Council Advisors
Home Our Practices Leadership Capital Careers Contact
« Return to insights

Addressing the Root Causes of Risk in Clinical Trials


As Pharmaceutical companies shift their emphasis away from the blockbuster model, they need to bring a broader portfolio of drugs to market. This escalates the complexity of clinical trials—the most costly and time-consuming component of the drug R&D cycle—through higher costs, recruitment challenges and new training demands. A potentially more serious problem is discussed less frequently, however: the increased risk to regulatory compliance and patient safety.

The FDA has increased its vigilance: the number of Warning Letters from the Office of Scientific Investigations has increased sharply – to an average of 15 per year in 2009-13, compared to an average of nine in the previous five years. This presents a major risk to Sponsors, Contract Research Organisations (CROs), Investigators and most importantly, patients.

In the FDA’s view[1] , the main causes of mistakes are overworked study staff, inappropriate delegation of tasks, inadequate supervision and insufficient involvement of the Principle Investigator. These all point to an overstretched system, in which procedures have become so cumbersome that they obscure true priorities.

A number of industry initiatives directly address some of the known problem areas. Risk Based Monitoring, for example, adjusts the level of supervision at a study site based on the potential risks associated with the trial. But such initiatives often take a piecemeal approach – so while these efforts may effectively address known problem areas, the poorly-understood ‘accidents waiting to happen’ lurk in weaker spots of the process.

Sponsors and CROs therefore need to employ a more systemic approach to uncover the most critical risks in the clinical trials process and eliminate their root causes.

Why Most Approaches to Clinical Trial Risk Reduction Miss the Mark

Failure to take an end-to-end view results in further complexity. When hastily conceived, some of the most well-intentioned solutions to problems fail to address the major underlying causes of risk. Many of these lead to unintended consequences that impact different times and places in the process—for example, protocol amendments, changes to training for investigative site staff or rework of reporting deliverables.

These problems may not increase an easily identified risk, but a proper assessment of their effect on the whole system reveals their significance. For example, protocol amendments can lead to miscommunication risks that compromise the selection and training of trial sites or the accuracy of the Informed Consent Document.

Additional safeguards add complexity and often create unintended consequences. While the benefit of individual changes may be clear and measureable, their costs disperse through the system and therefore become harder to see. For example:

  • Serious Adverse Event reporting requires careful control, with multiple complex forms to be completed, when the primary requirement is urgency.
  • Informed Consent documents become longer and harder for the subject to digest fully, when the primary objective is that they understand what they are signing.
  • Large numbers of documents arrive at a site each day that need to be read and actioned, distracting investigators from their core responsibilities.

These risks present major safety and patient rights issues. They also jeopardize the integrity of the study data, as the potential for data exclusion creates the risk of an insufficient sample size to achieve a definitive result.

Point solutions don’t deliver results that last. Serious improvement efforts must identify and fix root causes rather than provide more QC that further increase complexity. Although initially more time-consuming, a proactive approach enables CROs and Sponsors to reduce complexity, rework, lead time and costs in the long term.

Uncovering Risk: A Comprehensive Clinical Risk Assessment

Following a Warning Letter from the FDA, a global pharmaceutical company decided to take an active approach to risk reduction. The organization knew that a thorough study of risk would be an involved task, because it required an end-to-end view of the clinical trial process. However, only through rigorous study could the firm gain sufficient confidence that the key issues had all surfaced. Using a systemic approach, they:

  • Created a high-level map of the entire process to help break the task down into chunks that teams in the appropriate area of expertise could manage effectively.
  • Prioritised the processes that were inherently more likely to involve risk to patients, regulatory compliance or data integrity.
  • Created detailed process maps of those priority areas.
  • Conducted a structured risk assessment of each step in those priority areas.
  • Identified key risks and initiated improvement actions to discover root causes and fix problems.
  • Developed a Quality Management System to make managing and maintaining the improvements easier.

The study revealed insights on the underlying causes of risk which allowed the firm to strategically prioritize improvement actions and tackle core issues.

Keys to Lasting Results for a Clinical Trials Risk Assessment

The approach described above effectively directed a strategic risk reduction program. However, to ensure that these undertakings yield actionable lasting improvements (rather than a long report), risk assessments must bridge strategy with execution. To safeguard the success of these initiatives:

  • Communicate effectively with regulatory authorities, making your motives and goal clear. A document that formally assesses every aspect of risk in your process may be perceived as a liability rather than an asset, but the FDA warmly welcomed the approach in the case described above.
  • Involve the study sites as well as internal staff. They will provide deep insight into specific challenges they face. Often, issues created or made worse by the Sponsor or CRO provide particularly valuable guidance on improvement opportunities.
  • Do no treat a risk assessment as a one-time exercise. If you do, changing processes will make your efforts obsolete. However, if managed as an ongoing process and updated whenever problems arise or improvements are made, then risk reduction will become an integral and effective part of the Quality Management System.

Benefits to the Business

By using this proactive approach to risk assessment, Sponsors and CROs avoid compromises that often result from the pressure to react quickly when an issue flares up. Following this model reduces rework and complexity, rather than increasing excessive checks and ‘solutions’ that do not get to root causes.

Finally, as part of an overall drive to increase the effectiveness of Clinical Trials, a comprehensive risk assessment provides the depth of analysis required to make strategic rather than tactical improvements to the whole process, delivering lasting benefits.

About the Author

David Hampton is a Director of SSA & Company. He has 10 years of experience in partnering with clients in the Biopharmaceutical industry to drive efficiencies and performance improvements in Manufacturing, R&D and Clinical Trials. Contact [email protected] for more information.

[1] Investigator Responsibilities – Regulation and Clinical Trials – Leslie K Ball, November 2011


The post first appeared on SSA & Company.