Torkel Gren, Recipharm and Anders Millerhovf, CTC Clinical Trial Consultants discuss the steps needed for drug formulation during first-in-human (FIH) trials, if regulatory approval is to be achieved.
Drug Formulation
How a candidate drug is formulated for and assessed in first-in-human (FIH) trials are significant factors in determining whether it goes on to win regulatory approval.
No drug is approved unless it shows efficacy and a favourable safety profile in a Phase III trial. However, the path to late phase assessment begins when a promising compound is selected for development. Decisions taken during early phase development, when the compound is being prepared for the clinic, have a significant impact on its progression through late phase research.
To that end, it is vital that all steps along the early development pathway – from formulation through manufacturing and FIH studies – are carried out in an integrated manner, while the ultimate goal –approval – is kept in mind.
The formula for success is …
The first step on the pathway to clinic is formulation development. The aim is to choose a dosage form that can be produced to the correct quality specifications, quickly and cost-effectively. In general, simpler forms like oral liquids, powders or capsules are favoured.
In formulating a product for FIH a number of factors need to be considered. Of these, bioavailability and stability are of particular interest as they often present challenges.
In terms of stability, FIH formulations do not need a long shelf-life, they only need to be stable for the duration of the study. In contrast, formulations used in late-stage trials do need to demonstrate long term stability. In addition, bioavailability is vital in order to achieve an adequate exposure to the drug. This is just as important irrespective of phase. However, many advanced systems such as nanoparticles may have disadvantages in later stages as they will call for more complex formulations and consequently increase manufacturing cost.
In order to achieve satisfactory performance, the formulator may vary composition and processing:
Composition – it is critical the best combination of active pharmaceutical ingredient (API) and excipient is used to minimise waste and dosage form size. Usually, excipients used for FIH formulations are selected because they minimise API degradation and ensure the required release profile and stability characteristics.
Processing – producing FIH formulations is about balancing rapid, low-cost manufacturing with the need to establish a process that can be scaled-up. For example, when developing a process for an FIH formulation, it is important to ensure that it can be performed in a robust fashion on small batches. The process does not need to be identical in larger scale but it is advantageous if a similar process can be performed in large scale on standard pharmaceutical equipment.
… Keeping late stage trials in mind
When creating an FIH formulation it is important that late stage development is kept in mind.
The reality is that most drugs in clinical development fail, including those that show promise in FIH studies. Part of the reason for the high attrition rate is that key performance characteristics - such as solubility and bioavailability - that are easily achieved in simple FIH formulations are hard to replicate in the more complex dosage forms suitable for large, late stage trials and launch. It may be that these problems are eventually overcome but with significant delays.
To minimise the risk of such problems it is vital that teams involved in the development of FIH formulations work closely and share key data with those involved in creating formulations for later trials.
The rationale for this approach is that useful stability and bioavailability data can shape development and production of formulations for later phase trials and - potentially - commercialisation.
One of the most effective ways of doing this is to work with a contractor experienced in both early and late stage development.
Starting with the end goal in mind will allow challenges to be addressed early. Understanding of the parameters that impact drug quality and designing strong processes and control strategies will ensure manufacturing is optimised for late stage development. A lot of this can be achieved without delaying the FIH study.
Clinical trial planning
A number of factors need to be considered when planning and executing an FIH study, of which volunteer safety is always the primary concern.
There are well established safety protocols for Phase I studies, such as the use of single ascending dose (SAD) cohorts and multiple ascending dose (MAD) cohorts as well as the employment of adaptive protocols.
Also, as stated above, use of a formulation that is appropriate to the study is important. For example, if the candidate drug is considered a high-risk, it is preferable for it to be formulated for intravenous administration. A slow intravenous infusion can easily be stopped if serious/severe adverse drug reactions occur. Likewise dose escalation also needs to be considered during manufacturing to fit the planned dose levels in the FIH study and possible adjustments from the initial dose plan between cohorts.
Therefore it is very important that clinical trial teams work closely with those involved in formulation and manufacturing process development. In addition collaboration can help reduce any delays. For example, product development should be started when a quality API is ready, the clinical study should begin as soon as the regulatory approvals are in place and the product is released.
Goal in mind
It is also crucial to keep in mind that FIH studies are part of an overall clinical development programme.
Phase I studies are used to determine a candidate compound’s safety and side effect profile as well as how it is absorbed, metabolised, and excreted. Clearly this information shapes the design of later Phase trials.
Final thought
The pathway from laboratory to FIH studies is important because it is part of a longer journey. Phase I studies are the foundation which support the entire clinical development and regulatory programme and how they are conducted is key.