Adaptive Designs and Clinical Supplies

This is a guest post by Margaret Schubert.  Margaret is a Senior Pharmaceutical Development Specialist at Cato Research.

In a recent post, John Johnson discussed the FDA’s draft guidance on Adaptive Design Clinical Trials for Drugs and Biologics, particularly in the context of planning and designing a clinical trial.  My perspective concerns challenges related to clinical supplies (CS) presented by adaptive trial designs.

FDA defines an adaptive design clinical study as “a study that includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data (usually interim data) from subjects in the study.”  The two key words in this definition, especially in terms of clinical supplies, are ‘prospective’ and ‘modification.’

Adaptive trial design modifications which will affect clinical supplies include dropping or adding treatment arms, change in allocation to treatment arms, changes in planned sample size or dose groups and changes in primary endpoint. Each of these changes must be prospectively planned in order to assure a continued flow of clinical supplies for ongoing clinical trials.  Formulation development, manufacturing, analytical testing, batch scale up, packaging, labeling and distribution are each affected by changes in trial design.    While adaptive trials can potentially streamline drug development, inadequately planned CS activities can rapidly become an Achilles heel.

Adaptive trial designs compress the timelines for formulation development and manufacturing such that more advanced formulations must be developed earlier in the sequence of activities than with traditional designs.  Batch scale up is often required earlier as well, especially if combined Phase II/III designs are planned.  Analytical testing must keep pace with the changes in formulation, batch size and packaging, while information requirements for the NDA must also be considered at much earlier stages.  While the FDA guidance CGMP for Phase I Investigational Drugs provides consideration for early stages of drug development, requirements for the NDA filing may preclude these allowances in the case of adaptive trial designs.  Additionally, forecasting quantities becomes less predictable and more challenging.  Larger pharma companies will often significantly over-produce to allow for worst-case scenarios, but smaller pharma companies may not have the bulk active pharmaceutical ingredient (API) or budget to allow for massive overproduction and must often find more creative solutions to supply issues.

CS packaging, labeling and distribution must also be prospectively planned in conjunction with development of the clinical trial protocols rather than as an afterthought.  Many traditional clinical trial packaging and shipment plans provide site specific or even subject specific packaging configurations.  Adaptive designs require much more flexibility and creativity to make maximum use of available drug product and API supplies, again particularly for smaller pharma companies.  Complex trials with large numbers of sites in many countries or numerous dose levels present particularly daunting challenges for this type of trial.  Packaging, label requirements, language requirements and shipment issues are all impacted by adaptive designs.  Costly and time-consuming CS wastage, undersupply, and over-labeling can be avoided with creative solutions including multi-language or booklet labels or just in time and On­Demand labeling and packaging.

Finally, if any of the above drug development functions are outsourced, careful vendor selection and management for adaptive trials is even more critical than for traditional designs.  Capabilities, flexibility (adaptability), capacity and creativity must be proactively assessed for all activities involved.  Close monitoring of vendor activities to maintain accelerated but often variable timelines is required to maintain an uninterrupted flow of CS for adaptive clinical trials.

Prospective discussion and planning of potential trial modifications with regards to clinical supplies are the key to successful adaptive clinical trial conduct.  Without forethought, planning and discussion of all aspects of formulation development, manufacturing, scale-up, analytical testing, packaging, labeling and distribution, adaptive trial designs can rapidly become unwieldy and headed for failure.

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