By Mark Egerton
An effective drug product must deliver a new chemical entity (NCE) to the right place, at the right time, at the right concentration, for its beneficial effect to be expressed. The goal of the early development team is to deliver a drug candidate that is suitable for full commercial development, where nomination of the candidate is supported by a data package demonstrating some proof of safety and tolerability and proof of efficacy — albeit in a relatively small number of subjects. The project team must also recommend a drug product (e.g. formulation, dose strength) that will become the medicine that is available in the marketplace. For oral medicines, the competitive nature of the pharmaceutical industry inevitably means that a once or twice daily dosing regimen is key to success.
Oral drug products used in FIH (first in human) studies are often relatively simple (e.g. API in solution, suspension, or capsule). In most early development projects, the NCE must be transitioned into a more suitable form (e.g. formulated API in capsule or tablet) that can deliver reliable and reproducible exposure to enable the proof-of-concept study and subsequent progression into later development. NCEs currently emerging from the industry’s R&D pipeline, however, are often characterized with poor solubility and permeability, presenting significant challenges to optimization.
Conventional approaches to optimizing a drug product typically focus on a range of in vitro formulation systems which are screened in one or more preclinical in vivo models prior to selecting a small number of lead prototypes for testing in humans. The industry’s perseverance with this approach is surprising given its limitations. Translation of bioavailability between preclinical species and humans is poor, and the process is linear and “rigid” such that, if the formulations tested in the clinic fail to meet the target criteria, the project must retrench to the in vitro/preclinical phase. Since one cycle of this process can take up to 18 months and cost more than $1.5 million, the time and financial penalties on the development project are significant.
A NEW PARADIGM
Translational pharmaceutics offers a new development paradigm in which the screening and selection of candidate drug products is driven on the basis of human data. A technology platform that integrates formulation development, GMP drug product manufacturing, and clinical testing enables drug products to be manufactured and dosed in a clinical study within time frames as short as 24 hours. Furthermore, the clinical data obtained from one candidate drug product can inform the real-time manufacture and dosing of the next candidate within a 10- to 14-day cycle time.
The ability to respond to human data is maintained by the use of flexible clinical protocols and the incorporation of “design space” concepts into regulatory submissions, which secure preapproval to test a range of variable formulation compositions (as opposed to discrete predefined systems). There is no requirement for any in vivo preclinical screening of formulations. This innovative strategy ensures that all selection decisions are based upon human data, increasing the chances of success and the precision of the drug product that is finally selected.
Performance metrics from projects undertaken to date demonstrate that the time required to deliver an optimized drug product can be, at least, halved compared with the conventional process. The quantity of API consumed in this process is also reduced by 90% to 95% — delivering another significant benefit to the development project. Since this approach can be applied to all types of oral dosage forms, including solutions/suspension and solids, immediate release, and modified release, and can encompass all types of formulation technology, we anticipate that translational pharmaceutics will deliver a broad impact on overall development efficiency of oral medicines.
Dr. Mark Egerton is CEO of Quotient Clinical and has more than 20 years of experience in the pharma and biotech industries. He has worked in a range of organizations from large multinational pharma companies to private venture-funded biotech firms. He has a Ph.D. in biochemistry, and he began his pharmaceutical R&D career at Sandoz (now Novartis) in Switzerland and then Zeneca (now AstraZeneca) in the UK.