By Thomas Wicks, Chief Strategy Officer, TrialScope, Inc.
Clinical Trial Disclosure is a complex compliance challenge that clinical trial sponsors around the world face every day. The complexity of managing dynamic clinical trial data and working with evolving health authority requirements on a global basis can be significant, and the sheer quantity of trials being conducted today only increases the complexity of this task. ClinicalTrials.gov currently lists 189,593 studies with locations in all 50 states and in 190 countries. Therefore, it’s important to understand the context, history, and evolution of disclosure in order to appreciate the current rationale and increasing pressure for registering clinical trials and reporting trial results. In doing so, sponsors can illustrate corporate citizenship and improve their reputation for transparency, in the longer term moving toward the greater promise of transparency: accelerated science.
The Transparency Timeline
The Declaration of Helsinki represents the first major initiative in the timeline of transparency. It consists of a set of ethical principles developed by the World Medical Association to provide guidance to physicians and participants in research involving human subjects. The Declaration was first adopted in 1964 and has been amended 7 times. The General Assembly adopted the most recent version in 2013, which highlights the importance of prospective registration of trials as well as trial results reporting.
In 2000, www.clinicaltrials.gov was implemented as a result of the Food and Drug Administration Modernization Act of 1997 (FDAMA). FDAMA required the U.S. Department of Health and Human Services, through NIH, to establish a registry of clinical trials information for both federally and privately funded trials conducted under investigational new drug (IND) applications to test the effectiveness of experimental drugs for serious or life-threatening diseases or conditions. NIH and the Food and Drug Administration (FDA) worked together to develop the site, which was made available to the public in February 2000.
In 2006, a sponsor conducted a Phase 1 trial in healthy volunteers that caused catastrophic systemic organ failure in all six trial subjects. A controversy emerged because a similar study had been done in 1994 with similar outcomes. It was suggested that had the trial information been available on a public registry, perhaps the second trial would never have been conducted and patient safety would have been protected.
Just a year later, in 2007, the International Committee of Medical Journal Editors (ICMJE) instituted a policy whereby they would no longer publish any trial information that hadn’t been previously posted on a primary public registry. According to ICMJE policy, all trials must be registered at or before the onset of patient enrollment, as a condition for publication consideration. The rationale for this approach was to ensure a complete public record of trials run on a particular compound was available, regardless of the end result.
Recently, the World Health Organization (WHO) published a Statement on Public Disclosure of Clinical Trial Results, which requires the registration of trials before the first subject receives the first medical intervention in the trial. The Statement also specifies that key outcomes are to be made publicly available within 12 months of study completion, and the main findings of the study must be made available publicly within 24 months of study completion.
The FDA Amendments Act (FDAAA) of 2007 was also a key law in driving the submission of protocols and results to clinicaltrials.gov. The FDA Amendments Act, Title VIII required all Phase 2, 3, and 4 interventional trials to be disclosed. FDAAA requires registration no later than 21 days after the first patient is enrolled.
FDAAA also requires clinical trial results to be published no later than 12 months after the primary completion date (the date of the last patient’s final visit for data collection for the primary outcome of the trial) for an approved product, or within 30 days of receiving a marketing authorization for a new product/indication. Results must be disclosed for all interventional Phase 2, 3, and 4 trials of FDA-approved marketed products.
The Costs Of Non-Compliance
The agency has identified remedies for non-compliance, including public notice of failure or violations in the registry/results data bank and the withholding of remaining or future grant funding. These penalties can have a strong impact on a company’s reputation, as well as marketplace consequences. FDA inspections may also result in the issuance of a public warning or a corporate integrity agreement.
The FDA has also established fines for noncompliance, starting at $10,000 for the first event and $10,000 per day for every day late (if not corrected within 30 days).
Internationally, non-compliance may have additional consequences. The ICMJE can and will reject manuscripts, which means trials will not be discussed in a recognized, respected, and peer reviewed medical journal, significantly impacting physician acceptance and prescription behavior. Local IRB and Ethics Boards can also deny approvals or annual re-approvals if the trial is not registered and maintained.
Clinical trial disclosure is gaining exposure because of the risks associated with non-compliance. Transparency has evolved into an important effort that has strategic and operational impact on a sponsor organization.
Sponsors must commit to consistent and ongoing monitoring of emerging regulations and registry requirements by committing resources, identifying roles and responsibilities, and developing training and communication programs that align with their disclosure and compliance goals. Whether these disclosure resources are internal or outsourced, this role is becoming increasingly important as new requirements continue to develop and add complexity to the disclosure process.
Many sponsors struggle with the complexities of a decentralized approach to disclosure in which information is not accessible by global team members. This results in conflicting disclosure information being posted to global registries, redundant processes that manage the information, and increased compliance risks because data is inaccurate or not posted in a timely manner.
Sponsors should consider a centralized approach to managing disclosure information. This will ensure consistency across all publicly-available data, regardless of registry. A harmonized approach often requires the implementation of technology along with process changes. In particular, technologies that help manage the resources, tasks, and content within one environment aid in centralization and optimization of disclosure processes. These investments can minimize the risk of non-compliance, ensure consistency of publicly-available data, and reduce the resource requirements for managing and tracking disclosure information.
In the long run, the biggest impact is on healthcare providers and patients as new information is made available that might impact their care. Sponsors must continue to maintain awareness, an understanding of, and an appreciation for the public need for access to clinical trial information.