For most compounds, the route from preclinical to clinical is clear. A comprehensive safety preclinical toxicology package is generated; the data from that package is then used to design the first in human (FIH) study in a healthy volunteer panel. This Phase I study will test the compounds safety and tolerability, as well as its pharmacokinetics in single, and multiple ascending doses. The data study from the Phase I study provides the springboard for the rest of the drug development program.
The route for oncology compounds however, can be somewhat different. Traditionally drugs which have oncology indications have poor safety and tolerability profiles, to the point that dosing them in healthy volunteers presents too much risk, and could be considered unethical. This coupled with the vast unmet patient need for effective oncology treatments means that the FIH study changes from dosing healthy volunteers to dosing directly in patients.
The benefits from this strategy are plain to see; preliminary efficacy data far earlier than the traditional route, safety and tolerability assessments which are directly relevant to the expected patient group, and giving patients earlier access to new treatments. Regulatory agencies require a reduced preclinical data package for straight to patient studies compared to the healthy volunteer route for oncology drugs, saving the drug developer time and cost.
Equally, however, there are also acknowledged challenges with performing Phase I trials (of any type) in a patient population. Subjects involved in these studies are cancer patients for which there is no current efficacious treatment available to them. This often means there are severe co-morbidities which can cloud the safety profile of the new test products. The disease state of these subjects also brings with it inherent variability into the drug’s pharmacokinetics, often due to hepatic or renal impairment. This further complicates assessments of safety, tolerability and efficacy because the exposure of the compound from subject to subject can vary significantly. Furthermore, the recruitment and conduct can be logistically challenging, and could require multiple sites and a much longer study duration than a traditional Phase I study in healthy volunteers.
In recent years, there has been a paradigm shift as drug discovery has improved. This has led to a generation of oncology targeted molecules which are more specific, and rely less heavily on general cytotoxicity. These new generation molecules, known as molecularly targeted agents (MTA) usually have a favourable safety profile, which can make them suitable for dosing in healthy volunteer studies.
There are significant, tangible benefits for studying oncology molecule in healthy volunteer studies, for example:
- Less variability within the population
- By their nature, healthy volunteers have more consistent physiology specifically regarding clearance routes, leading to less variable pharmacokinetic data
- Absence of co-morbidities makes assessing drug related adverse events clearer
- Logistically less challenging
- Studies in healthy volunteers can be run at any Phase I clinic with experience translating oncology molecules into healthy volunteers
- Studies can usually be conducted at a single site
- Healthy volunteers are ubiquitous to the general population, leading to a simpler and often quicker recruitment
In combination therefore, where safety allows, there can be compelling drivers for the use of healthy volunteer trials in the development of oncology molecules. In the past 5 years at Quotient we have performed over 50 Phase I studies of various types to reduce the time and cost of the development of oncology molecules. Examples have included:
- FIH studies where a molecule has presented significant biopharmaceutic challenges and formulation selection to ensure adequate bioavailability has been uncertain
- Relative bioavailability studies to optimize formulation compositions that were previously dosed only in oncology patients
- A full spectrum of regulatory clinical pharmacology studies including food effect, 14C ADME and DDIs
Getting preliminary information on efficacy as early as possible is of significant importance to oncology compounds in order to ensure that any patients taking the compound are not being exposed to ineffective or sub-therapeutic levels of the drug. With a healthy volunteer study, this understandably becomes more difficult, but not impossible. Healthy volunteer studies can still deliver meaningful pharmacodynamic data. An understanding of the pharmacology of the drug can allow for the use of clinically relevant biomarkers, for example in the following paper: https://www.sciencedirect.com/science/article/pii/S0149291818304272 , inhibition of basophil activation was used as a substitute marker for efficacy for a drug which targeted the PI3K delta pathway, and the data generated from this study helped to inform on the recommended Phase II dose.
Unlike other indications, translating an oncology molecule into a healthy volunteer study has a unique set of challenges, which is especially true for FIH studies. Medical review of the safety data will be required to assess whether the drug is suitable for healthy volunteer studies, following which a gap analysis of the preclinical safety package needs to identify if the regulatory agencies will require additional studies beyond what would be expected for a direct to patient route.
While the majority of the oncology development industry are still geared towards patient studies, traction is slowly building to align with other indications, and the use healthy volunteers for the Phase I drug development program.