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Optimizing clinical protocol development to enhance research productivity
Introduction
Executing a clinical trial that achieves high-quality results within expected timelines and budget is extremely difficult. Delays in study startup are one of the primary reasons studies fail to achieve their initial timelines and budgets, because such delays cascade through the entire study timeline and can lead to hasty decisions by research sites and key vendors.

At the center of clinical drug development is the clinical research protocol. Envision the drug development process as a flowing stream. Strategic activities that proscribe clinical studies, such as the development plan and target product label, are found upstream of the protocol, accompanied by all of the information that rationalizes the proposed clinical research (e.g., preclinical data). At around the same point in the flowing stream as protocols, and directly linked to them, are tactical work products, such as project budgets, resource plans, and trial materials manufacturing plans. Downstream of protocols are the myriad operational activities that lead to study execution. To understand why protocols are the key to maintaining an uninterrupted, smooth, fast flowing drug-development process stream, bear in mind that protocols directly inform, instruct, guide, or provide a rationale for nearly all study startup activities and their work-products – everything from site identification and feasibility to trial registry filing.

Within the study startup phase, our experience has been that protocol development accounts for a majority of delays. Delays in finalizing the protocol lead to delays in key operational decisions including: finalizing the study budget, contracting with a CRO and other vendors, selecting supporting technologies like EDC and IVRS, and finalizing site selection. Finalizing the protocol is also critical to selected sites gaining IRB/Ethics Board approval to participate in the study.
Delays in developing the protocol are endemic to many clinical development organizations because the protocol development process (PDP) itself is generally poorly defined and, when it is defined, rarely followed as intended. Protocol development in many organizations is viewed as an “art,” with the assumption that the protocol emerges from a sort of creative chaos. While there is some truth to this view, it offers little opportunity for improving the study startup activities necessary to meet aggressive development timelines and increasingly stringent budgets.

Many clinical development organizations are realizing that they need to improve the efficiency with which they develop protocols. The key to driving efficiency in the PDP is to understand where the current process fails. Most processes have delays because they fail to bring together the right people with the right information at the right times to make decisions quickly and to be able to immediately implement those decisions. Fortunately, novel technologies and proven process-improvement methods are available to significantly improve the efficiency of the PDP.

Preparing for change

When considering changes to complex processes, it is advisable for organizations to view their existing processes systemically – as an open system with inputs, outputs, and connections between system components that determine overall system behavior. It is sufficient for this overview that readers appreciate that a systemic view of complex processes is useful to challenge conventional process-deficiency thinking, uncover previously unnoticed areas for improvements, and recognize how changes in individual system components are likely to affect overall work outputs. In this regard, it is worth mentioning that although processes are run by people and people can act irrationally, it is generally possible to predict how people with common goals will react to specific changes in their work environment. The tricky bits are figuring out how the whole system will react when an individual component is changed and which component(s) to change for maximal effect.

Below is a list of selected factors that, in aggregate, determine the PDP structure and dynamics.

• Author functional expertise and roles
• Organizational control over content
• Reuse of content from prior protocols
• Learning from company and external “best practices”
• Quality reviews – internal and external
• Dependent operations
• Dependent documents and information systems
• General communications of protocol information throughout and outside of the organization

To illustrate how this list can be used in PDP design, consider the first factor listed: the functional experts that should be contributing to protocols. For each functional expert group that is considered, provide justification for a positive or negative response to the question “Should this group be contributing?” Likewise, organizational control over content is addressed by determining the specific type of protocol content requiring control, and if content is to be controlled, how and when it should be controlled.

Notice that this type of systematic exploration is also useful for identifying areas of mismatch between currently employed technologies and business needs. To avoid inflating performance expectations, PDP owners and change managers should keep in mind that initial responses to these questions may later be demonstrated empirically – either through simulation or actual implementation – to be sub-optimal in the context of a fully developed process.

Emerging PDP best practices

Given that clinical development organizations are increasingly addressing the need to improve the PDP, some best practices are emerging. Ultimately, the goals of most of these initiatives seek to achieve four primary improvements:

• Clarifying roles and responsibilities to reduce the number of roles involved in the development of the protocol and to ensure that those roles are focused where they can contribute most value;
• Ensuring that protocol execution feasibility is consistently and comprehensively considered during the PDP to avoid costly rework caused by late modifications of protocols;
• Limiting the number of review cycles to ensure that each review cycle that is conducted adds value and is a worthwhile investment of time;
• Addressing the increasing number of operational decisions that need to be determined early enough in the process to allow for the selection and development of systems like EDC and ePRO.

