First in Human (FiH) studies in healthy volunteers – a 10 years review
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1
Bayer AG, Department of Clinical Pharmacology CV/HEM, Germany
Background: The tragic incident of Rennes, in which a healthy volunteer died in a FiH study, led to a European draft guideline
on “Strategies to identify and mitigate risks in FiH and early clinical trials” including recommendations for starting doses, dose
escalation, and maximum doses for FiH trials.
Methods: We reviewed all Bayer cardiovascular FiH trials from 2006 – 2016 with respect to the proposed dosing
recommendations.
Results: 24 FiH studies (22 NCEs, 2 biologicals) were performed. 7 compounds were stopped during or after FiH (insufficient PK
n=5, lack of tolerability n=2; hypotension). 20 NCEs started below and 2 (well-known mechanism) with or above the anticipated
minimum effective dose (MED). For biologics MABEL approach was used. Ratios of actual vs predicted exposure for the first
dose were within 3-fold for > 70% of compounds. Doses were escalated up to a factor of 3 (low doses) and 2 (higher doses). PK
and PD were measured at all dose steps. No MTD approach was used. For NCEs highest doses planned exceeded start doses by
a mean of about 100 fold (equaling about 8 dose steps) and MED of about 50 fold. Due to the MABEL approach higher increases
above starting doses were planned for biologics. Maximum doses administered exceeded the anticipated MED by a mean of 30
fold (NCEs and biologics).
Conclusion: Major components of the guideline apply already now; starting doses were chosen higher for known MoA.
Maximum doses exceeded the anticipated therapeutic dose to cover for potential variability in patient exposure/response.
Keywords:
Safety,
prediction,
Dose,
escalation,
First in human,
FIH
Conference:
EUFEMED 2017, London, United Kingdom, 17 May - 19 May, 2017.
Presentation Type:
Poster
Topic:
EUFEMED 2017 CONFERENCE
Citation:
Jung
D-,
Mueck
W- and
Wensing
G-
(2019). First in Human (FiH) studies in healthy volunteers – a 10 years review.
Front. Pharmacol.
Conference Abstract:
EUFEMED 2017.
doi: 10.3389/conf.fphar.2017.62.00002
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Received:
29 Aug 2017;
Published Online:
25 Jan 2019.
*
Correspondence:
Dr. David - Jung, Bayer AG, Department of Clinical Pharmacology CV/HEM, Wuppertal, Germany, david.jung@bayer.com