Three Tensions Transforming Clinical Operations Excellence

Pharmaceutical and biotechnology companies are navigating an especially challenging operating environment as they confront, navigate, and address 3 primary “tensions” that may ultimately result in profound organizational transformation: (1) the shift from a legacy compliance-oriented culture toward one guided and grounded in critical thinking, (2) the trade-off between collecting increasingly rich data sets and the imperative to gather only essential and relevant data, and (3) the need to simplify protocol design while enabling fit-for-purpose approaches tailored to site capabilities and patient preferences.

These tensions are not transient. They are pushing organizations to rethink their planning practices, operating models, application of technologies, collaborations, and approaches to risk. As the complexity of the diseases under investigation increased, sponsors historically leaned heavily on standardization and compliance with prescriptive, well-established processes. This helped to ensure regulatory compliance and data integrity but contributed to longer clinical trial timelines, worsening enrollment performance, and increasing inefficiencies. The current operating environment demands a more dynamic equilibrium—one that preserves scientific rigor while enabling risk-proportionate judgment, agility, and focus.

The final International Council for Harmonisation (ICH) E6(R3) guidelines provide a timely and forward-looking road map for mitigating these tensions. They emphasize quality by design, risk proportionality, and stakeholder centricity, encouraging sponsors to move beyond check-the-box compliance and toward more thoughtful, context-based decision-making. Rather than prescribing rigid processes, ICH E6(R3) promotes principles that enable sponsor companies to optimize clinical development by aligning scientific objectives, operational feasibility, and patient needs.

Three tensions: A deeper dive

The first primary tension—between compliance orientation and critical thinking—reflects a cultural inflection point within sponsor companies. For decades, compliance has been the dominant organizing principle, reinforced by regulatory expectations and internal quality control systems. Standard operating procedures, checklists, and audit readiness have shaped behavior, often incentivizing risk avoidance rather than opportunistic behavior. Although this model has ensured consistency and minimized compliance risk exposure, it has also constrained initiative taking and the pace of innovation adoption.

A shift toward critical thinking requires redefining how quality and regulatory compliance are conceptualized and operationalized. Instead of equating quality with strict compliance with predefined processes, organizations must embrace a more outcome-oriented perspective—focusing on whether activities meaningfully contribute to participant safety and key end points, the intent of compliance, data integrity, and scientific validity. This transition necessitates empowering staff to exercise judgment, question assumptions, and adapt processes based on context. Staff and team empowerment introduces new risks, however, particularly in highly regulated environments where deviations from standard practice can trigger scrutiny.

ICH E6(R3) addresses this tension by advocating for proportional risk-based approaches and quality-by-design principles. It encourages sponsors to identify critical-to-quality factors up front and to tailor processes accordingly. In practice, this represents a shift away from a one-size-fits-all compliance model to an adaptive and more customized approach, in which resources and oversight are dynamically aligned to the most essential and relevant data supporting primary and key secondary efficacy and safety end points. The challenge for organizations lies in operationalizing this philosophy—embedding critical thinking into practice, training, performance metrics, and leadership behaviors, while maintaining a defensible and documented compliance posture.

The second primary tension, between the pursuit of richer data sets and the pursuit of essential data, has been amplified by advances in digital health technologies, artificial intelligence–enabled solutions, real-world data, and biomarkers. The marginal cost of collecting additional data has decreased, while the perceived value of collecting larger and richer data sets has increased. Sponsors are increasingly tempted to capture expansive data elements, anticipating strategic curiosities and regulatory inquiries. To date, this tendency has led to massive increases in the volume of data collected per protocol, increased site and participant burden, and diminished data quality.

From an economic perspective, this tension reflects diminishing returns: Beyond a certain point, additional data contribute little incremental value, given the complexity, operational costs, and ethical issues they introduce. Excessive data collection can obscure signal detection, delay database lock, and increase the likelihood of errors. Moreover, it negatively affects enrollment performance and overall study feasibility.

Addressing this tension centers on pivoting to essential, decision-grade data—data that are directly linked to primary and key secondary study end points and regulatory requirements. This pivot requires rigorous up-front planning to define what data are truly necessary to answer the scientific question at hand. ICH E6(R3) reinforces this pivot by encouraging sponsors to focus on critical data elements and justify data collection strategies based on their relevance to study objectives. It also supports the use of innovative data sources and technologies, provided they are fit for purpose and appropriately validated.