Taking advantage of emerging protocol-authoring technology is one approach to achieving these goals. However, technology alone is insufficient. Technology must be coupled with careful process redesign to ensure that organizational objectives are achieved.

For any type of protocol process redesign to be successful, it needs to be supported by all functional areas that are involved in creating and executing protocol content. Unless all stakeholders’ needs are considered, it is unlikely that the final result will be sustainable.

As an example of successful PDP redesign, one development organization recently took the following steps:

• Gained senior management agreement to improve the PDP, including supporting and enforcing the new process;
• Identified technologies to enhance the PDP;
• Facilitated a series of cross-functional meetings to redesign the PDP and capitalize on new technology, specifically to ensure that a concept protocol was in place to support operational decisions; that a limited number of reviews were conducted by those who had the greatest value to offer; and that feasibility reviews were included as a formal part of the PDPs;
• Documented the revised process and worked with senior management to determine how the revised process would impact existing roles;
• Created training to support the new technology, new processes and new rolls;
• Conducted a highly supported rollout of new technology, processes and roles.

Generally speaking, any change effort, such as the one described above, must start with strong senior management backing, and that support must remain equally strong during the training and rollout of the new approach.

Implementing new technologies
As mentioned earlier, systematic explorations of factors that contribute to PDP design decisions commonly illuminate the need for new technology to meet business needs. In the case of the PDP, an extensible clinical protocol application is a practical technological solution for meeting those needs.
Extensible clinical protocols, sometimes called e-protocols or structured protocols, when fully realized, are semantically modeled representations of protocols with all key information structured to allow it to be manipulated and analyzed with aid from computers. A semantically modeled structured protocol offers opportunities for completely novel functionality to support existing business needs.

For example, consider a requirement for organizational control of protocol content. Suppose that a research sponsor has determined that a frequent cause of study start delays is related to protocol changes made late in the PDP process after certain critical-path operations have already been triggered. They might want to test "locking" portions of the protocol as it is being developed. Some document management systems are capable of locking document sections if those sections are saved as separate documents (or document versions). However, they cannot prevent changes to one document (version) that could affect another. To visualize this, imagine a protocol synopsis approved at Day 30 and then “locked” in a document management system. On Day 45, a protocol author adds a treatment arm in the full protocol under development. The full protocol is not reviewed by operations personnel until Day 60, when a discrepancy between the two protocol versions is first noticed.

The above scenario can be prevented with an extensible protocol application, because protocol synopsis concepts are simply reused in the full protocol. There may be many instances of a study concept like treatment arm in a protocol, but there is a unique concept of treatment arm represented in an extensible protocol model, albeit one that may have many different associated values (i.e., there may be multiple treatment arms). Because concepts are easily recognized by the protocol model, organizations can employ functionality we call concept locking.

A concept lock may be implemented in different ways. In the example given here, protocol owners might want to lock the concept of treatment arm at Day 30 to coincide with synopsis approval. If an author were then to try to add another treatment arm after Day 30 without permission to do so, the change could be disallowed or, in a less stringent implementation, it might only trigger an e-mail alert.

Although the foregoing example suggests a simple solution to the problem of late protocol changes, protocol concept locking is a potent means of controlling written content that can have unintended consequences if used injudiciously. Therefore, we advocate a stepwise approach to its implementation, anticipating likely responses to its use, while considering the need to alter other elements of the PDP in parallel in order to achieve the desired result.

Conclusions
Delays in study startup are one of the primary reasons studies fail to achieve initial timelines and budgets. Within the study startup phase, protocol development accounts for a majority of delays; therefore, many clinical development organizations are realizing that they need to improve the efficiency of their PDP.
The key to driving efficiency into the PDP is to understand where the current process fails. In this regard, we advise that organizations view their existing processes systemically, i.e., as an open system, with inputs, outputs, and connections between system components that determine overall system behavior.
Taking advantage of facilitative protocol-authoring technology is one approach clinical development organizations are employing to achieve more efficient PDPs. However, technology alone is insufficient. Technology must be coupled with process redesign to ensure that objectives are achieved. For example, an extensible clinical protocol application, when used judiciously and in harmony with process redesign, has the exciting potential to improve the efficiency and effectiveness of study startup and related development activities.

About the Authors:
Fredric Cohen, M.D., is VP, Clinical Strategy for Fast Track Systems, Inc.
Gary Tyson is SVP and Practice Area Leader for Campbell Alliance

Sponsored by Fast Track Systems, Inc., collaboratively written with Campbell Alliance.