Compliance with legal requirement to report clinical trial results on ClinicalTrials.gov: a cohort study

Summary

Background

Failure to report the results of a clinical trial can distort the evidence base for clinical practice, breaches researchers' ethical obligations to participants, and represents an important source of research waste. The Food and Drug Administration Amendments Act (FDAAA) of 2007 now requires sponsors of applicable trials to report their results directly onto ClinicalTrials.gov within 1 year of completion. The first trials covered by the Final Rule of this act became due to report results in January, 2018. In this cohort study, we set out to assess compliance.

Methods

We downloaded data for all registered trials on ClinicalTrials.gov each month from March, 2018, to September, 2019. All cross-sectional analyses in this manuscript were performed on data extracted from ClinicalTrials.gov on Sept 16, 2019; monthly trends analysis used archived data closest to the 15th day of each month from March, 2018, to September, 2019. Our study cohort included all applicable trials due to report results under FDAAA. We excluded all non-applicable trials, those not yet due to report, and those given a certificate allowing for delayed reporting. A trial was considered reported if results had been submitted and were either publicly available, or undergoing quality control review at ClinicalTrials.gov. A trial was considered compliant if these results were submitted within 1 year of the primary completion date, as required by the legislation. We described compliance with the FDAAA 2007 Final Rule, assessed trial characteristics associated with results reporting using logistic regression models, described sponsor-level reporting, examined trends in reporting, and described time-to-report using the Kaplan-Meier method.

Findings

4209 trials were due to report results; 1722 (40·9%; 95% CI 39·4–42·2) did so within the 1-year deadline. 2686 (63·8%; 62·4–65·3) trials had results submitted at any time. Compliance has not improved since July, 2018. Industry sponsors were significantly more likely to be compliant than non-industry, non-US Government sponsors (odds ratio [OR] 3·08 [95% CI 2·52–3·77]), and sponsors running large numbers of trials were significantly more likely to be compliant than smaller sponsors (OR 11·84 [9·36–14·99]). The median delay from primary completion date to submission date was 424 days (95% CI 412–435), 59 days higher than the legal reporting requirement of 1 year.

Interpretation

Compliance with the FDAAA 2007 is poor, and not improving. To our knowledge, this is the first study to fully assess compliance with the Final Rule of the FDAAA 2007. Poor compliance is likely to reflect lack of enforcement by regulators. Effective enforcement and action from sponsors is needed; until then, open public audit of compliance for each individual sponsor may help. We will maintain updated compliance data for each individual sponsor and trial at fdaaa.trialstracker.net.

Funding

Laura and John Arnold Foundation.

Introduction

Non-reporting of clinical trials can distort the evidence base for clinical practice, breaches researchers' ethical obligations to participants, and represents an important source of research waste.¹ The imperative to report all clinical trial results is widely recognised, for example by WHO and the Declaration of Helsinki.2, 3 Cohort studies have historically shown that the results of clinical trials are routinely left unpublished.4, 5 However, new laws in the USA and EU now require results of certain trials to be reported rapidly in tabular form onto a clinical trial registry, in addition to any other potentially slower forms of dissemination such as journal publication.6, 7, 8

The Food and Drug Administration Amendments Act (FDAAA) of 2007 is a US law that requires certain interventional clinical trials to report their results directly to the US trial registry ClinicalTrials.gov, within 1 year of the primary completion date (the date of the last participant's final follow-up visit for measurement of the final primary outcome). The US research community generates a large proportion of global trials, and ClinicalTrials.gov is the largest registry in the world; additionally, as of November, 2019, half of the ten largest pharmaceutical companies in the world are based in the USA. This legislation therefore has the potential to substantially improve trial reporting.9, 10 Since its passage in 2007, competing interpretations of the FDAAA have created confusion over which trials are required to report, and undermined independent assessment of FDAAA compliance.11, 12, 13

Research in context

Evidence before this study

Non-reporting of clinical trial results has been well documented for several decades, and represents a substantial threat to the integrity of the evidence base for all of clinical medicine. The Food and Drug Administration Amendments Act (FDAAA) of 2007 aimed to address this issue. Previous studies examining compliance were hindered by ambiguities in the legislation and incomplete data that blocked identification of applicable trials; most studies only included small subsets of trials. The Final Rule clarifying the Act was implemented in 2017. A search of PubMed and Google Scholar for “FDA Amendments Act” finds no complete assessment of compliance with the Final Rule. Compliance with similar new EU rules on trial reporting was assessed in 2018 and was found to be poor, with only 3601 (49·5%) of 7274 trials reporting results.

Added value of this study

To our knowledge, this is the first study to assess compliance with the Final Rule of the FDAAA of 2007. This law was widely celebrated as a solution to the problems of publication bias and clinical trial reporting. Our findings raise important questions around lack of enforcement and the need for public accountability. All our data and software for downloading, processing, and analysing raw data are shared openly for independent review and re-use; this is the gold standard for reproducibility and facilitates other researchers in the field. We will maintain updated compliance data for each individual sponsor and trial at fdaaa.trialstracker.net as an open public service to help sponsors who aim to comply fully with the law.

Implications of all the available evidence

The FDAAA 2007 was reasonably expected to ensure results reporting for the large number of trials conducted under the regulatory authority of the USA. Using data extracted from ClinicalTrials.gov up to Sept 16, 2019, our findings show that compliance has been poor and is not improving. It is encouraging to note that results reporting is more common among trials with an industry sponsor, and among those conducted by a sponsor with a large number of registered trials. This suggests that research experience and robust internal governance processes can contribute to improved performance. However, with 2487 trials conservatively identified as breaching the law in our study, it is concerning to note there has been no enforcement by the FDA to date. Action by regulators would improve compliance; until then, public accountability through tools such as fdaaa.trialstracker.net could help.

US legislation typically requires rule-making by relevant executive agencies to fully clarify and implement all or parts of a law. This process involves the proposal of a draft rule, an open public comment period, and finally the publication of a Final Rule in the US Federal Register. The Final Rule of Clinical Trials Registration and Results Information Submission was proposed by the US Department of Health and Human Services in 2015, and published in the Federal Register in late 2016 for implementation in January, 2017, a full decade after passage of the FDAAA 2007.¹⁴ This Final Rule specifically clarified which trials are covered by the FDAAA 2007, when and how they should register and report, and which trials can request delays.15, 16 The characteristics of trials covered by the legislation were robustly described using unambiguous inclusion criteria with direct links to data fields on ClinicalTrials.gov. The FDA was also empowered to enforce the law by levying fines greater than US$10 000 per day on the sponsor of each trial for non-compliance.¹⁴

The first trials covered by this new and improved legal regime became due in January, 2018. In this cohort study, we set out to describe the extent of compliance with the FDAAA 2007 trial reporting rules, describe compliance at the level of individual sponsors, and explore factors associated with compliance.