From the start of Phase I to the completion of Phase III, the average clinical trial cycle has been increasing in recent years. Examining figures from the top 20 biopharma companies by R&D spend, data shows an average cycle length increase of seven months between 2020 and 2024, with cycle times now standing at 100 months (eight years).[i]
As sponsors face longer timelines, many are looking for opportunities to reduce white space – the unproductive gaps in development that occur during trial execution and when transitioning a drug between clinical phases. Many times, white space can be avoided through more effective planning or smarter approaches to protocol design. So, during study design, what options and opportunities can clinical trial teams consider to mitigate potential sources of white space in clinical development?
Adaptive trials
In 2021, a Tufts study concluded that sponsors with non-expedited review programs were facing an average transition time of 17 months when moving their molecule between Phases II and III. [ii] Adaptive and seamless trial designs offer an opportunity to close these gaps. Such trials combine two or more phases (generally Phase II and III) into a single adaptive study design, with decisions as to how to adapt the study based on interim analyses of the data. Common adaptations include the addition of an extra treatment arm or the discontinuation of a less successful one.
Seamless trial designs are not a new concept, but they are gaining traction[iii] and have been supported by the FDA as a way of improving efficiency in drug development[iv]. Adaptation rules must be fully pre-specified in the protocol, requiring extensive upfront planning as sponsors evaluate the full range of potential scenarios that could occur in development. As a result, initiating an adaptive trial takes longer than launching a traditional one, but once operational the reduction in white space is likely to offset the additional planning time.
Avoiding protocol amendments
When white space emerges mid-study, it is often driven by slow or failing enrollment, with an estimated 80% of trials experiencing delays due to recruitment problems[v]. Sponsors frequently respond by amending the protocol – a necessary move to avoid trial termination, but one that can significantly extend cycle times.[vi] Given that up to 45% of protocol amendments are considered avoidable, stronger protocols are essential in avoiding these amendments and getting trials right first time.[vii]
To consider an example, excessive inclusion/exclusion criteria are a common driver of slow recruitment and protocol amendments. When eligibility criteria is overly restrictive, the trial’s enrollment is impaired, particularly if the criteria has not been thoroughly validated with real-world patient data to support the target population exists. To put this into context, one study analysed 326 patients diagnosed with non-small-cell lung cancer to determine how many would qualify for two specific trials. Around 80% failed to meet the eligibility requirements. [viii]
By simplifying and broadening eligibility criteria, sponsors can accelerate their enrollment periods and avoid the need for a time-consuming protocol amendment.
Patient-centric protocol design
Beyond considering broader eligibility criteria, recruitment-related delays may be mitigated by placing greater emphasis on patient centricity in protocol design. By prioritising the patient’s experience and consulting patient advisory groups on potential trial designs, sponsors can create a study that is more appealing, accessible and convenient to participants, possibly helping to boost enrollment numbers and minimise patient dropouts.
Technologies like electronic patient-reported outcomes (ePRO), telemedicine, and mobile phone-based remote patient monitoring platforms could help to keep patients engaged in the trial, improving retention. At the same time, combining these technologies with other elements of decentralisation such as mobile clinical services can reduce the amount of site visits the participant is required to make.
When visits are necessary, patient-centric options include flexible scheduling and travel reimbursement, reducing the logistical and financial burdens of the trial. Meanwhile, when creating patient-facing materials such as consent forms and medication instructions, consider whether these are written in a way that is easy to understand rather than alienating patients with medical jargon or over complexity.
Overall, better protocol design is one of the most effective ways to prevent white space in clinical development. By incorporating the patient’s perspective in clinical trials, simplifying inclusion criteria, anticipating operational challenges, and embracing flexibility through innovative trial designs, sponsors can find ways to keep trials moving efficiently from activation to final results.
[i] https://www.statista.com/statistics/1419920/biopharma-clinical-trial-cycle-time/ [ii] https://www.appliedclinicaltrialsonline.com/view/characterizing-white-space-in-the-quest-to-drive-development-speed [iii] https://pmc.ncbi.nlm.nih.gov/articles/PMC4799596/ [iv] https://www.fda.gov/media/78495/download [v] https://pmc.ncbi.nlm.nih.gov/articles/PMC7342339/ [vi] https://www.appliedclinicaltrialsonline.com/view/acknowledging-cycle-time-impact-protocol-amendments [vii] https://pmc.ncbi.nlm.nih.gov/articles/PMC9811046/ [viii] Fehrenbacher L, Ackerson L, Somkin C: Randomized clinical trial eligibility rates for chemotherapy (CT) and antiangiogenic therapy (AAT) in a population-based cohort of newly diagnosed non-small cell lung cancer (NSCLC) patients. J Clin Oncol 27, 2009 (suppl 15s; abstr 6538)
