In clinical trials, turnaround time and data accuracy are critical. The cost of a one-day delay in a drug being brought to market can be as much as $4 million-$5 million.(1) Likewise, paperwork-based errors in the clinical trial process – whether they occur at the sponsor level, the contract research organization (CRO) level or the institutional review board (IRB) level – can have serious downstream effects, negatively impacting study efficacy and time-to-market.
It is essential, therefore, that all participants in clinical trials – sponsors, CROs and IRBs – take steps to improve both efficiency and accuracy. Doing so requires that organizations look beyond symptoms to uncover the true causes of delays and errors. The holistic, rather than granular, application of positive change allows for maximum effect and return on investment (ROI). Additionally, new processes must be implemented in such a way as to become part of institutional culture, ensuring the consistent, ongoing success of future efforts.
In order to address these concerns, several successful organizations associated with the clinical trial industry have begun implementing Lean Six Sigma principles. Developed in the early 2000s by Michael George, now the Director of the Institute of Business Entropy(2), Lean Six Sigma is a combination of two distinct ongoing business improvement practices, Lean and Six Sigma.
The former, Lean, is a system designed to “maximize customer value while minimizing waste,” according to the Lean Enterprise Institute (LEI).(3) Lean focuses on eliminating waste along entire value streams, creating “processes that need less human effort, less space, less capital, and less time to make products and services at far less costs and with much fewer defects, compared with traditional business systems. Companies are able to respond to changing customer desires with high variety, high quality, low cost, and with very fast throughput times. Also, information management becomes much simpler and more accurate.”(4) Positive changes are created through the use of Kaizen Events – focused, multi-day initiatives designed to deliver sustainable, continuous improvement and lasting cultural change.
Six Sigma, meanwhile, “is a disciplined, data-driven approach and methodology for eliminating defects (driving toward six standard deviations between the mean and the nearest specification limit) in any process.”(5) To be in compliance with Six Sigma goals, the rate of defects – anything outside of customer specifications – must be limited to 3.4 per 1 million opportunities. This is a perfection rate of 99.99966 percent, often referred to as 3.4 DPMO (or 3.4 defects per million opportunities).(6)
Lean Six Sigma strives to combine the best of Lean and Six Sigma methodologies. Data-driven decision-making in the Six Sigma vein uncovers the root of problems, Lean principles are used to improve productivity and Kaizen Events are implemented to create rapid, lasting change. “The resulting one-two punch becomes a formidable tool for attacking the problems that enlarge the difference between annual revenues and the bottom line,” wrote Bonnie Smith in ‘Quality Progress,’ the flagship publication of the American Society for Quality. “The two initiatives work together, achieving results consistently superior to what either system could achieve alone. It’s a classic case of the whole being greater than the sum of the parts.”(7)
Classically, Lean and Six Sigma principles were applied primarily to manufacturing situations, with eyes on eliminating wasted raw materials and scrapped pieces. However, both methodologies – and the consequent Lean Six Sigma methodology – apply equally well to academic and service-oriented pursuits, such as the conduct of clinical trials. By seeking the true root of issues, sponsors, CROs and IRBs are able to address study and review delays and paperwork-based errors, improving time-to-market and overall accuracy. The result is studies that are completed more quickly, more profitably and with the best possible ethical oversight, protecting the rights of human subjects and vulnerable populations.
In this paper, we address the use of Lean Six Sigma principles in the clinical trial industry by taking two distinct perspectives. The first is that of Copernicus Group IRB, a North Carolina-based review board that has improved turnaround time and reduced errors by implementing CLASS – the Copernicus Lean And Six Sigma initiative. Included is input from Steve Laton, a lean improvement specialist at North Carolina State University’s Industrial Extension Service who assisted Copernicus Group IRB in establishing CLASS. The second explores Lean Six Sigma at major clinical trial sponsors, including input from Lean Six Sigma Green Belt Soo Bang, who oversaw a continuous process improvement program at Pfizer.
Copernicus Group IRB (CGIRB) is an independent institutional review board established in July 1996, whose primary responsibility is to ensure that the rights and welfare of human research subjects are protected. The CGIRB board reviews research protocols and study-related information, as well as investigator qualifications and resources to ensure regulatory compliance.
CGIRB has a long-standing tradition of meeting or exceeding the standards for industry certifications. In 2004, the Research Triangle Park, N.C., company became one of the first organizations to be awarded full accreditation of the human research protection program by AAHRPP, the Association for the Accreditation of Human Research Protection Programs, Inc., and was awarded full reaccreditation in 2007 and 2011.
CGIRB has long focused on process improvements. The company affirmed its commitment to quality management in May 2010, when it became the first IRB to receive ISO 9001:2008 certification. After performing the intense internal audits required by ISO, CGIRB began looking at methods for reducing waste and limiting non-value-added activities, with eyes on improving response time and achieving 100 percent data accuracy in every submission. The exploration of numerous process improvement systems and methodologies led the company to embark upon a Lean Six Sigma program in partnership with North Carolina State University’s Industrial Extension Service (IES).
The goal of the Copernicus Lean and Six Sigma (CLASS) initiative was the minimization of non-value added activities and the reduction of variation – eliminating rework, reducing costs and improving customer satisfaction, both internal and external. This is achieved through an employee team-based approach, led by a facilitator, which promotes employee empowerment and positive morale. Success is determined by measuring internal and external errors, client feedback and employee involvement. Surveys, metrics review and error Sigma rates are routinely analyzed to measure the effectiveness of improvements.
