From formulation development to Phase 1 clinical trials: Adopting an integrated approach to take new drugs quickly and safely to proof of concept

The complexity of getting a drug to first in human (FIH) studies means that development teams face a multitude of challenges as they navigate the route from formulation development and small-scale GMP manufacture, through to the management of their phase 1 clinical trial. Challenges in meeting timelines, adhering to regulations, overseeing trial complexity, and getting clinical material manufactured, call for a strategic roadmap that enables fast generation of data to build value in a compound.

Early phase development considerations 

Early phase development ensures that a compound achieves results during preclinical and FIH studies. Attrition rates are high; therefore, the use of simple formulations is most appropriate as they demand lesser investment in development time and costs. Drug developers are also at an advantage if they can plan the development of an early phase product in a way that provides a basis for later stages. 

Generating results quickly means that a drug product can move through the clinical phases faster. In the case of negative results, cost and further work can be saved by aborting the programme if problems are identified that cannot be rectified.

Common challenges during early phase development 

Stability and bioavailability challenges are routinely encountered in early phase development. A drug may suffer from poor stability in a solution or suspension and will need to be mixed with a liquid vehicle prior to administration. Bioavailability issues can also frequently be linked to poor solubility. At this stage, questions must be asked about whether formulation development is the right solution to a bioavailability challenge or if a modified molecule might present a superior development route. 

FIH trial considerations: close collaboration between CRO and CDMO 

In the planning, management and running of a FIH trial, patient safety is the primary endpoint. A new drug substance is usually tested in single ascending dose (SAD) cohorts and multiple ascending dose (MAD) cohorts. Both the SAD and the MAD can be done within the same protocol using a combined approach. 

An internal safety committee will review all safety data together with pharmacokinetic data between all dose cohorts. A flexible bioanalysis team will be fundamental in ensuring the quick handling of data received during the cohorts, while an established biometric data management process for the safety data needs to be in place as well as routines for determining key pharmacokinetic parameters. 

On the pathway to phase 1, the necessary development work for a pharmaceutical product is complex and problems may stretch across multiple disciplines. Multi- disciplinary collaboration at the various stages will not only increase the chance of success but will also speed up the pathway to clinic. 
 
Finally, the use of combined adaptive study designs can contribute huge value. The additional cost for using this type of approach can also be saved through a reduction in the number of studies necessary, while also creating significant time savings. 

Final thought 

While the use of simple formulations is imperative in progressing a compound to phase 1 trial, it is important to look at the broader picture during the early stages. Considering the implications of manufacturing a product to commercial scale from the outset can establish a more connected and efficient process. Collaboration between multiple disciplines and the adoption of integrated approaches to formulation development and trial management will be vital for developers in achieving their FIH milestones.

If you require support you can find out more about Recipharm’s development services and phase 1 support service Recipharm Pathway to Clinic®.