat Pain Following Surgery in Children Ages 6 to <17 Years of Age” (NCT02633969). This non-randomised Phase IIA clinical trial enrolled 30 children who were scheduled to undergo elective surgery across five states. The study was not blinded and used a parallel assignment, where two experimental groups received the same treatment (Indomethacin Capsules twice daily for up to three days) but at different doses: group 1 received “low dose”, and group 2 received “high dose”. The primary outcome was plasma concentrations of Indomethacin 0-12 hours after the first dose using the “estimated typical value for clearance (tvCL)”. The secondary outcome was the safety of Indomethacin Capsules at “low dose” and “high dose” measured by the incidence of adverse events from baseline to Day 3 or early termination.

Clinical discussion

Pain is common in hospitalised children with 99% of paediatric patients who receive surgery reporting pain. Treatment options and dosing for postoperative pain in children can be challenging. The European Society for Paediatric Anaesthesiology (ESPA) recommends ibuprofen, diclofenac, or paracetamol as oral treatment options for systematic analgesia. Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID) like ibuprofen and diclofenac that reduces pain by decreasing the formation of prostaglandins.

A Cochrane systematic review of indomethacin for the treatment of acute postoperative pain in adults (over 12 years old) was published in 2004. They found only one study of 59 women that met the inclusion criteria and concluded indomethacin was “not significantly better than placebo in relieving postoperative pain”. The review was updated in 2007 and identified no further studies. The authors state “conclusions about the clinical efficacy… cannot be made unless more studies are conducted for a variety of surgical procedures, and different doses… are assessed”. The review also recommended that appropriate study designs (such as a randomised, double-blind, placebo-controlled trial) are needed.

Legislative discussion

We intend that this series should occasionally shed light on interesting issues around transparency rules, and how registry data is used. You can read some general background about the FDA Amendments Act 2007—and why a trial is considered “due”—here and here.

This study’s sponsor currently has FDA approval for 20mg and 40mg doses of indomethacin in adults. This trial was conducted in an entirely paediatric population. While we do not know the motivations behind this trial it is possible that the sponsor is seeking to expand the indication of their treatment to include children, or expand their patent protection, or perhaps both. In any case, we suggest that the non-reporting of this clinical trial should be considered in future regulatory decisions regarding this treatment, and that the relevant authority should insist the sponsor complies with FDAAA 2007 and its requirement to report trial results within 12 months of completion.

Furthermore, while publication in an academic journal does not meet the legal requirements of the FDAAA 2007, no publication related to this study could be found when searching Google, Google Scholar or Pubmed. With the lack of evidence for or against the use of oral indomethacin for the treatment of acute postoperative pain, it is vital that this unreported trial publishes its results in accordance with the legal requirements of the FDAAA 2007: especially since the study is in children, a population where managing pain after surgery is challenging.

Conclusion

This unreported trial was sponsored and conducted by Iroko Pharmaceuticals with no specific PI identified. As of October 24, 2018, this trial is currently 266 days overdue to report. We hope the investigators will share the results of this trial soon.

Georgia C Richards is a doctoral researcher at the Centre for Evidence Based Medicine at the University of Oxford.

Competing interests: GCR is a joint NHS National Institute of Health Research (NIHR) School for Primary Care Research (SPCR), Naji Foundation, and Rotary Foundation Scholar, studying for a doctor of Philosophy (DPhil/PhD) at the University of Oxford.

Ben Goldacre is a doctor, author, and director of the EBM DataLab at the University of Oxford. He co-founded the AllTrials campaign for trials transparency.

Competing interests: BG has received research funding from the Laura and John Arnold Foundation, the Wellcome Trust, the Oxford Biomedical Research Centre, the NHS National Institute for Health Research School of Primary Care Research, the Health Foundation, and the World Health Organization; he also receives personal income from speaking and writing for lay audiences on the misuse of science.

Nicholas J DeVito is a researcher at the EBM Datalab at the University of Oxford.

Competing interests: ND is employed on BG’s LJAF grant and is a Naji Foundation scholar at the University of Oxford.