What the US statute requires of a trial's registration and results
In the United States, the Food and Drug Administration Amendments Act of 2007 requires certain clinical trials to be registered on ClinicalTrials.gov and their summary results to be posted there. Later requirements, its Final Rule among them, have extended which trials must post results and what must be submitted. A bill proposed in 2012 and 2013 would have extended these duties to further trials.
Which trials the Act covers and who must post
The FDA Amendments Act of 2007 required certain applicable clinical trials to be registered at initiation and to report summary results on ClinicalTrials.gov after completion. It required trial sponsors to reveal trial results to participants and patients, physicians and independent researchers. The law was intended to facilitate enrolment, allow the trials' progress to be tracked and address the lack of timely dissemination of research findings. In general, an applicable trial is a controlled clinical investigation, other than a Phase 1 investigation, of an FDA-regulated drug, biologic or device. A controlled clinical investigation generally includes interventional studies, with one or more arms, that have one or more US sites, are conducted under an investigational new drug application or device exemption, or involve a product manufactured in the US and exported for research. ClinicalTrials.gov has a checklist for deciding which trials are applicable.
Posting is a statutory mandate for the sponsors and others, namely principal investigators, responsible for certain clinical trials of FDA-regulated drugs, biologics and devices. The mandate is independent of any decision to publish a manuscript.
Registration
Before 2007, posting study methodology on ClinicalTrials.gov had been optional. Registration has been required since September 2007 for applicable trials initiated after 27 September 2007, or initiated on or before that date and still ongoing on 26 December 2007. A 2020 account has registration due no later than 21 days after the first participant is enrolled. Accounts from 2014 and 2018 instead have a trial's protocol elements, or methods, posted before the study can begin.
The registration summarises the protocol, such as its brief title, design, study type, phase, primary outcome measure and eligibility criteria, and the recruitment, such as the enrolment start and completion dates, locations and overall recruitment status. Its required content also includes contact information and administrative data elements.
Results
Section 801 of the Act requires results for applicable clinical trials no later than twelve months after the primary completion date. The primary completion date is the date the final participant was examined or received an intervention for the final collection of data for the primary outcome, whether the study concluded according to the pre-specified protocol or was terminated. Where there is more than one primary outcome measure with different completion dates, it is the date on which data collection is completed for all of them. Results may then need to be updated after the study completion date, which is defined in the same way but for the primary and secondary outcome measures and adverse events, for example the last participant's last visit. Results are submitted either after the primary completion date, if they are partial, or after study completion. If the primary completion date and the study completion date fall close together, it may be possible to submit one record within the twelve-month deadline.
Results disclosure on ClinicalTrials.gov may be delayed by submitting a certification that the trial reached its study completion date before the drug, biologic or device was initially approved, licensed or cleared by the FDA for any use, or that the trial investigates a new use not included in the labelling. A request to extend the deadline for submission of results for good cause can also be made.
From September 2008, summary results were due for trials of approved products within 12 months of the primary completion date. Two accounts, from 2014 and 2018, instead count the 12 months for an already approved drug from study completion. In the 2014 account, this requirement covers phase 2 to phase 4 studies, and the results, including adverse events and a brief abstract, have to be posted whether or not a publication exists. Under the requirements as revised in 2017, results for a drug not yet approved have to be posted within 30 days of approval.
From September 2009, summary results had to include certain adverse event information. As of 2013, the Act's reporting requirements included a 500-word abstract and summary data tables of baseline characteristics, participant flow, outcomes and adverse events, with no narrative, discussion or conclusion. One medical-affairs director at a pharmaceutical company, speaking in 2013, judged them minimal. Presented in tables, this information is not always interpretable to clinicians and patients.
The Final Rule and later requirements
The Final Rule on clinical trials registration and results information sharing, for section 801 of the Act, took effect on 18 January 2017. The US Department of Health and Human Services published it in September 2016. It mandates registration and the submission of summary results on ClinicalTrials.gov for certain clinical trials of drugs, including biological products, and devices. It clarified which studies have to post, expanded the transparency requirements of posting beyond the basic statutory requirements, and required the National Institutes of Health to post submitted records within specified time frames. It extended results submission to trials of products that are not approved, licensed or cleared, which eased concerns about bias in the literature and the possible selective publication of only approved products.
From January 2019, sponsors have had to state whether there is a plan to make the individual participant data, including data dictionaries, available to other researchers. Results first submitted on or after 1 January 2020 for trials starting on or after 18 January 2017 are posted publicly within 30 days of submission, whether or not the registry's quality-control review is finished. The posting includes any comments identifying a major issue and a note that review has not concluded, and every version of the reviewed record is then posted until the review concludes.
Consequences of not posting
Responsible parties that fail to post, including the grantee institution, can be held accountable for non-compliance, and grant funding from Health and Human Services agencies can be withheld. Non-compliance can bring substantial civil monetary penalties and criminal proceedings. Under the requirements as revised in 2017, failing to comply can incur a penalty of $10,000 a day past the statutory deadline.
The bill that would have extended the Act
In August 2012 Ed Markey, then a US representative and later a senator, proposed the Trial and Experimental Studies Transparency Act to expand the registration and reporting requirements of the 2007 Act, and the bill was reintroduced in May 2013. As proposed, the bill would:
- require registration of all interventional studies of drugs, biologics and devices before the first participant is enrolled, regardless of phase (Phase 1 included), design (single-group trials included) or approval status
- strengthen the requirement to post results on ClinicalTrials.gov within one year of trial completion, irrespective of approval status
- require all foreign trials used to support US marketing to be registered and to comply with the reporting requirements: 80% of drugs entering the US market had been clinically tested overseas but had not been required to register
- mandate results for medical interventions never approved for any indication, while allowing their submission to be delayed up to two years after completion
- require results reporting whether or not an application is submitted to the FDA, so that adverse outcomes would be posted even for a product its manufacturer abandoned, alerting others to potential dangers and putative toxic effects that would warrant monitoring of that class of agents
- improve the transparency of results, so that companies are less able to hide negative study results, safety signals and adverse events
One concern was that the bill would increase rather than decrease publication bias. Sponsors may feel less compelled to publish results because the basic results would already be in the public domain as a data dump without interpretative value for patients. Time pressure and a desire for low visibility may also result in more positive trials being submitted quickly to journals while negative ones are posted on the register. Another concern was the effect on journals: if they accept manuscripts after public posting, it may affect how their publications are scored in Journal Citation Reports.
Observational safety data
Neither the 2007 Act nor the proposed bill mentions the need to post observational safety data, even though drug safety registries are often mandated as a postmarketing commitment. Nor does either address publishing mandated observational safety data in peer-reviewed journals, which one medical-affairs director at a pharmaceutical company, speaking in 2013, held to be a compelling need.