The Evolution of Adaptive Protocols: Early Clinical Development

In traditional early phase studies, discrete protocols and studies have been used for healthy volunteer and patient populations. However, over the past decade, a trend toward incorporating multiple study populations into one protocol has slowly gathered momentum among drug developers.

Instead of the standard approach where studies are designed to address a primary focus, a parallel study method — a format that incorporates multiple endpoints and objectives, modifications, treatment arms and dose selections into a single protocol — is being rapidly adopted. This results in more complex protocols but provides a flexible, adaptive and proactive approach.

The Benefits of Early Development Protocols

The evolution of early development protocols is driven by the desire to generate pharmacodynamic data and initial signals of efficacy. Managing study design in this way has multiple benefits.

Increased chance of success

In addition to being a more ethical approach, applying flexible decision-making on an ongoing and real-time basis reduces the burden of ineffective treatments. It also reduces the overall sample size by directing patients to dose levels or treatment arms that are showing a more positive outcome.

Improved prioritization

Promising pipeline candidates with a strong early development protocol may see a positive impact to the net present value of an early-stage asset.

Decreased timelines

A flexible and adaptive protocol provides the potential to expedite drug development timelines by decreasing the overall duration of the early development/Phase I stage. Expediting time to market in this way is extremely valuable for those who ultimately benefit from improved therapeutic care.

Resource efficiencies

Combining phases and creating a single protocol allows efficient resourcing and the retention of knowledge within a single team. Creating these continuities yields efficiencies and advantages for the contract research organization (CRO) and the sponsor when it comes to budget and historical knowledge.

Reduced financial impact

In addition to resource efficiencies for the overall budget, combining multiple phases reduces the financial impact within the startup phase. Requirements to submit ongoing data to the applicable authorities and committees is a more cost-effective strategy compared to the close and start of single protocols.

Stakeholder engagement

It has been shown that adaptive protocols increase investigator, site staff, volunteer and patient engagement as a result of efficiencies in site training, startup processes and program continuity.

Protocol Design: Starting with the End in Mind

Protocol design and development, with an expert focus on statistical considerations, are critical to ensuring success. Adaptive protocol designs allow for a flexible decision process, applying change with progression while maintaining robust confidence in the validity and integrity of the data. Designing and developing an adaptive strategy within the study protocol can be viewed as time-consuming, especially during the time-sensitive startup phase when the demands for a final protocol can be critical for downstream milestones. That said, when the protocol is thoughtfully designed and carefully constructed, it allows sponsors to consider:

• Refining the sample size
• Dropping treatment arms or doses
• Combining multiple study phases into a single design
• Redefining the primary endpoint

Combining statistical data, operational metrics and feedback, and data science enables:

• Quick, unbiased decision-making
• High-quality data production
• Correct and robust power calculation
• Targeted, proactive recruitment strategies

In addition to the protocol, patient-facing materials, such as the informed consent form, must ensure clear communication. The possibility for change needs to be ethically sound and clear to all involved, including investigators, site staff and cross-functional team members, like clinical monitors, statisticians, data managers and vendors.

Further operational considerations need to be carefully considered and planned in adaptive designs, particularly when multiple countries or centers are involved. A proactive and documented approach to decision-making, such as whether data is provided in a blinded or unblinded manner, ensures robust data quality and integrity are maintained. Potential changes made based on these decisions will have implications to the electronic case report form and data collection points. Therefore, a robust data cleaning plan and a flexible approach to visit scheduling become essential for timely data review.

In addition, a rapid turnaround on amendments to documentation and systems — such as electronic data capture, electronic diaries or patient-reported outcomes (e.g., ePROs, eCOA) — must be fully understood in the planning phase, ensuring these steps enable efficient change and adaptation of the protocol design.

Choose a development partner that understands how adaptive protocol designs can propel your study forward.

Our dedicated, global and highly experienced cross-functional early development team is ready to support you through this journey. Each member brings the right mix of early phase and global clinical development experience to provide a consultative approach to successfully design and deliver an adaptive protocol design that meets your unique needs.

The partner you select for your early phase studies is critical in enabling you to achieve your overall development timeline efficiently and within budget. You need a CRO that has an established network of carefully selected sites centered on quality, medical safety and unparalleled expertise.

The PPD clinical research business of Thermo Fisher Scientific has a global network of Phase I clinical sites that offer access to a diverse pool of healthy volunteers and specialty populations across four continents. With more than three decades of experience conducting Phase I trials, and more than 800 Phase I studies conducted in the past five years, our streamlined services help establish proof-of-concept by reducing time and cost from your development timeline. Each step of the process is conducted with an eye toward supporting later-phase programs and regulatory submissions.