In this white paper, Broughton summarises the ‘historical’ development plan for pharmaceuticals, the changes that have occurred with regards to differential development including the requirements for biologicals, the typical challenges the industry faces now and, in the future, the opportunities this brings.
This white paper forms a simplified reference point for developing pharmaceuticals both now and the future and some of the choices/challenges companies have.
Many scientists working within the pharmaceutical sector over the past 30 years will recognise the typical pre-clinical safety development plan (see figure 1).
The duration of discovery activities is defined by the speed of success and the amount of screening conducted, therefore they are included here for completeness only. Once promising targets are identified via efficacy studies, disease models and Pharmacokinetics (PK) studies, the initial safety screening occurs with in-silico structure activity modelling and in vitro mutagenicity assays to candidate selection with in vivo screens to identify target organ toxicity and cardiovascular endpoints.
Once candidate selected, and in many cases, this may involve multiple compounds of the same class, development begins in earnest with dose-range general toxicology studies re-assessing the previously identified target organ toxicity with an aim to defining early exposure safety margins in both rodent and non-rodent species. Concurrently, costly drug synthesis is green lit alongside key formulation development activities, analytical method development and validation exercises. To coincide with the arrival of the GMP drug substance with appropriate certificate of analysis, the safety assessment studies comprising a battery of general toxicology, safety pharmacology, genetic toxicology and formulation stability will commence to support entry into the clinic. The readout of these studies, subsequent regulatory submission and internal safety board swiftly leads into the first clinical trial, typically in healthy volunteers.