Advancing clinical trials by optimizing protocol amendments through process excellence and simulation modeling

By Neelesh Harmalker, Amrita Purohit and Roger Apolinar

• Pharmaceutical firms struggle to reduce their 10–15 year development cycles and control rising costs due to issues like low patient retention and intricate protocols
• This article delves into leveraging process excellence methodologies, such as process modeling, to optimize clinical trial timelines
• The Protocol Amendment process in Exhibit 1, when simulated, consistently took 6.5 months and cost roughly $800K
• By improving communication efficiency by 50% through ‘what-if’ scenario planning, the completion time dropped to 3.6 months, cutting costs to $460K
• Using continuous improvement and process modeling, companies can speed up drug development without solely relying on AI/ML

Clinical trial problems keeping us up at night

Bringing advanced medicines to patients at an unprecedented pace requires pharmaceutical companies to re-examine their 10–15 year development cycles and dig deeper into root causes of escalating costs exceeding $2.6B per drug*.

Issues hampering their speed and efficacy of clinical trials, include items such as:

• Suboptimal patient recruitment and retention due to unforeseen delays
• Complex protocol designs leading to increased number of amendments
• Inefficient data collection and management at trial sites
• Fragmented stakeholder collaboration and communication

This paper explores the application of simulation modeling tools coupled with process excellence methodologies to overcome these obstacles and help pharmaceutical organizations optimize trial timelines, leading to faster drug to market, and reduced clinical trial costs.

Process excellence techniques to address the situation

Process excellence methodologies, such as Lean Six Sigma, focus on waste reduction and continuous improvement, and provide a framework for problem-solving and optimization, and can be used to solve clinical trial efficiency issues.

ZS has conducted multiple value-stream mapping (VSM) sessions with large pharmaceutical clients to help encourage cross-functional collaboration and identify process activities, highlight friction points and gaps, discuss process step durations, and brainstorm potential solutions. The end-to-end visuals assist organizations in seeing beyond siloed functions and drives understanding the full impact of their work with upstream and downstream hand-offs.

Process modeling originates from manufacturing and is an enhancement of value-stream mapping that leverages virtual representations of the current process and adds the ability to model Time, Resources, and Cost dimensions in real-time. Using these models, organizations can test multiple scenarios to identify bottlenecks and quantify the impact of changes and interventions to the process. This approach can be applicable to each stage of the clinical development lifecycle from Clinical Trial Strategy, Design & Planning, Conduct, through Closeout.

Process modeling can be done today without having to navigate the InfoSec process, leveraging readily available data. This offers a distinct advantage compared to technologies requiring infrastructure overhauls, such as AI/ML models.

Clinical trial optimization perspectives on modeling protocol amendments

For potential clinical trial operational improvements, our process and R&D experts at ZS mapped the detailed end-to-end process and used process modeling strategies to highlight industry-centric challenges. These include complexities in protocol design and inefficient resource allocation during diverse clinical trial phases, attributed predominantly to disjointed communications and collaborations.

Incorporating amendments in study protocols necessitates an array of procedural steps:

• Articulation of the underlying reasons for the proposed changes
• Detailed description of the specific modifications being instituted
• Evaluation of the potential repercussions of the modifications on the study’s integrity, objectives, and participant safety
• Revised versions of any documents influenced by the protocol alterations, including informed consent forms and investigator brochures, are imperative
• Depending on the nature of the amendment, resubmission to regulatory authorities and/or ethics committees might be necessitated
• Comprehensive communication of the changes to all pertinent stakeholders is crucial

The complexity and extent of protocols can impact dropout rates and the burden on investigators, leading to deviations from the intended study design. By streamlining trial protocols and processes and forging collaborations with regulatory authorities, organizations can strike a balance between regulatory compliance and operational efficacy.

In the example below, we showcase how the protocol amendment process can be updated to influence the length of the study by weeks, if not months.

Exhibit 1: The Protocol Amendment process is illustrated above, detailing the roles engaged in revising clinical trial protocol amendments, as dependent on protocol complexity, study scale and scope, and necessary approvals.

Using process modeling, we identified factors that influence the timeframe of implementing a protocol amendment (highlighted in Exhibit 1):

1. Communicating proposed changes to stakeholders can extend the timeline due to questions or concerns.
2. Changes that pose participant risks or deviate from approved ethical guidelines may need extra approval from an IRB or ethics committee, especially for large studies.
3. After approval, changes must be quickly communicated to teams, sponsors, and study sites to ensure timely implementation.

While Regulatory Authority approval processes are beyond the team’s span of control, protocol design, coordination of changes, communication of approved protocol amendments, and verification of proper implementation are areas that organizations can influence.

Complex and lengthy protocols contribute to higher dropout rates, increased burden on investigators, and deviations from the intended study design. By streamlining trial protocols and procedures and standardizing processes, forms, and data collection methods, you can enhance data quality, boost efficiency, and make adoption simpler for sites and investigators. Organizations can also collaborate with regulatory authorities to develop simplified protocols that strike a balance between regulatory compliance and operational efficiency.

The financial benefits of streamlined clinical trials go beyond just immediate cost savings, highlighting the significant advantages of faster market launches. Launching even a few months earlier can translate into millions of dollars in savings. To illustrate, consider that each Protocol Amendment costs roughly $500K; by refining the amendment process, embracing a continuous improvement approach, and striving to reduce — or even eliminate — certain amendments, the savings can accumulate into the millions.

When subjected to simulation analysis, the Protocol Amendment process depicted in Exhibit 1 consistently demonstrated a completion time of 6.5 months, incurring resource costs of approximately $800K. By engaging in ‘what-if’ scenario planning aimed at expediting the most influential factors, particularly by streamlining communication for proposed and approved changes by 50%, the time required for completing an amendment plummeted to 3.6 months, with associated resource costs reduced to approximately $460K*.

Using traditional methods, measuring the business impact of such a process change would have been too complex. Instead, the development of a current state model enabled the team to instantaneously gauge the impact within seconds, all while maintaining the continuity of ongoing process activities.

Getting to the answer that supports the bigger goal

The intricate landscape of clinical trials necessitates a mixture of data-driven perspectives and technical acumen. By embedding process excellence and modeling techniques within their frameworks, pharmaceutical organizations can discern bottlenecks, inefficiencies, and risks, facilitating informed decision-making and precise interventions. This approach, coupled with our deep R&D expertise and capabilities at ZS, can revolutionize clinical trial processes, accelerate drug development, and elevate healthcare outcomes, thereby fostering a transformative impact on global healthcare ecosystems.

This post contains contributions from Jonathan Rowe, Steve Redden, Ronald Du, Mona Abdel, Josh Dhanpat, and Richa P. Singh.

*https://www.phrma.org/policy-issues/research-and-development-policy-framework

*Assumes hourly rates ranging from $50 to $200, based on role.

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