Company insight Hybrid FIH trials: Advantages and challenges
SGS is the world’s leading inspection, verification, testing and certification company, and it is recognised as the global benchmark for quality and integrity. Nariné Baririan, director of consultancy and clinical pharmacology, Katrien Lemmens, medical director CPU, and Arash Ghalamkarpour, associate medical director, at SGS respectively, discuss the advantages and challenges of first-in-human (FIH) studies in hybrid clinical trials.
F
irst-in-human (FIH) studies are the key translational studies in the drug development process linking preclinical studies to late phase clinical trials. Except for genotoxic/cytotoxic oncology drugs, FIH clinical studies are traditionally conducted in healthy volunteers (HVs), which seems ideal for this type of early clinical research. There are many benefits of conducting FIH trials in HVs, such as a straightforward recruitment process with usually available large database in a clinical pharmacology unit (CPU), absence of major comorbidities and concomitant medications, possibility of long-time confinement, intensive assessments (for example, PK sampling), acceptance of wash-out periods and placebo groups, and low drop-out rate.
regulatory authority challenges related to risk/benefit justification.
FIH clinical trials have evolved from the traditional dose and toxicity-finding studies in HVs to innovative complex study designs, sometimes requiring both HVs and patient’s involvement. These hybrid trials may be seen as a solution to benefit from having both HVs and patients in the study, while simultaneously mitigating the potential downsides. That being said, hybrid trials should not be considered a one-size-fits-all approach.
Design an appropriate hybrid FIH trial
There are multiple different considerations to take into account prior to commencing a hybrid trial. Does the CPU or clinical
“FIH clinical trials have evolved from the traditional dose and toxicity-finding studies in HVs to innovative complex study designs, sometimes requiring both HVs and patient’s involvement.”
Not a one-size-fits-all approach However, there are also a number of drawbacks to consider. HVs won’t gain any particular health benefit from the administered drug, and pharmacodynamic/ efficacy data might be limited in scope, or of no use, as the target pathways are often expressed only in the pathological cells. Other disadvantages when performing the FIH study exclusively in HVs are difficulties when extrapolating a healthy subject’s data to patients, conservative doses selection and escalation criteria, required strong preclinical data, limited number of multiple dose exposures, and
Clinical Trials Insight /
www.worldpharmaceuticals.net
research organisation (CRO) have the capacity to support a complex hybrid trial? There are a number of CPU-related challenges when conducting hybrid trials within a phase-I unit. However, if recruitment allows, performing the HVs and patient parts in the same unit would be of extremely added value. No trial method will survive a poor study design, therefore, when conducting hybrid FIH trials with patient involvement, it’s crucial that the design is appropriate. It should be investigated whether addition of patients into the study is justified and efficient to observe response to treatment
within a rather short study timeline. Another challenging aspect is regarding patient accessibility and recruitment, since early phase studies in general are not of high therapeutic benefit for patients. Moreover, only a subpopulation of patients may be eligible for the early phase hybrid trials with less comorbidities – so called ‘healthy patients’. When assessing the feasibility of such trials, qualified clinical trial sites that are capable to perform the study should be identified. Regulatory requirements must also be taken on board when designing a hybrid FIH study and, if necessary, a scientific advice can be sought with the agency. Similarly, consultation with patients and patient associations should be taken into account. To be also considered, with the inclusion of both types of population in the same study, multiple objectives are included in a single protocol resulting in increased trial complexity. So, there is a need of a flexible protocol and robust regulatory basis. Additionally, small biotech companies working on one individual project will likely have a different clinical trial strategy compared with large institutions, which is also influencing the choice of population for FIH studies. For some pathologies, FIH trials are particularly well-suited in hybrid clinical trial models.
Thus, how should clinical study teams determine whether or not to run a hybrid trial? It must be answered using a science- driven approach within an experienced multidisciplinary team rather than hunches or mere assumptions. ●
www.sgs.com/cro 37
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