Brian MacKenna, Nicholas 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. Our FDAAA TrialsTracker shows all individual trials that breach this legal requirement. Once a week, we write about one unreported clinical trial: you can read more background here.

Trial NCT01656733

This week’s unreported trial is titled: Nicotine Replacement for Smoking Cessation During Pregnancy (NCT01656733). This phase 4 trial enrolled 154 participants smoking at least 5 cigarettes per day. All received behavioural counselling. Participants were randomised to receive a 6-week course of treatment with either nicotine replacement therapy (NRT) via an inhaler, or placebo, followed by a 6-week taper. The primary outcome was 7-day smoking prevalence at 32-34 weeks gestation; secondary outcomes included birth weight, exhaled carbon monoxide and cigarettes smoked per day.

Clinical discussion

The NHS advises that smoking during pregnancy can lead to increased risk of premature delivery, miscarriage, stillbirth, or sudden infant death, and that quitting smoking is one of the best things a mother can do for her baby. NICE guidance states that there is mixed evidence on the effectiveness of NRT in helping women to quit during pregnancy, but does recommend that NRT can be offered after discussion on risks and benefits. The Royal College of Gynaecologists supports this advice by advising pregnant women that NRT is safer than smoking.

A Cochrane review in 2015 found that there is borderline evidence to suggest that NRT combined with behavioural support might help women to stop smoking in later pregnancy, but there was insufficient evidence to conclude whether or not NRT had either positive or negative impacts on rates of miscarriage, stillbirth, premature delivery  or birth weight. They identified that placebo-controlled trials, such as this unreported trial, are needed.

Legislative discussion

We intend that this series should occasionally shed light on interesting issues around transparency rules. Here we describe an interesting example of dates being repeatedly changed on a trial’s registry entry. When a study is registered, the sponsor must include an anticipated primary completion date if the actual primary completion date for the study is not yet known. The anticipated date must then be updated within 30 days of the trial reaching its actual primary completion date. Clinicaltrials.gov maintains an archive for every trial reflecting any amendments to the trial record. The registry record for this trial has been amended a number of times. Notably the sponsor has provided three different “actual” primary completion dates since August 2017. These range from “June 2, 2016” to “July 2, 2017.”

In our view this is an example of poor data stewardship by the trial sponsor and PI. While some allowance should be made for the corrections of mistakes, repeated major changes to the primary completion date once it has been marked as “actual” are confusing for anyone reviewing the trial record. More importantly, if registry data is not current and accurate, then the rules around timely trial reporting cannot be enforced, and compliance cannot be assessed. This can only perpetuate the problems around non-reporting of trial results, and publication bias.

Conclusion

This unreported trial was sponsored by UConn Health in collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), a part of the NIH. Pfizer provided in-kind support in the form of free inhalers. The study PI is Cheryl Oncken MD MPH  of UConn Health. As of 20 August 2018, this trial is 49 days overdue to report. We hope the investigators will share the results of this trial soon.

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.

 

Brian MacKenna is an honorary research fellow pharmacist at the EBM Datalab at the University of Oxford.

Competing interests: BMK works for NHS England as a pharmacist adviser and all other declarations can be read here.