White space refers to unproductive gaps in drug development, when progress stalls due to scientific barriers or because of process, communication, or decision-making inefficiencies. As speed-to-market and competitive pressures increase, white space is a key concern for drug developers and their contract research organisations, and one study suggests it may even be on the rise when transitioning drugs between clinical development stages.
In 2021, the Tufts Center for the Study of Drug Development published an analysis of Phase II-III transition times for drugs approved between 2008 and 2018, focusing on non-expedited review programs only. Their analysis revealed that 82% of the development programs had white space of approximately 17 months between Phases II and III. Moreover, the average length of white space increased over the decade; between 2008 and 2013, the average phase transition was 12 months, but between 2014 and 2018 this almost doubled to 21.6 months.
So, what are the primary causes of white space across the drug development lifecycle, and what opportunities exist to address them?
The problem with sequential processes
Drug development models have traditionally followed a linear structure, where each step waits for proper completion of the previous one before commencing. Such sequential processes can hinder efficiency across many aspects of development – from study start-up workflows, where sponsors typically wait for a finalised protocol before beginning feasibility work, to cross-functional reviews and sign-offs, where the protocol moves serially through different functions (clinical, biostatistics, regulatory, etc.), with each group reviewing only after the prior group has provided approval.
Sequential processes are a key driver of lost time in drug development, but addressing them can be challenging, since they are often built into risk management practices, standard operating procedures, and governance culture.
Meanwhile, data lags frequently worsen the challenge, with statisticians typically waiting for the final data to be cleaned and locked before starting programming, for example. This shows the ripple effects that a last patient last visit (LPLV) delay can have on clinical statistical report drafting and regulatory submission readiness. In this example, the resulting white space could be minimised by adopting a ‘rolling lock’ model, whereby data is locked at the patient cohort or visit level, or even by commencing statistical programming in parallel with late-stage data cleaning. In general, greater use of parallelisation offers significant opportunities for white space elimination, but this must be exercised carefully and strongly supported by directional insights.
Decision-making delays
Data lags are also a key concern when it comes to decision-making-related white space, with sponsors often postponing the decision to advance to the next phase until all data is available. This, too, has its ripple effects. While waiting on a go/no-go, downstream teams are unable to begin pre-designing the next protocol or engaging with vendors. With this preparatory work on pause, it can then take a while to mobilise such operations even after the green light has been received, contributing to further delays.
As technology advances, AI could become capable of predicting the likely outcomes of a trial before full data readout. Armed with this information, sponsors could then begin earlier preparation of their next-phase protocols and strategies, which could help teams to act as soon as the final results are confirmed.
Regulatory back-and-forth and ‘clinical hold’
Regulatory back-and-forth is a major source of white space between drug development phases. When investigative new drug (IND) applications, protocol documents, or dossiers are sent to regulators before all details are aligned, multiple rounds of clarification questions will result before the application can proceed.
If regulatory expectations are not met, the biggest risk is a clinical hold, when the FDA delays a proposed clinical investigation until the problems it identified are resolved. According to a report by America’s Seed Fund, product quality issues are the most common reason for a clinical hold, followed by clinical and toxicology concerns. In these situations, sponsors may be required to adjust their manufacturing process or conduct further studies to lift the hold. However, if the hold is still not lifted within a year, the IND application may be considered by the FDA for Inactive Status.
To avoid such delays from occurring at key junctures in development, it’s highly recommended to align with regulators as early into the development process as possible, discussing key questions during a pre-IND meeting, for instance. To ensure smooth regulatory interactions, sponsors must craft a comprehensive clinical development plan detailing every aspect of their development strategy to be discussed with regulators. As feedback is received, the plan is adjusted based on the agency’s requirements and expectations, which may help to avoid major delays later on.
In a recent whitepaper from clinical research organisation Fortrea, the company discusses opportunities to minimise white space, focusing on strategies that can be followed during early-stage development to build white space reduction into clinical development plans and ensure early alignment with regulatory agencies. Download the whitepaper below for a detailed guide on white space reduction opportunities in early development.