Operationalizing this shift demands stronger cross-functional alignment among clinical, biostatistics, data management, and regulatory teams. It also requires challenging entrenched assumptions about what constitutes “essential data.” Organizations must develop governance mechanisms that scrutinize data collection plans, enforce discipline, and prioritize simplicity without compromising scientific rigor. In doing so, sponsors achieve scientific objectives while reducing participation burden, improving data quality, and accelerating timelines.

The third primary tension—between simplifying protocol design and enabling fit-for-purpose approaches—sits at the intersection of standardization and customization. Protocol complexity has increased significantly over the past 2 decades, driven by scientific ambition, regulatory expectations, and a dramatic increase in the number of protocol end points, many of them tertiary, miscellaneous, and exploratory in nature. Customization manifests itself in more procedures, more eligibility criteria, and more operational requirements, all of which contribute to longer cycle times, higher costs, and poorer enrollment performance.

There is growing and widespread recognition that a uniform approach to protocol execution is suboptimal. Investigative sites vary widely in their capabilities, infrastructure, and patient populations. Patients themselves have diverse preferences and constraints, influencing their willingness and ability to participate in clinical trials. A rigid, traditional protocol design failed to accommodate these preferences, variations and capabilities.

Fit-for-purpose protocol designs seek to reconcile these competing demands by tailoring protocols and execution strategies to the specific context of each study. This includes considering site feasibility, patient convenience, and regional differences in health care delivery. Decentralized or hybrid trial models may be appropriate for certain populations, while traditional site-based approaches may be necessary for others. Similarly, protocol procedures can be streamlined or adapted based on their criticality and feasibility.

ICH E6(R3) explicitly supports this approach by emphasizing proportionality and stakeholder engagement. It encourages sponsors to design protocols that are feasible, participant centric, and aligned with real-world conditions. However, implementing fit-for-purpose strategies introduces complexity at the executional level, requiring more sophisticated planning, complicated logistics, fragmented collaborations and coordination, and omnipresent oversight.

Accommodating transformation

To effectively manage these tensions, pharmaceutical companies must adopt more integrated and agile operating models. First they need to empower staff at all levels to exercise judgment and take ownership of outcomes. This involves redefining roles, revising training programs, and aligning incentives with desired behaviors. Leaders must model critical thinking and foster an environment that encourages analytical thinking, adaptive and responsive practices, and innovation.

Sponsors should treat participant and site engagement as foundational principles. This means inviting and involving patients and investigative site staff early in the protocol design process to amplify and accommodate their feedback and perspectives. By aligning protocol design and feasibility with the realities of patient lives and site capabilities, sponsors will improve recruitment, retention, and overall study performance.

Effective communication and collaboration, internally and externally, are essential. The 3 primary tensions are inherently cross-functional, requiring alignment among clinical, regulatory, data, and operational teams. Silos must be broken down, and decision-making processes streamlined, coordinated, and integrated to enable timely and informed actions. Externally, closer collaboration with regulators, contract research organizations, contract service vendors, and technology partners can facilitate coordinated and proactive support of fit-for-purpose designs, promote collaboration efficiency and performance, and reliably predict compliance.

An underpinning of the operational excellence required to navigate these tensions must be the use of real-time data and advanced analytics. Predictive models, risk indicators, and performance dashboards can provide early signals of emerging issues, enabling proactive intervention. By leveraging data more intelligently, sponsors can balance rigor with efficiency, focusing resources where they are most needed.

ICH E6(R3) serves as a critical enabler. It provides a principled framework from global regulatory agencies that legitimizes this profound operating transformation. It is unprecedented to have anticipatory regulatory guidelines, signaling a progressive regulatory stance that recognizes the need for adaptability, innovation, critical thinking, stakeholder centricity, and agency in clinical development.

Sponsor companies are navigating profound interrelated tensions that challenge traditional operating paradigms. Companies that successfully manage these tensions will be at a competitive advantage, better positioned to deliver improved quality, efficiency, and speed. The key to this transformation will ultimately depend, however, on how effectively sponsor companies translate these transformational tensions into sustainable organizational change and operating practice.

Ken Getz, MBA, executive director and research professor, Tufts Center for the Study of Drug Development, Tufts University School of Medicine