Four Disclosure Compliance Risks that Clinical Trial Sponsors Should Identify and How to Avoid Them


Trial disclosure regulations around the world continue to evolve, are not well harmonized across jurisdictions and can be fairly complex.  There are over 40 countries or regions with mandatory trial disclosure regulations and over 30 trial registries for posting clinical data.  While trial sponsors have developed policies, processes and systems to address key trial disclosure requirements, few have evolved systems for continuous monitoring of trial disclosure and registry requirements, or have the systems to monitor and harmonized disclosure of trial information globally. Four practices in particular rise to the surface as major risks for trial sponsors regarding current and ongoing compliance.

  1. Inadequate monitoring, interpretation and implementation of evolving regulatory and registry requirements

Trial regulations are evolving globally. This constant movement requires centralized monitoring and evaluation of global disclosure laws such as the NPRM in the US, and the EU Clinical Trials Directive in Europe. In addition, requirements such as the Declaration of Helsinki, WHO, and ICMJE guidelines must also be tracked and considered in the disclosure policy.

Decentralized or local/regional monitoring and evaluation of disclosure regulations and requirements, usually means that the organization is relying on local affiliates, development partners, and contract organizations to manage regional disclosure.  Establishing a corporate disclosure policy becomes more challenging and creating the “Big Picture” view across regions or jurisdictions to assess overall compliance becomes more difficult if not impossible.
Trial registries also continually update technical and data requirements, requiring ongoing analysis and potential system updates. These updates may be related to evolving rules for data entry that require changing a field from optional to mandatory, adding dependencies between data fields, etc. They may also be caused by evolving technical requirements such as new file formats or upload procedures on clinical trial registries. Without centralized monitoring of registry requirements, it become difficult do keep systems, work instructions and SOPs up to date, which can cause delays in completing data disclosure task on individual registries and results in missed regulatory deadlines and non-compliance.

  1. Not harmonizing disclosure across regions, registries, and departments

Trial data may be made public in many forms, such as through the many trial registries, on websites maintained by the trial sponsor, as well as in publications and posters. This trial data may be made public by different departments in different regions. For example, some of the over 30 trial registries are populated directly by the sponsor, such as the clinical operations group posting trial information on clincialtrials.gov in the US.  Other registries are populated by health authorities.  For example in the EU, the National Competent Authorities make elements of the clinical trial application that was submitted by the sponsor’s regulatory affairs department public on the EU Clinical Trials Register group. At the same time, affiliates may be registering trial information on local registries such as CTRI and ReBEC, while the publications group works separately to publish articles in peer reviewed journals. The information from all of these sources are available to the public, allowing readers to compare data on the various registries, websites, posters and publications.  There are instances where discrepancies in the published information have been reported to regulatory agencies and have been discussed in publications.

  1. Not creating original content with disclosure in mind

Protocols authored without consideration for the impact to data transparency can increase the scope of disclosure significantly and cause inconsistencies in disclosure across registries. For example, clincialtrials.gov requires reporting an outcome measure with multiple timeframes as distinct outcome measures. This means that a study with 4 secondary endpoints, each assessing outcomes at weeks 1, 4, 8, and 10 would turn into 16 secondary endpoints and the trial sponsor is then required to report results on each of these endpoints individually. There are cases where sponsors had to report on over 100 secondary endpoints identified in the protocol. Thoughtful content design, early discussion, and clear definition of secondary vs. exploratory outcomes reduces the additional reporting burden that can be created by unknowing protocol authors.
Trial registries like clinicaltrials.gov and EudraCT also have specific rules on how information is to be entered into their systems.  For example there are limits to the length of the study title imposed by the registries, and the registries do not agree on the allowable length.  If these limitations are not considered, the study title on each registry may differ and not reflect exactly the title in the protocol.  While these differences may not be a compliance issue, in aggregate they result in a lack of consistency that can lead to confusion and the appearance of poor controls or even noncompliance.