Lean Six Sigma-style process improvement at CGIRB began with the formation of a management steering committee to map out a strategic plan and goals for the effort. Cross-functional teams and project leaders/point-people were chosen from CGIRB’s pool of employee volunteers and subject matter experts to carry out the chosen method of process improvement – a 10-step process coupled with Kaizen Events. The CLASS Kaizen Events were based on value-stream mapping (the targeting of waste within a process or workflow for reduction or deletion). The cross-functional teams comprised a combination of process owners and “internal suppliers” who fed data into the process. This allowed for both sufficient institutional knowledge on the processes being modified and “fresh eyes” to suggest additional possibilities for the removal of waste and non-value-add activities.
Reducing turnaround time for amendments
After establishing the baselines for the CLASS initiative, CGIRB embarked on the first of three Kaizen Events. The first event was designed to improve turnaround time and reduce the (already low) number of errors during the review of an amendment submission. CGIRB’s Kaizen Events begin with a process workflow being examined from start to finish. From there, the workflow is broken down into steps, and the time it takes to complete each step is noted. Wasted time between steps is accounted for, and an ideal version of the workflow – one with less non-value-add time – is mapped out. Tools are identified allowing CGIRB team members to realistically and sustainably reach the idealized workflow, and the improved process goes into production. In the case of amendments, a quality control (QC) checklist was added to CGIRB’s routing cover sheet to simplify internal submission processing. This change alone resulted in an immediate decrease in turnaround time and errors. Based on continuous monitoring and user feedback, the QC checklist was moved from the routing cover sheet to a submission comments area within the document workflow, further improving adherence to best practices and decreasing processing steps. The final result was a 20 percent reduction in turnaround time on one of the most involved submission types generally handled by IRBs.
Improving shipping times
CGIRB’s second Kaizen Event, undertaken in October 2011, involved the streamlining of workflows within the company’s document shipping area. A number of non-value-added areas were identified within the department, including the shipping area being split between separate rooms and the use of separate computers for shipping study documentation via FedEx, UPS and the U.S. Postal Service. As a result of the Kaizen Event, CGIRB consolidated the shipping department to a single room, improving communication between staff members and enhancing staff collaboration. CGIRB also implemented a best-in-breed Pitney Bowes automated shipping system, vastly reducing technological redundancies within the department and cutting the time needed to deliver documents to clients.
Ongoing at the time of this writing was CGIRB’s third Kaizen Event, focusing on corrections. The process involved the identification of the root cause of the company’s top five most frequent errors and the creation of a streamlined QC process within the correction workflow. The goal is to further improve review turnaround time while maintaining quality and regulatory standards.
A cultural shift
A cultural shift toward constant collaboration and continuous process improvements has been inherent in CGIRB’s Lean Six Sigma program. Departmental goals have been further aligned with CGIRB’s mission, vision and values and an increasing number of facilitators have been empowered over time. Likewise, daily accountability is promoted, in three key ways:
The results of CGIRB’s CLASS initiative have been striking. The turnaround time for certain specific submission types have been reduced by an average of 20 percent, with a marked decrease in errors. Review standards have been maintained, meeting CGIRB’s ultimate priority of the protection of human subjects and vulnerable populations.
“The CLASS initiative promotes collaboration across teams, giving team members the opportunity get to know colleagues in other departments,” said CLASS project facilitator and CGIRB Assistant Director for Project Management Sherry Seabock. “All team members agree to work toward an improved process with an open mind, speak with data and encourage a ‘please try’ attitude with mutual respect for all.”(8)
Lean Six Sigma methodology has also proved effective at the sponsor level. Soo Bang, an active clinical research professional, led a 2010 initiative at Pfizer focused on the improvement of academic medical center contract cycle time through the use of Lean Six Sigma methodology.
Like all Lean Six Sigma projects, the initiative began with a data-based discovery process that challenged the original hypothesis on the cause of delays when working with academic medical centers. In the case of the 2010 effort, it was assumed that the high percentage of oncology studies within the pool of contracts with academic medical centers was resulting in a slower average study time, due to the complicated nature of oncology research. However, statistical analysis showed that oncology studies were not causing undue slowdowns.
Armed with this information, empowered team members and CRO staffers embarked on a value-stream mapping exercise, ultimately identifying three potential causes for delays. Three potential methods of improvement were then put into place:
As a result of the Lean Six Sigma initiative, contract cycle times when dealing with academic medical centers were cut by more than 50 percent. The improved cycle times provided opportunity for rapid site activation and opportunity for clinical trial performance on par with non-academic sites that typically operate under shorter contract cycle times.
The Lean Six Sigma approach was integral to the success. Because of its inherent focus on addressing the root causes of problems and delays, the methodology allowed the sponsor to create real, lasting, sustainable change, improving profitability and positively affecting patient outcomes, rather than simply handling downstream symptoms.
“There are so many tools within Lean Six Sigma training that make you think about things differently,” Bang said. “One of the major principles of Lean Six Sigma is value-add and non-value-add activities. A lot of what we do as sponsors, CROs and IRBs every day are non-value-add activities. If organizations are thinking about eliminating those, they are able to instill a culture of productivity. In that situation, quality comes from the design of the process, rather than blaming it on people.”(9)
As proven by the result of initiatives at Copernicus Group IRB and a leading sponsor (which conducted its effort in conjunction with multiple CROs), Lean Six Sigma methodology is a valuable tool for organizations within the clinical trial industry. Because of its data-driven decision-making, sustainable change, positive cultural shifts and emphasis on discovering the root cause of issues, such a process is tailor-made for the field. When deployed properly, Lean Six Sigma initiatives can allow sponsors, CROs and IRBs to reduce both study times and error rates. This, in turn, creates studies that are more profitable and bring life-saving pharmaceutical products to market faster without sacrificing regulatory standards or human subject protection.