While development of pharmaceutical products has traditionally followed a phased approach, a continuous model of development is possible and offers substantial reductions in development timelines and risk. Historical chokepoints demanded a “batched” approach during trials and between phases. Many things have changed, but the chokepoints largely remain. It’s time to do something about them.
The chokepoint during trials is often the availability of clean, actionable data. Technology is rapidly addressing this issue. For example, tablets, Health Decisions’ digital pen (SmartPen™), and some e-PRO tools enable immediate availability of data. Rapid validation and correction enables tracking minute-by-minute rather than monthly or quarterly. Even more important is coupling that immediacy to performance metrics, enabling continuous evaluation and refinement of key operational considerations such as enrollment strategies. Immediacy of information enables us to determine safety and efficacy and identify operational problems much more quickly. With the appropriate infrastructure, we can respond immediately. Technology also enables immediate data collection as electronic source, obviating the need for source verification.
Whether a problem lies with study design, choice of population or the drug itself, early knowledge enables midcourse adjustments. Frequent midcourse adjustments to operational details can improve efficiency in countless ways. We can also immediately incorporate new information with existing knowledge, enabling us to project the most likely future scenario. This enables big decisions that optimize the course of a whole development program and even portfolios, whether by adding resources to accelerate development of promising candidates or shifting resources to other candidates with brighter prospects.
Often between-phase delays are a remnant of the paper-CRF days. Fully cleaning data waits until the end of the study. Only then can there be an analysis that provides a basis for determining next steps. Regulators are accustomed to waiting until the very end and the sitting down to consider final trial data. Without question, it is easier to review a trial a single time during gaps between trial phases, with everything you need in front of you. However, this perspective is no longer necessary and can be very costly.
Furthermore, seamless adaptive designs have the potential to eliminate traditional between-phase gaps and transform development into a single continuous process. Don Berry states, “Phases of drug development are arbitrary labels that describe a process that is—or should be—continuous.” (Stat Sci 2004; 19:175–87). However, regulatory processes are anything but continuous and can seldom keep pace with the available trial design methodology.
The FDA does offer programs to accelerate development – Fast Track, Breakthrough Therapy, Accelerated Approval and Priority Review. But these programs rightly focus limited resources on areas of greatest need. They are the exception that proves the rule: unless products meet the criteria for these special programs, they have to wait. In practice, virtually all products wait.
The reason for many regulatory delays is simple – resource constraints at the FDA. We may be able take a practical step that sweeps needless between-phase delays aside. The Medical Device User Fee Amendments of 2012 provide a model. The amendments authorize the FDA to collect user fees for review of premarket device submissions with the goal of enabling the review process to meet stated performance goals.
Why not enact similar legislation to increase resources available to the FDA for reducing between-phases delays? Needless to say, pharma companies would have no influence over the expedited review process. They would pay to expedite an independent assessment that might or might not be favorable. What pharma would get is:
- a way to address the routine delays that reduce the Net Present Value or threaten the viability of many products; and,
- the power to decide on their own terms which of their products merit an earlier review.
The only test of whether a product receives an earlier review under this program would be the sponsor’s decision to pay the user fee. There would be no need to prove that products meet any other criteria. The result of expedited review in each case might be failing faster rather than advancing faster. Pharma would win either way, whether by freeing funds for other projects or gaining earlier market access for successful products. Ultimately, patients would win, too, through earlier access to new medicines that bypass typical between-phase delays.