  1. Poor processes for updating source data in a timely manner

Certain trial transparency regulations have established due dates for disclosure requirements based on specific events.  For example, the FDA Amendments Act currently requires registration of a protocol within 21 days of first patient enrollment and updates to the registration within 15 days of enrollment status change (e.g. changing from ‘recruiting’ to ‘active not recruiting’, ‘completed’, ‘terminated’, etc.).  The challenge for sponsors is often that this information may not be updated in a timely manner in their clinical trial management system (CTMS).  This delay in updating the CTMS can mean a delay in completing a required disclosure task, causing the sponsor to be out of compliance.

Another example is the requirement that study results must be disclosed within 30 days of a product’s approval, which requires the disclosure team to be informed immediately when an approval has been received.  However, some sponsors lack the processes for tracking applications associated with a particular trial and notifying the disclosure teams appropriately.  Instead, they rely on institutional knowledge, that the disclosure team is somehow aware of all approvals and what studies are related to an application.

Consequences

The four common scenarios described above are not just poor practices. Depending on the jurisdiction, noncompliance with trial disclosure regulations may results in fines.  The FDA Amendment Act includes a provision to levy a $10,000 fine for non-compliance, giving the sponsor up to 30 days to remediate the deficiencies.  After 30 days, the FDA will fine $10,000 per day for each study that remains noncompliant until the issues are resolved.  Additionally, future grant funds may be withheld from an investigator or institution failing to comply with disclosure law.  Aside from these financial penalties there are other consequences for failing to comply with disclosure requirements:

  • IRB or Ethics committees may withhold approval of the trial, or hold up the annual recertification. This has occurred either because the there was no evidence of compliance with disclosure regulation, or with corporate commitments.  For example, withholding approving for Phase I studies that have not been registered, but where the sponsor had accepted the Declaration of Helsinki which requires registration of all studies in humans.
  • Unfavorable publicity through articles in medical journals that are often critical of disclosure compliance, and are picked up by the press.
  • Recently, 85 pension funds and asset managers representing investments over $3.9 trillion joined the AllTrials initiative, calling on industry sponsors to register and disclose results for interventional trials. It is conceivable that these fund managers will incorporate disclosure compliance into their investment decisions.

Recommendations

Sponsors can avoid these practices and the associated risks by considering implementation of the following practices.

  • Establish a clear corporate policy on trial disclosure that is fully endorsed and supported by the executive leadership of the organization including the Chief Medical Officer. Active leadership engagement, especially with larger trial sponsors that attract more attention in recommended because it signals the level of engagement required to streamline processes and overcome internal resistance.
  • Consider establishing a policy that supports a broader commitment to transparency than is absolutely required by regulation. While this can be a factor in developing a more positive public image, a broader policy is also a pragmatic response to the evolving data disclosure requirements. Organizations like AllTrials are proposing full registration and results disclosure for all interventional trials related to products currently in the market, with an ongoing effort to retroactively disclose data for trials going back at least to 1990.  Some sponsors have already made public commitments to this retroactive disclosure.
  • Centralize data disclosure across geographies and departments. Sponsors should commit to developing a central tracking and coordination capability to support trial registration and results disclosure to registries around the world.  Ideally, this centralized management of disclosure would extend to include coordination between departments that share clinical data outside of the organization, such as regulatory affairs, clinical operations, and the publications group.
  • Establish a regulatory monitoring capability to track disclosure regulations and the changing trial registry requirements, ideally managed by a dedicated disclosure expert or specialized service provider.
  • Develop a set compliance tracking reports and key performance indicators to provide an early warning system for potential risks and to provide an ongoing assessment the sponsor’s disclosure processes.
  • Implement a disclosure system to streamline the workload, ensure compliant and harmonized disclosure across registries and jurisdictions, and automatically create the necessary compliance reports as well as tracking key metrics and performance indicators.
  • Update standard operating procedures or work instructions to establish the processes for keeping the CTMS data up to date in a timely fashion and for communicating approval status for products to the trial disclosure group.