From formulation to clinic

Shaping an integrated drug development roadmap

The pathway towards first in human (FIH) studies is complex, with drug developers facing a multitude of challenges as they navigate the route from formulation development and small-scale GMP manufacture through to the management of their Phase I clinical trial. Many developers struggle to meet their desired timelines, adhering to changing regulations, overseeing trial complexity and getting clinical material manufactured, creating a real need for a more strategic roadmap that enables them to generate data quickly and build value into their compound.

Torkel Gren, General Manager at Recipharm Pharmaceutical Development, and Anders Millerhovf, CEO at Clinical Trial Consultants (CTC), discuss the key considerations in early phase formulation development and suggest a more integrated approach to take new drugs quickly and safely to proof of concept.

Key considerations for overcoming formulation challenges

Keep things simple: The main priority of early phase drug development is to ensure that a compound achieves results during preclinical and FIH studies. Early phase development, therefore, tends to focus on simple formulations with the aim of keeping both time and cost to a minimum.

Although an oral suspension, for example, may not be appropriate for commercial sale, it can be a satisfactory formulation for a Phase I study. Attrition rates are high, with just 10% of new candidates successfully being launched to the market. Therefore, the use of simple formulations can be most appropriate as they demand less investment in development time, while also making it relatively simple to vary the dose as required.

Success in early phase trials demands that new formulations of a compound be developed that are suited to larger studies, large-scale manufacture and commercial marketing, particularly in terms of shelf-life, economy and maximum therapeutic benefit. Although the goal for many smaller companies may be to sell a project at an early stage, these points remain a high priority as a complicated path to market will have implications when trying to attract a high price.

Drug developers are at an advantage if they can plan the development of an early phase product in a way that provides a basis for later development stages. This needs to be balanced against the need for simplicity, as stated above, and the need for speed and cost-efficiency. The use of formulation principles and excipients that are suitable for a commercial product should be considered whenever possible. However, one trend that could have a limiting impact on this type of approach is the pharmaceutical industry’s shift towards specialisation in drug development. While specialisation has its place, in this instance it can bring challenges as the parties that are active in early development don’t necessarily have the necessary expertise for later stages.

Timing is everything: Although timelines are important at all stages of drug development and manufacturing, they are perhaps most crucial during early formulation development. Generating results quickly means that a drug can move towards commercialisation faster. Alternatively, in the case of negative results, cost and further work can be saved by aborting the programme at any initial signs of problems that cannot be rectified.

There is little point in developing a formulation before a drug candidate has been selected or before the API has been manufactured in a large enough quantity. A more realistic strategy is to begin formulation development with small quantities of non-GMP material. However, this is not an approach that should be taken lightly. It is associated with its own risks as the solid-state properties of different batches vary considerably at this stage. Regardless, this type of work with early batches can contribute useful information to the drug development process.

Despite its importance, formulation development is often not given the necessary attention during the early stages and is often started too late. The need to forward plan is vital in ensuring an effective FIH study. It is recommended that planning for the development and manufacture of a drug product should commence at least one year before the start of a trial.

Overcoming poor bioavailability and stability

Challenges related to stability and bioavailability are routinely encountered in early phase development. In many circumstances, 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.

During Phase I, stability poses less of a challenge as drugs are not necessarily required to have a long shelf-life, although they must remain stable for the duration of the study. This warrants the need for simple stability studies to be established for each formulation.

Bioavailability issues can frequently be linked to poor solubility. It is vital that a formulation is developed that maximises the chance of good exposure — even if this contributes additional time and cost. 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.

The practicalities of implementing FIH trials

In the planning, management and running of an FIH trial, safety for the participating healthy volunteers or patients is the primary focus... and also 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. During an FIH trial, it is essential that a protocol is adaptive and that the delivered dose can be adjusted by the internal safety committee in between the dose cohorts within the limits stated in the protocol.

During the early stages of manufacturing planning, clinician input is also essential. If the investigational medicinal product (IMP) is considered to be a high-risk compound, it is preferable for the dose to be administered intravenously. This means that the clinic can stop the infusion if subjects experience side-effects. Dose escalation between cohorts is also important to consider during manufacturing. The problems are reduced by using oral solutions or infusions; but, if a capsule should be used, the potential future dosing steps need to be considered.

An internal safety committee will review all safety data together with pharmacokinetic data between all dose cohorts in an FIH study. A flexible bioanalysis team will be fundamental to ensure the quick handling of data received during the cohorts, whereas an established biometric data management process for the safety data needs to be in place, as well as routines to determine key pharmacokinetic parameters to ensure that data can be presented and evaluated prior to the next planned dose level.

Shaping the pathway towards clinical trials

On the pathway to Phase I, the necessary development work for a pharmaceutical product is complex and there are considerable risks that problems that stretch across multiple disciplines will go unsolved. This can present even more challenges when different contract partners are used for different services, such as API manufacture, formulation development, clinical trial management, clinical implementation and bioanalysis. Collaboration across the different disciplines at the various stages will not only increase the chance of success, but will also speed up the pathway to clinic.

Detailed plans should be established that include input from all disciplines. Although details will be subject to change, open communication will help to mitigate any potential challenges. Collaboration can also reduce any delays between the different stages — product development should be started when a quality API is ready, the clinical study should begin when the regulatory approvals are in place and the product is released, and bioanalysis should commence when samples from the first subjects are ready and then run in parallel with the remaining part of the clinical study.

Finally, the use of combined adaptive study designs can contribute huge value. The additional cost of using this type of approach can also be saved through a reduction in the number of studies necessary, while also creating significant time savings.

Closing thought

Although the use of simple formulations is a tactical imperative in progressing a new compound to Phase I trials, it is important to look at the broader picture during the early stages. By taking steps to consider the implications of manufacturing a product to commercial scale from the outset, a more connected and efficient process can be established.

Collaboration between multiple disciplines and the adoption of more integrated approaches to formulation development, and subsequent trial management and implementation, will be vital for drug developers wishing to achieve their FIH milestones and proof of concept.

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