European Union (EU) regulations require the disclosure of clinical trial results for all studies within 12 months of the global end of trial or within six months for pediatric studies. As shown on the University of Oxford EBM DataLab’s EU Trials Tracker, out of the approximately 8,000 studies that have completed and provide a global end-of-trial date, about 50% are still missing results.
This analysis understates the issue, because there are approximately an additional 17,000 trials on the EU Clinical Trials Register (EU CTR) that have likely completed, but where the publicly available data is inadequate for assessing actual compliance. By looking at the anticipated study durations in the clinical trial application (CTA), and the study completion dates on ClinicalTrials.gov, it is estimated that 64% of these trials also are missing results.
In addition to assessing that trials are likely missing results, the EU Trials Tracker lists over 17,000 trials as having inconsistent data. For most sponsors this represents a bulk of the identified issues, and while over two-thirds of these “inconsistent” trials have already posted results, addressing the remaining data issues can be challenging.
While compliance with results disclosure requirements in the EU leaves significant room for improvement, an analysis of compliance by type of organisation clearly shows that the larger industry sponsors that made an early commitment to disclosure are performing far better than smaller industry sponsors and non-industry organisations.
Unfortunately, compliance with current results disclosure regulations in the US is not better, with 40% of completed studies missing results according to Final Rule (42 CFR Part 11) requirements.
The main causes of non-compliance
The question is why, after all this time, the disclosure of clinical trial results appears to remain so insufficient. There are two main causes for this persistent non-compliance that organisations can control and two additional factors in the control of regulators and registries.
Organisations may lack of reliable processes for determining and managing disclosure obligations.
More than 90 countries have requirements to disclose trial data on one of over 30 trial registries. Many organisations, especially smaller industry sponsors and academic institutions, have not documented these requirements, nor developed the checklists for assessing where and when trial data must be made public. Even if the guidance exists to determine the disclosure obligations, many organisations lack a system for managing the disclosure timelines, assigning tasks, and tracking the compliance status of all trials.
Organisations may fail to maintain a comprehensive list of all the trials for which they are responsible.
Each merger, acquisition, and divestiture of companies or products requires an assessment to determine who will assume the disclosure obligations of all trials affected by the transaction. However, few companies have a reliable process for documenting the portfolio of historic trials and sourcing the original trial data at the time of the transaction. This is particularly difficult where the acquired entity had previously made acquisitions of its own.
For academic institutions, the main problem is determining all trials conducted by investigators affiliated with their institution, especially if these were registered under the investigator’s name rather than the institution’s name. Additionally, when investigators leave an institution there are often no processes for determining who then will be responsible for disclosure, resulting in abandoned trials.
On trial registries such as the EU CTR, certain data can only be updated by the local health authorities, a process that has not always been reliable.
Roughly 2/3 of trials identified on EU Trials Tracker as having “inconsistent data” actually have reported results but are labeled has having data issues primarily because the global end-of-trial date is not shown in any of the clinical trial application (CTA) forms, or because the trial appears to still be enrolling participants in some countries, although an end-of-trial date is available. Why? Either the organisation’s local representative did not inform the national competent authority (NCA), or the NCA did not update the EudraCT system.
The trial registries may not collect, or make publicly available, all the data necessary to determine compliance with disclosure regulations.
The recently published EU Trials Register determines that almost half of trials that completed more than one year ago are still missing results. There are scenarios where results cannot be disclosed: withdrawn trials where no patient was treated, expanded access or compassionate use programs conducted under a protocol, and non-interventional studies that were nonetheless posted on EU CTR. However, EU CTR does not give sponsors the ability to provide clarification. Because of this, most sponsors will not be able to achieve 100% disclosure compliance on the EU Trials Tracker.
How sponsors can address these issues
Step 1: know your studies
Create a comprehensive list of all acquired products and businesses, as well as their acquisitions, at least back to 2004. As a final step to completing this internal trial register, search EU CTR using the names of all associated organisations to find associated clinical trials. Tip: When searching EU CTR, remember to search for naming and spelling variations.
Step 2: Claim, correct, assess, disclose
Using this comprehensive list, contact EU CTR to claim these studies where necessary, or work with the original investigator. Next, triage the studies:
- Confirm that the study status and completion date on EU CTR are correct. If not, work with the local competent authorities to correct the records.
- List any studies ending more than 12 months ago that do not yet have results posted in EU CTR (six months for pediatric studies).
- For completed studies missing results, verify whether the study status and end-of-trial date are correct and disclose results immediately if the data are correct or if correcting the data means that results are still past due, or
- Determine that results are never due if correcting the data means results are not required. Note: We recommend documenting this decision.
Following this two-step process will significantly improve compliance. However, there are limitations.
- It is not possible to search Phase 1 studies on the public EU CTR site if there are no pediatric participants. The primary source for these studies will be your organisation's records.
- While some information may be out of date on EU CTR, it may take time to correct because all changes must be made through the responsible national competent authority.
- Some sponsors do not agree with the workarounds required to post specific results data on EU CTR (for example, posting cross-over studies or entering “99999” instead of “n/a” where “not applicable” is the appropriate response and therefore choosing to withhold results disclosure until these issues are addressed).
Keeping up with disclosure of study results for the EU can be overwhelming — and time consuming. Once you play catch-up, however, it’s important to stay on top of ongoing disclosure efforts. That way, your organisation won’t continually find itself out of compliance.
Thomas Wicks is chief strategy officer for TrialScope.