Metrics

Powell explains that the fit-for-purpose approach involves purposeful trade-offs in resourcing support levels for early- development stage compounds. "The advantage is that by limiting our upfront investment, we are now effectively supporting an early clinical pipeline which has increased more than 50% in the last three years with the same headcount and budget as before," he says. "Additionally, early compounds are proceeding to critical decision points faster then they ever have before. The trade-off is that for those selected compounds that make it successfully past proof of concept, there could be a significant amount of concentrated API and formulation work necessary to progress the programs and support timely progress in late-stage clinical development. But we are looking at our resource allocation across the entire product portfolio and feel these trade-offs are worth it."

Bristol-Myers Squibb has developed specific metrics to quantify the cost and time benefits in this fit-for-purpose model. The company has reduced the amount of API that it produces for early-stage clinical-trial materials by approximately 50%. The company also uses a metric to assess the time it takes between declaration of an exploratory candidate nomination (ECN), the term the company uses to identify an early-stage drug candidate that has moved from the discovery phase to early development, and the start of the first good laboratory practice (GLP) toxicology studies. The rate-limiting aspects of this metric are normally the availability of GLP API. Using that metric of time from ECN to first GLP toxicology studies, Bristol-Myers Squibb has been able to reduce this average time from a historical base of approximately six months to essentially zero time, meaning that GLP toxicology studies can start immediately upon ECN declaration. That is a time savings that directly allows projects to reach critical decision points sooner than ever before and faster than industry benchmarks. A direct result of working more efficiently is that the Pharmaceutical Development group can now support a clinical development pipeline with 64 active compounds with the same number of people that previously supported 40 compounds.

Powell explains that the fit-for-purpose model was adapted by Bristol-Myers Squibb three years ago and was born out of the need facing many companies of how to do more with less. "In evaluating our strategy in drug development, I assumed that our resource allocation for early drug development would be tied into the company's overall R&D organic growth projections, and we needed to adopt a model that would fit into those constraints," says Powell. "We needed to accept some trade-offs in implementing the model and get comfortable with the idea that not every compound would be supported at the same level early in development."

Although delaying formulation optimization is part of the fit-for-purpose model, the company still deploys new formulation technologies for specific compounds where necessary in early development, notes Powell. Examples are technologies that enhance the bioavailability of poorly water-soluble molecules. As a consequence of the increased number and diversity of new molecules coming from combinatorial chemistry and high-throughput screening in drug discovery, solubility has emerged as an important problem that often has to be solved before dose selection in clinical studies. Solid-based systems, such as coprocessed solid dispersions and liquid-based systems, are both amenable to the model. Coprocessed solid dispersions can be manufactured using spray drying at small scales without extensive optimization and be delivered in either simple powder-in-a-bottle or powder-in-capsule formulations. Lipid/surfactant solutions are amenable to the bottle-based approach as well as hard-gelatin capsule formulations. If the drug candidate proceeds to commercialization, both approaches can be readily extended to larger-scale manufacturing—spray drying or hot-melt extrusion for the solid-based approach, or soft-gelatin capsules for the liquid-based approach. Powell concludes that the selection of the solubilization approach mirrors the fit-for-purpose model for poorly soluble compounds: the choice is based on a balance of cost versus technical considerations that are appropriate to the candidate in early development.

Powell sums up the fit-for-purpose model: "It is all about how to best apply money, people, and technology to reach the key development decision points for every compound as fast and as efficiently as possible. We think this is an overall model that best addresses those issues."

Reference

1. PhRMA, Pharmaceutical Industry Profile (Pharmaceutical Research and Manufacturers of America, Washington, DC, 2010).