Amidst escalating development costs, increased molecule attrition, and reduced R&D productivity the general philosophy in the last decade for first-in-human (FIH) studies has been to “go simple” and use rudimentary fit-for-purpose/phase formulations.
A major benefit of this strategy is to minimize the upfront CMC investment, which (in theory) will reduce the time and cost of generating initial clinical data to characterize safety, tolerability, pharmacokinetics, and pharmacodynamics. As such, many FIH drug products are therefore simple formats, such as solutions, suspensions, powder-in-bottle, or powder-in-capsule, which require minimal development investments and can be prepared in a compounding pharmacy or basic manufacturing or dispensing processes.
There are, however, some risks, which challenge the validity of a simple fit-for-purpose/phase philosophy in the context of today’s drug development priorities. First, most new chemical entities (NCEs) today present significant biopharmaceutics challenges, such as poor solubility, which greatly affect drug delivery success 1. Formulation technologies and GMP manufacturing operations are frequently needed to develop enhanced dosage forms for optimal delivery and bioavailability of the drug in the clinical study. Secondly, the major value inflection point in early development is not the speed at which you achieve FIH, but rather the time it takes to get to proof-of-concept (POC) in a patient population. Simple FIH formulations will typically not “have the legs” to be utilized in early patient studies – where a suitable solid oral dosage form is required. This presents a number of hurdles for the development team to manage; extra time, increased cost, and the technical risks associated with product development.
In other words the current development model is self-contradicting – by “kicking the formulation can down the road” the time, cost, and flexibility benefits of the FIH trial are countered by the delays and risks in achieving an accelerated POC milestone.
A new approach is therefore needed – how can we achieve accelerated timelines while still managing CMC investments and mitigating development risk? We believe the answer lies in retaining a relentless focus on good science and program integration, which includes:
- Understanding the biopharmaceutics properties and risks of NCEs
- Using the Developability Classification System (DCS) to inform formulation strategy and technology selection2
- Leveraging in silico and biorelevant in vitro characterization methodologies to simulate and predict the clinical performance of molecules and formulations
- Retaining simplicity for FIH drug products, using pharmacy compounding or basic manufacturing processes, but using enabled GMP intermediates if needed (e.g. spray-dried dispersions (SDDs), micronized drugs) to ensure adequate bioavailability
- Look to evaluate different formulation technologies and dosage forms within the FIH study or in parallel to select a lead system to move forward
- Exiting the FIH study having already developed a clinically proven solid oral drug product for patient trials
- Seamlessly start Phase II trials on time with an immediate supply of clinical trial material
This new model is not conceptual. Quotient Sciences has been designing and performing these programs for pharma and biotech customers for over a decade with integrated pharmacy compounding, GMP manufacturing, and clinical pharmacology operations.
A Tufts CSDD research paper has described how Quotient Sciences' Translational Pharmaceutics® platform has been used to significantly accelerate FIH-POC programs. This approach can save on average 15 months of development time for POC, equating to reduced R&D costs of $135m and an overall financial gain for molecules reaching the market of over $250m.
In today’s world, proven early drug development strategies are now available to reach both the FIH and POC milestones quickly and cost-effectively. It doesn’t have to be one or the other.