What’s Next in Clinical Trial Transparency?

The recent news from France regarding serious adverse events in a phase Ia trial has gotten a great deal of press coverage. The coverage spans industry as well as business publications and news outlets. Industry peers continue to await results of the probe into the incident to better understand how and why it happened and how it can be avoided in the future. This type of increased exposure will most likely translate into greater pressure and potentially increase the scope of clinical data transparency regulations.

The unfortunate fact that a life was lost and several others were significantly impaired adds a very real and emotional element to the discussion of transparency. It brings the conversation to actual, live people, who in some cases are healthy volunteers going into a study of this nature. Though this type of tragedy cannot and should not be politicized, it can be used as a learning moment as well as a simple reminder about how and why life sciences professionals do our jobs on a daily basis.

Transparency, at its core, is a continuing effort to share relevant information with other stakeholders (researchers, patients, health care providers and patient advocates) so they can better understand options and availability of potential therapies.

History of Clinical Trial Transparency

To understand this call for greater transparency, it may be helpful to consider the history of trial disclosure. Perhaps the earliest formal trial register was a data bank of information on the results of AIDS research, which included information on clinical trials and treatments. The data bank, known as the AIDS Clinical Trials Information System (ACTIS), was required in the Health Omnibus Extension of 1988 as a way to collect and share research, as well as provide information on potential treatments as they were being developed. This was followed in the U.S. by the Title 113 of the FDA Modernization Act of 1997 (FDAMA 113), which required the registration of protocols related to research into serious or life-threatening diseases and conditions. It was in follow up to FDAMA 113 that the National Library of Medicine created the trial registry known as ClinicalTrials.gov, which was launched in February of 2000.

The calls for greater transparency continued after the launch of ClinicalTrials.gov, starting in 2003 with questions around suicide risk- associated serotonin reuptake inhibitors (SSRI) and whether these risks had been properly communicated to regulators. Then in 2004 a diabetes drug and a Cox 2 inhibitor (a non-steroidal anti-inflammatory drug) were in the news, followed in 2006 by a bovine pancreatic trypsin inhibitor (used to limit bleeding during surgery), where one of the concerns was whether known risks had been fully disclosed. In March of 2006 a phase Ia (first in man) study of a compound known as TGN1412 caused six healthy volunteers to be hospitalized with a very severe adverse reaction. In a subsequent analysis of this case, it was realized that knowledge of a similar study run 12 years earlier in 1994 might have helped prevent this tragedy but information on this previous study was not available to researchers or regulators. At the same time, there was skepticism concerning the FDA’s independence, with the media describing a “revolving door” for executives between industry and regulators. Against this background, Maine enacted a law in 2005 requiring the public disclosure of clinical trial protocols and results. That same year, the International Committee of Medical Journal Editors (ICMJE) began requiring the registration of trials prior to study start as a condition of publication, and Israel, Italy and South Africa passed trial disclosure regulations.

It was with Title VIII of the FDA Amendments Act (FDAAA) of 2007 that the requirement to register all phase II through IV interventional trials was introduced in the U.S., which included the requirement to disclose results publicly on ClinicalTrials.gov. In the European Union the requirement to make information on phase II through IV interventional trials public had been passed in 2004, though the EU clinical trials registry did not go live until 2011. These legal requirements for transparency mean that more data on clinical trials are available than ever before, though the scope of this transparency continues to evolve as demands for more and earlier disclosure continue to grow.

Complex Content Management Challenge

While transparency has many definitions and levels, it can be a significant effort for life sciences companies that have to track clinical trial data as they move and evolve throughout the clinical trial lifecycle. From an operational perspective, it is not an easy task. Data are often stored in multiple systems, potentially being provided by partner organizations. They also are constantly being updated as changes to a protocol are implemented. This content is constantly moving throughout various processes that impact its integrity and ultimately, impact disclosure activities.

This transforming of content as it evolves requires sponsors to be good at clinical content lifecycle management, a term that refers to the evolution and management of content as it passes through the clinical trial lifecycle. This process is complex and is framed by equally complex compliance requirements that vary from region to region. Not only is the content moving and changing, but international compliance requirements are moving and changing as well. This represents a complex content management challenge that requires a systemic approach to managing, tracking and disclosing variable information to multiple registries or public sites.

The study in France was a phase I study, which current disclosure requirements for the U.S. (ClinicalTrials.gov) do not address. In the EU (https://www.clinicaltrialsregister.eu/) information on phase I studies in adults are currently not made public, though new regulation requires disclosure of a study between 12 months and 30 months after completion. However, the new EU regulation does allow authorities to make the information available early, where an overriding public interest applies. Current regulations do not require it, but some companies are already taking a broader approach to developing and implementing their disclosure policies and voluntarily disclosing phase I trials, though this is not yet common practice.

Promise of Broader Transparency

The promise of a broader transparency policy is greater access to information on clinical trials to the public and other researchers. This can encourage enrollment in clinical trials, promote better-informed use of medicines, support application of new knowledge in future research and possibly prevent exposure of participants to unnecessary risks.

The World Health Organization (WHO) and World Medical Association (WMA) have both previously recommended disclosure of all phase I trials. In addition, various groups, including the AllTrials initiative, have called for greater transparency across the board. AllTrials made news in 2015 when the group announced an alignment of 85 different investor groups, representing €3.5 billion ($3.68 billion) in investment funds, supporting their efforts to encourage life sciences companies to provide greater transparency. This was the first time that compliance became an issue that could impact the company financially. (Since 2007, there has always been a threat of financial penalties for companies that don’t disclose properly in the U.S. registry. This penalty fee could be as high as $10,000 per day per study. However, we have yet to see a case where that penalty was enforced.)

AllTrials continues to advocate for greater transparency as do other professional organizations. The ICMJE recently posted proposed requirements for sharing clinical trial data and requested feedback. Their proposal would require sponsors to share with others the deidentified individual-patient data (IPD) behind the trial results presented in the article (including tables, figures and appendices or supplementary material) no later than six months after publication.

Popular press including the New York Times and the Atlantic have also recently begun to share the personal stories of participants in various clinical trials, noting how a lack of transparency impacted their individual experiences.

Conclusion

The convergence of all of these different pressure points suggests that disclosure will become of greater importance to life sciences companies as they navigate the challenges of operational efficiency, internal concerns over patient privacy and intellectual property and a basic agreement on an organization’s level of transparency. The topic has long been a focus of the clinical operations arena and regulatory and compliance departments. However, its prevalence in recent news is now directing the topic much higher in the organization, all the way to the C-suite.

The recent tragedy in France is causing some to call for greater transparency, which includes calling for regulators to broaden the scope of disclosure requirements to include phase I studies. In the coming months, a review of the study in France may point to additional opportunities to further mitigate risks in these types of studies. One lesson learned from the TGN1412 study is that information on the trial should be made public to inform future research.

Corporate sponsors are also aware that brand integrity can be improved or significantly compromised by the company’s disclosure policy. This may have financial implications far beyond a penalty fee for non-compliance. Clinical trial regulators and sponsors now must evaluate their disclosure policies, requirements and practices and determine where they want to be positioned on the disclosure spectrum. It is a tough position that will require balancing of the needs of many stakeholders.