The first‐in‐human (FIH) clinical trial is an important milestone for each development program. For small (bio)pharma companies the FIH trial requires a significant investment, and every sponsor wants to make sure that all is well set for starting the trial. It is indisputable that successful execution of the FIH trials does require sponsors to coordinate the task with thorough consideration and planning across many disciplines. Especially, selection of the starting dose requires a cross‐functional collaboration, where preclinical knowledge needs to be transformed into clinical applications. This step could become a large hurdle which could even retard the progress of the program, if planned and strategic alignments are not reached within the project team as well as adequate actions are not taken well in advance of the FIH trial.
Over the past years, Venn Life Sciences as a consultant company, has been exposed to a significant number of FIH trials both in healthy volunteers as well as oncology patients. In this blog, we like to highlight several considerations, based on these experiences, that will need to be addressed for defining the starting dose and beyond in the FIH trial.
MABEL or NOAEL?
The EMA’s FIH guideline says, “Depending on the level of uncertainty regarding the human relevance of findings observed in nonclinical studies and the knowledge of the intended target, the starting dose should either be related to the MABEL (Minimum Anticipated Biological Effect Level), PAD (Pharmacologically Active Dose) or NOAEL (No Observed Adverse Effect Level).” Thus, the choice of MABEL- or NOAEL-based starting dose selection must be driven by overall assessments of available data and risk-based considerations. Typical factors for the assessments include but are not limited to:
It is highly recommended to make a rationalized choice of the MABEL- or NOAEL-based approach (e.g. using decision tree) with adequate documentation in investigator’s brochure, as this is a critical point of review by the competent authority/ethics committee.
Do you have sufficient/adequate data set for MABEL calculations?
To employ the MABEL-based starting dose establishment approach, it is essential that relevant data sets have been generated by the sponsor. Unlike toxicology (NOAEL)-based approach for FIH dose selection, which is rather straightforward, the type of data required for MABEL calculation can differ case by case (e.g. in vitro and/or in vivo data and in recent years increasingly involve modelling and simulation). Since generation of relevant data may take several months, any absence of relevant data for the MABEL calculation could cause a significant delay in the program. Therefore, it is pivotal that the project team plans this exercise way in advance of the FIH preparations.
How to define “minimum” effect?
One of the most frequently asked questions in terms of MABEL calculation is what degree of a biological response is considered “minimum”. Unfortunately, there is no standard answer for the question, and this is nowhere well-defined in the guidelines, as there are multiple unique factors that may need to be considered for each investigational product. For example, since receptor occupancy required for efficacy are expected to be different between antagonists and agonists even if the same receptor is targeted, different considerations are likely required for defining the MABELs for such cases. Ultimately, the sponsor is responsible to scientifically justify underlying rationale for defining the MABEL.
Starting dose calculation
While mechanistic state-of-the-art modelling (e.g. PK/PD and PBPK) is increasingly used in the calculation of the starting dose based on NOAEL, PAD and MABEL, it should be emphasized that the EMA guideline also refers to the application of allometric factors. Unless the drug product is associated with significant safety risk in human based on preclinical finding and/or a certain drug class (e.g. immune stimulator) and thus requires more sophisticated mathematical approach, empirical allometric scaling approach in combination with a simulation of exposure-pharmacological response relationship in human might also be sufficient for the starting dose selection for the FIH trial in healthy volunteers. Irrespective of approaches chosen, careful deliberation on the planning of the starting dose assessment is required, as unnecessary assessments during this process may also cause a delay in the program and a needless financial burden.
Applying safety factors
After the calculation of the MABEL, PAD, or NOAEL, additional safety factors are applied to account for several potential risks, such as the relevance of animal models, any uncertainties in the estimation of the MABEL, PAD, or NOAEL, or other unique safety or pharmacodynamic characteristics of the investigational product. Inadequate assessment of the safety factors may result in unnecessary risk for volunteers, or unnecessarily low doses in the first cohorts and as such additional dose escalation cohorts may be needed.
Be clever in trial design/protocol
Despite of all exceptional efforts and fancy mathematical MABEL calculations, pharmacokinetic properties might behave differently in human in the FIH trial, especially at the low starting dose, where PK tends to be non-linear. The clinical trial protocol, therefore, should clearly define the dose escalation rules to allow for the dose escalation to proceed in a scientifically, ethically as well as financially acceptable way. For example, the clinical protocol should include adequate language to allow for more aggressive dose increments, in case the observed exposure at the starting dose is significantly lower than predicted. Otherwise, volunteers will continue to be administered at dose levels even lower than the MABEL, which may result in the need of additional cohorts, or in the case of patients, treatment at an unnecessarily low and ineffective dose. We highly recommend authoring an adaptive FIH protocol, which will allow adjustments in the dosing schedule, circumventing delays in the trial execution.
Tom Habraken (MSc) is Consultant Clinical Pharmacokinetics at Venn Life Sciences. He has over 6 years of experience in pharma/consultancy industry. He is an expert in Clinical Pharmacokinetics and has been involved in FIH trials in healthy volunteers as well as oncology patients. Tom is also an organizer and trainer of Venn’s Pharmacokinetics Course (LINK).
Marieke van den Dobbelsteen (PhD) is Senior Consultant Clinical Development as well as acting as Group Leader in Clinical Trial Management and Medical Writing Team at Venn Life Sciences. She has over 25 years of experience in pharma/consultancy industry. She is an expert in early drug development (early-clinical) and has ample experiences in managing as well as providing consulting for early clinical development including FIH trials.
Theo Reijmers (PhD) is Consultant Pharmacometrics at Venn Life Sciences. He has over 6 years of experience in pharma/consultancy industry (+ >10 years in academia). Theo is a pharmacometrician and has ample experience in PK/PD translational modelling in early-stage drug development (e.g. human dose prediction for first-in-human studies). He also has experiences with submitting modelling related output to FDA and EMA.
Katsuhiro Mihara (PhD) is Senior Consultant Clinical Development as well as acting as Head of Clinical Development Department at Venn Life Sciences. He has over 25 years of experience in pharma/consultancy industry. Katsu has a broad knowledge on early clinical development, clinical pharmacology as well as translational science and has been involved in numerous numbers of early-stage clinical projects as well as scientific due diligence projects for investors/pharma.
If you are interested to learn more about how to define a safe starting dose for your FIH trial, please contact Venn life Sciences at BD@vennlifesciences.com. We would welcome the opportunity to discuss efficient set up of your FIH trial and other related aspects.