For two decades companies and scientists have been obliged to post information and results of clinical trials on the US federal website clintrials.gov from the FDAAA 2007 act. This is part of the effort to get more transparency, more data made available to the public and to be sure that failed or unsuccessful studies are made public.
This has not been happening as much as had been hoped and expected.
In 2017 Health and Human Services issued a final rule (42CFR11) went into effect in January 2018. This rule listed the requirements and had FAQs covering the details of clintrials.gov. It covered almost all studies done in the US and some abroad. Studies underway were to be listed with protocols or summaries of the study. Results were required to be submitted within 1 year of study completion. See https://clinicaltrials.gov/ct2/manage-recs/fdaaa for details. Penalties for failure to comply included fines of up to $12,103 per day. Originally $10,000 but with adjustments for inflation.
On January 13, 2020 the journal Science published an article entitled “FDA and NIH let clinical trial sponsors keep results secret and break the law”. As the title suggests, compliance with the HHS rule have not been good.
Of the 4700 trials noted in the article, 44.7% were reported on time, 31.6% were not reported at all and 24% were reported late. Science notes that through September 2019, for sponsors with at least 5 trials, thirty companies, universities and medical centers never met a single deadline. In fact, these organizations failed to report any results for 67% of their trials and averaged 268 days late for those they did report.
Late or non-reported trials were seen from major academic institutions such as MD Anderson, Mass General, Mayo Clinic, UCSF, U of Chicago, U of VA, NY State Psychiatric Institute, Yale, Dana Farber, Mt. Sinai as well as federal institutions including the National Cancer Institute, National Institute of Allergy and Infectious Diseases, VA Office of Research and the National Heart, Lung and Blood Institute. Average late reporting was up to 214 days.
Several major industry organizations had a much better reporting record with several having no late or missed reporting studies: Allergen, Amgen BMS, Alcon, Abbvie, Boehringer Ingelheim, J&J and Bayer. Others had a few late studies but no unreported studies. Twenty big pharma companies met all requirements. Average late reporting was much better compared to the 2017 data. Several institutions improved their reporting compared to 2017 included Memorial Sloan Kettering, Duke and Johns Hopkins.
Also this month, another group that has been following this situation from Oxford University published similar results in Lancet See : https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)33220-9/fulltext
Their methodology was slightly different. They used clintrials.gov data from March 2018 to September 2019. They reported on 4209 trials and found 1722 (41%) reported on time with rates of 50% from industry, 34% from non-industry and 31% from US government sponsors. 71% were done only in the US and 71% involved drug intervention.
The median delay was 59 days when reporting was done at all. They noted that industry was more likely to be compliant than academic and governmental institutions. Sponsors running large numbers of trials were more compliant. The authors noted that “compliance with the FDAAA 2007 was poor and not improving.” They note that FDA itself does not track compliance. Many trials are not even entered into clintrials.gov even though they should be.
The Oxford group also has a website called FDAAA TrialsTracker. This has a listing of over 2900 trials and a very user friendly website https://fdaaa.trialstracker.net/faq/ . One can find the trial title, ID#, sponsor, completion date and days overdue.
The “headline” statistics from this site are:
3673 out of 5331 trial were reported = 68.9%
The US government could have imposed fines totaling: $7,157,173,419
Fines claimed by the US government: $0
The Oxford group has also founded an organization called AllTrials. They state on their website: “The AllTrials campaign was launched in January 2013 and calls for all past and present clinical trials to be registered and their results reported. It is an initiative of Ben Goldacre , BMJ, Centre for Evidence-based Medicine, Cochrane Collaboration, James Lind Initiative, PLOS and Sense about Science and is being led in the US by Sense About Science USA, Dartmouth’s Geisel School of Medicine and the Dartmouth Institute for Health Policy & Clinical Practice. Since then, the AllTrials petition has been signed by 94907 people and 747 organisations.”
Comments
In the past several years officials at NIH and FDA had said that they feel reporting of high quality data on clintrials.gov is important and that these agencies would pursue this. However, as the Science article notes, “NIH and FDA officials do not seem inclined to apply that pressure.” They quote an FDA enforcement official saying “FDA has limited resources and we encourage voluntary compliance…We’re not going to blanketly accept an entire list of trials that people say are noncompliant.” The Science article then notes that “In response to Science’s findings, a spokesperson said an absence of posted results on ClinicalTrials.gov did not mean a trial sponsor has broken the 2007 law.” They did not explain how they came to this conclusion. Clearly a lack of transparency from FDA and NIH.
Pharmacovigilance Implications
In regard to drug safety and pharmacovigilance, it is clear that we could be getting much more safety data that we are getting now. The safety data submitted to FDA in clinical trial reports, DSURs, IND reports and elsewhere, are proprietary and are rarely made public until reported on clintrials.gov or in NDA approvals. Sometimes the data is only revealed in Summary Basis of Approval documents after an NDA approval. Data is, of course, found in the FDA-approved drug labeling. Sometimes some trial data is published in journals and presented at conferences but often minimal safety data is included. This includes information on not just new drugs but on new uses (indications) for marketed drugs and for comparators.
There are new innovative and adaptive techniques for clinical trials aiming to shorten trials, get efficacy data with fewer patients and get drugs to more patients more quickly. This is laudable but the downside is that there is less safety data being collected. More safety information will then have to be gotten after marketing.
Clearly we should be getting all required data on clintrials.gov.
Unfortunately, it does not seem that drug safety is high on anyone’s agenda.
