Moving a promising drug candidate from the laboratory to first in human (FIH) trials is a complex, multistage challenge requiring expertise in formulation development and clinical trial management. It is vital that early phase development and manufacture of materials is completed quickly and efficiently with consideration for later-stage trials and commercialization in mind to keep costs low.

An integrated, structured approach is critical to successfully navigating a pathway from the laboratory to the clinic. Experienced contractors are ideally positioned to help drug companies avoid the early phase development pitfalls that can see projects fail at a later stage.

This article discusses how linking formulation development to the planning and executing of FIH trials can help to take new drugs quickly and safely to proof of concept.

The clock is ticking
Delays in early phase drug development have significant cost implications for pharmaceutical companies.
The earlier a candidate product can be brought to market, the more revenue it generates for the developer which in turn allows them to invest more in research and development to support the generation of new medicines.

As a result, drug companies are under pressure to quickly identify the most promising candidates and safely move them into clinical trials. They also need to know when to halt development of a compound that has no potential.

Despite this, it is important drug companies do not rush early phase projects. One common pitfall is the temptation to use non-Good Manufacturing Practice (GMP) material during initial formulation work to save time.
While this approach can provide useful data, the solid-state properties of non-GMP material can vary greatly from bath-to-batch which may mean that the study start is delayed due to unexpected problems such as stability or dose homogeneity.

A better approach is to begin planning the development and manufacture of a drug product at least one year before the start of FIH trials. Effectively enacting this requires expertise and experience in process development and production management and that the teams involved can collaborate in an integrated manner.

Formulations for development success
When initiating a phase I study there is seldom time and money available for extensive formulation development. Around 63% of projects  are cancelled in early stage clinical development due to a poor safety profile.
Pressure is added as compounds that are successful in a FIH study usually need to be reformulated for later stage studies where factors like shelf life, rather than stability for the duration of the trial, become a factor. Drug companies can put themselves at a significant advantage if the formulations they use during early phase research can act as a foundation for the development of the formulations they will use in later stage trials. In some cases, it is possible to achieve this without increasing the cost and time schedule significantly.

There is a growing body of opinion that stability and bioavailability should be carefully considered during the development of formulations for FIH trials. The rationale here is that stability and bioavailability data are not only important for the FIH trial but can help shape the development and production of formulations for later phase trials and potential commercialization. Starting with the end goal in mind will allow potential challenges to be addressed early. Understanding of the critical parameters that impact drug quality and help to design strong processes and control strategies will ensure the manufacturing platform is optimized for late stage development.

Paying attention to these characteristics at the earliest possible stage also allows for more informed go/no-go development decisions, which ensures pharmaceutical companies are making the most of their R&D budgets.

API supply
Supply of active pharmaceutical ingredients (APIs) during early phase development is likely to be limited, which is often why simple formulations are favored for FIH studies as they require less drug substance for development.

Most sponsors call on contract development and manufacturing organizations (CDMOs) to produce drug substance for early phase trials as they are often better placed to develop production processes quickly in compliance with GMP.

Quality systems
The set up and maintenance of a suitable quality system is complex, and this is another reason why CDMOs are often used. In the European Union (EU), batches of medicinal product must be certified by a qualified person (QP) before they can be released. The purpose of the QP release is to guarantee that a product is safe to use. To ensure a swift release process, it is often advantageous when all parts of the manufacturing process, including quality control (QC), packaging and labelling are performed by one supplier.

Logistics, planning and safety in FIH trials
An integrated approach to early phase drug research that links formulation development to the planning and executing of FIH trials has many advantages for pharmaceutical companies. Collaboration can accelerate the study start-up by allowing subject screening to start as soon as the project has been cleared by regulators. Also, working with a partner that can coordinate all aspects of drug production processes can help to manage the complexity of the FIH study while ensuring necessary flexibility as needs change.

Perhaps most importantly is the impact an integrated approach can have on participant safety. Safety is one of the core elements of any FIH trial with an internal committee supervising the safety of the research subjects and evaluating pharmacokinetic data from each cohort before taking a formal decision on the dose for subsequent cohorts. New drug substances are usually tested in single ascending dose (SAD) cohorts and multiple ascending dose (MAD) cohorts. It is critical that dosages can be adjusted during such studies to identify the safe limits for subsequent studies. If predetermined toxicity criteria (dose limiting toxicity) are met, then this committee has the authority to terminate the trial. It is vital that anyone involved in monitoring a candidate’s safety, pharmacokinetic and pharmacodynamics properties communicate with formulation developers.

If the investigational medicinal product (IMP) is a protein or considered a high-risk compound, it is preferable to administer the dose intravenously which allows the clinic to stop the infusion if the subject should experience adverse reactions.

It is imperative that these factors are kept in mind during both the production and formulation of trial materials and that teams responsible for early phase formulation development communicate with those who will plan, design protocols and run the trials. Planning should begin early and involve the sponsor and all its partners. The focus is the production of a trial synopsis that defines the project’s objectives and endpoints. This document will be the blueprint for the study protocol.

Pathway to success
Successfully moving a compound from the lab to the FIH clinic is most effectively achieved using an integrated approach in which each stage feeds into the next in a predictable manner.

Planning a strategy that guides the candidate molecule seamlessly through formulation development and manufacture to delivery and administration to FIH study participants is the fastest, most cost-efficient way of completing such a project. Sometimes it is even possible to conduct multiple stages in parallel, such as clinical trial management and bioanalysis, further expediting timelines.

Working with contractors that have a broad range of integrated capabilities and experience is often critical to bringing a new drug to market quickly and safely. 

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Torkel Gren is Senior Director, Science & Technology Officer at Recipharm  AB. He holds degrees in Pharmacy and Business Administration as well a PhD in Pharmaceutics (Uppsala University). He has worked in the pharmaceutical industry since 1988 and has held a number of scientist and manager positions in Europe and US. He was lead formulator and co-inventor of Detrol OD/Detrusitol SR. Torkel is vice chairman of the board of the Swedish Pharmaceutical Society.