European institutions risk steep FDA fines over unreported clinical trial results

Major European institutions are at risk of steep FDA fines for violating American transparency laws, a review by TranspariMED has found.

Some of the institutions affected have an excellent disclosure record on the European trial registry EudraCT, but do not routinely upload clinical trial results onto the American ClinicalTrials.gov trial registry.

This exposes them to the risk of accidentally breaking U.S. law and facing fines that could run into millions of dollars.

This blog first presents some examples of institutions at risk, and then discusses how European trial sponsors can navigate these challenges.

Examples of institutions at risk of FDA fines

Under the 2007 FDA Amendments Act (FDAAA), even foreign institutions running trials outside the United States can be required to make their clinical trial results public.

For example, if your trial involves a drug or medical device manufactured in the U.S. and exported for use in your study, the trial must make its results public on ClinicalTrials.gov within 12 months of its primary completion date.

Any institution violating FDAAA faces a fine of $10,000 for every day the trial’s result is not uploaded. So if you upload your results 100 days after the legal deadline, you could be facing a one million dollar fine.

Examples of institutions already at risk:

University Hospital Leuven

The Belgian hospital failed to report the results of cancer trial NCT03784066 on time. In total, University Hospital Leuven now has four trials that violate U.S. disclosure laws, and is running the risk of being fined up to $28 million by the FDA.

University Hospital Leuven is associated with the university KU Leuven, which has a fantastic disclosure track record of 98% on the European trial registry. Presumably, like most European universities and hospitals, University Hospital Leuven simply is not aware that some of its trials are legally required to make their results public on ClinicalTrials.gov.

Queen Mary University of London

QMUL is a front-runner in clinical trial transparency. It cleaned up its record on the European trial registry in the wake of a parliamentary enquiry several years ago, and now maintains a perfect 100% reporting rate on the European trial registry. However – like many other UK institutions – it apparently failed to roll out transparency measures across its entire trial portfolio. Thus, trial NCT03908073 slipped through its research governance net, and the university now risks an FDA fine of over $10,000 for every day the problem remains unresolved.

European Organisation for Research and Treatment of Cancer

EORTC too does extremely well at clinical trial transparency in Europe, but may not to be keeping such good track of its ClinicalTrials.gov portfolio. Advanced Hodgkin Lymphoma trial NCT03517137 is now 55 days overdue, in violation of U.S. federal law. Potential FDA fine to date: $290,000.

Medical University Innsbruck

Innsbruck has a respectable track record in reporting its trial results in Europe. However, the university has so far failed to report the results of NCT04353596, accumulating $440,000 in potential FDA fines to date. The trial in question recruited 2016 Covid patients to determine whether stopping treatment with ACE-inhibitors or angiotensin receptor blockers will improve health outcomes including overall survival. On ClinicalTrials.gov, the university states that the trial was completed in February 2021, so its results are now over two months overdue there.

Note: The same trial was also registered on the European trial registry, where it is also missing results. However, according to data entered there by the university, the trial was only completed in December 2021. Ensuring consistency across multiple trial registries remains a challenge even for strong institutions. (While the WHO generally discourages multiple registrations of the same trial, in this case it was unavoidable due to regulatory requirements in each of the two jurisdictions.)

Heidelberg Engineering GmbH

This German company has failed to make public the results of three medical device trials, most recently trial NCT02785029. Potential FDA fines: $27 million. European Union trial reporting rules only apply to clinical trials of investigative medicinal products, so maybe the device company assumed that results reporting on registries was voluntary in its sector. However, under United States laws, some medical device studies (in addition to some drug trials) must make their results public.

Some European institutions seem to have pre-empted the risk. When Karolinska Institutet tackled its unreported trials on EudraCT

How can my institution avoid an FDA fine?

Is this a real risk?

Yes. The FDA is now slowly starting to enforce the law - and it is under increasing pressure to accelerate its enforcement in the near future. It is unclear how the FDA selects which institutions to target, so it is entirely possible that your institution is next on the list.

Worse, the FDA typically writes to the investigator running the trial, not the institution – but the institution is responsible for paying the fine. So if one of your researchers ignores the initial letter from the FDA, your institution could be facing an expensive surprise a few weeks later.

Is my institution at risk?

This is not easy to determine. The FDAAA Trials Tracker lists all trials that have become due under the law since 2018, so you can check there for recent trials. However, a subsequent court case extended the applicability of FDAAA back to 2007, so the Tracker cannot help you to detect older trials that are in violation of the law and may attract an FDA fine.

You will probably have to go through all your studies listed on ClinicalTrials.gov and use this checklist to identify trials that are subject to legal reporting requirements, and then upload their results.

What should I do now?

As a first step, you should email the PRS support team at ClinicalTrials.gov (register@clinicaltrials.gov) and ask them for advice. They are extremely helpful and usually respond within 24 hours.

Can I avoid triggering FDA reporting requirements for future trials?

No. If your trial is subject to FDAAA, it must by law be registered on ClinicalTrials.gov. (Otherwise the FDA can fine you for not registering the trial there, as well as for not reporting its results!) Therefore, registering your trials on other trial registries does not avoid the problem.

IMPORTANT: Registering a trial on ClinicalTrials.gov does not automatically trigger a legal requirement to report results there. Only a small minority of trials fall under FDAAA. The law applies to these trials whether you register them on ClinicalTrials.gov or not.

There is absolutely no reason to stop using ClinicalTrials.gov.

How can my team manage this risk for future trials?

You have two options:

• The best option is to adopt WHO best practices and ensure that the summary results of every interventional clinical trial are routinely uploaded onto every registry where the trial was registered within 12 months of trial completion. This may seem a lot of work, but many institutions already do this, not least because more and more funders are demanding it. In the long term, it will be much easier to have a single policy and process covering all clinical trials than having to manually check legal, regulatory and funder requirements for every new trial.

Example: Karolinska Institutet in Sweden has centralised clinical trial registration and results reporting for all of its trials, across all trial registries.

• The second best option is to manually screen all new trials and flag those that will have to report results according to various national laws and the rules set out by different funding bodies.

Example: The Charite in Berlin is uploading all due results onto the European trial registry, but does not yet routinely upload results for all of its trials onto ClinicalTrials.gov or other registries. However, the Charite did upload the results of this completed FDAAA trial.

Where can I find support?

• As noted above, the PRS support team at ClinicalTrials.gov are extremely helpful. They also have excellent support and training materials on their website. Uploading trial results onto the American registry is far easier than for the European registry.

• The QUEST trial reporting manual and other useful resources on the TranspariMED website can help you to set up strong trial registration and reporting systems and processes within your university or hospital.

• To get help with results reporting on ClinicalTrials.gov (and understanding FDA rules), you can apply to join the Clinical Trials Registration and Results Reporting Taskforce, a peer-to-peer support group (no cost). They usually only admit U.S. institutions, but if your institution has a large portfolio of trials on ClinicalTrials.gov, they might make an exception.

• For help with results reporting on the European EudraCT and CTIS trial registries, you can join a similar taskforce that has recently been launched in Europe, and check out the official EudraCT and CTIS support materials.

And… keep tuned to the TranspariMED blog.