Nick DeVito and Ben Goldacre
Today we describe a trial that reported late, in breach of the FDA Amendments Act 2007. This late reporting is especially notable, because the FDA themselves are a collaborator on the trial in question. The FDA can impose a fine of $10,000 a day for every overdue or unreported trial, and today’s trial was left unreported for 82 days. The FDA issuing (or not issuing) fines on a trial for which they are a collaborator raises interesting issues around conflict of interest.
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. Each week we write about one unreported clinical trial: you can read more background here
, and past entries are here
This week’s late reported trial is titled “A multi-center, randomized study of cyclosporine or corticosteroids as an adjunct to plasma exchange in the initial therapy of thrombotic thrombocytopenic purpura” (NCT00713193
). This phase 3 trial had an enrollment of 16 participants according to the registry entry. Participants with thrombotic thrombocytopenic purpura were randomly assigned to receive either cyclosporine or prednisone as an adjunct to plasma therapy. The primary outcome was frequency of exacerbations over 30 days. The secondary outcome was the number of exchange procedures to achieve clinical remission and the relapse rate after tapering the adjuvant immune-based therapy over 2-5 years.
Thrombotic thrombocytopenic purpura is a blood disorder
in which clots form in blood vessels throughout the body leading to oxygen deprivation to various organs, bleeding issues, and skin blemishes. Thrombotic thrombocytopenic purpura is rare, with incidence estimates ranging
from “between 1 and 13 cases per million people depending on geographic location.” Untreated thrombotic thrombocytopenic purpura, however, is usually fatal and even successful treatment can lead to relapses. Standard treatment is plasma exchange therapy with high dose corticosteroids such as prednisone. This trial examines whether cyclosporine, an immunosuppressant in use since the 1980s, could be an effective adjunct to plasma therapy treatment compared to the standard use of prednisone as an adjunct.
During the writing of this piece, the sponsor submitted results to ClinicalTrials.gov on 11 December 2018. Under the FDAAA requirements to report within 1 year of the primary completion date, it was 82 days late to report. Although we usually focus on unreported trials, we felt this trial still warranted discussion given the collaborator and topics involved. While results have been submitted (very late) the quality control process for this submission means it will likely be a month or more before actual results are available on ClinicalTrials.gov.
This trial has an academic sponsor, Ohio State University, who are responsible for ensuring that the trial is reported on-time, but notably a collaborator is listed: The FDA. In this case, the FDA was the funder of this research via the FDA Office of Orphan Products Development. The FDA resources for Orphan Product Clinical Trials Grants Program
note that funded research is required to maintain their regulatory responsibilities, which for this trial would include reporting results to ClinicalTrials.gov
within one year of primary completion.
The US Food and Drug Administration (FDA) is charged with enforcing compliance with the FDA Amendments Act of 2007, including the trial reporting provisions detailed in the final rule
. Once a sponsor is informed of a breach, they have 30 days to comply or face potential fines in excess of $10,000 a day the trial remains unreported. Of note, this is $10,000 a day in 2007 money, which is over $11,600 today. For this trial that was 82 days late, they could have imposed fines of $601,588.
To date, concerningly, the FDA have never issued a single fine on any breaching trial. Our data at fdaaa.trialstracker.net
as of 20 December 2018 shows that they could have imposed fines of over $1.3billion to date. Recently the FDA released draft guidance
on how they plan to enact enforcement activities and invited comment. The AllTrials campaign submitted a comment
, along with many others, supporting effective enforcement action by the agency.
We have previously explained how the law views journal publications, rather than registry reporting. A journal article detailing this trial was published in 2017. This publication does not meet the FDAAA 2007 reporting requirements. The law requires sponsors to post results directly onto the register, and for good reason: while journals have repeatedly been shown to breach reporting guidelines such as CONSORT, registry reports require you to give data on all prespecified outcomes. The published evidence to date shows that registry reports are more complete than journal publications.
Indeed, the journal publication associated with this trial exemplifies some of the issues around reporting, and raises some additional questions about the registration and results of this trial. While the journal article refers to the trial registration explicitly, much of the information provided is incongruent with the registry entry for this trial. This means the registration is either incorrect or out of date, either of which is also a violation of the FDAAA 2007. For example:
shows an actual enrollment of 16 participants; the journal article states 26 were enrolled and treated.
entry lists the trial status as “Completed” while the article states that “the study was halted after a planned interim analysis.” This means it should be listed as “Terminated” with the rationale for termination provided on ClinicalTrials.gov
The primary outcome, measuring exacerbations between the two arms, match. The secondary outcomes, however, do not match. The paper reports “the effect of each immunosuppressive therapy on ADAMTS13 biomarkers in the context of clinical response criteria” while the registry lists the “number of exchange procedures to achieve clinical remission and the relapse rate after tapering the adjuvant immune-based therapy.” This was a long-term outcome, so it may have been impossible to measure, given the termination of the study: but this is not addressed in the manuscript (CONSORT requires all outcome switches to be flagged and explained). Meanwhile ADAMTS13 biomarker measures are reported in the paper, but never mentioned in the registry entry (again, CONSORT permits additional non-prespecified outcomes, but only if they are flagged as such, and explained).
These discrepancies above show the importance of a properly maintained registry entry along with full reporting of results, on the register, in accordance with the law. It is concerning that the FDA, the organisation in charge of ensuring compliance with the whole of the FDAAA 2007, is the funder of research that has failed to meet registration and reporting requirements.
This late reporting trial was sponsored by Ohio State University in collaboration with FDA. The PI is Dr. Spero R Cataland. As of 11 December 2018, this trial submitted results 82 days late and will likely not be available for public viewing until well over 100 days after it was due to report results, and more than 465 days after it completed.
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.