Laboratory data in healthy volunteers: reference values, reference changes, screening and laboratory adverse event limits in Phase I clinical trials

Sibille, M.; Deigat, N; Durieu, I.; Guillaumont, M.; Morel, Dominique; Bienvenu, Jacques; Massignon, Denis; Durand, D. Vital

doi:10.1007/s002280050586

Cited by 15 publications

(33 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… ¶ Un‐published data from the same healthy male population (same clinical pharmacology unit, see ref. [11].). …”

Section: Resultsmentioning

confidence: 98%

“… * Young male healthy subject data. Normal range values determined by non‐parametric procedure (2.5–97.5% of the distribution of data) [11]. …”

Section: Resultsmentioning

confidence: 99%

“… † Young male healthy subject data. Spontaneous variation limits (changes) determined by the 2.5–97.5% interval of variation in phase I conditions [11]. …”

Section: Resultsmentioning

confidence: 99%

“…The normal ranges and the calculation of the normal spontaneous variation reported here as an example are derived from data collected in one clinical pharmacology unit (Association de Recherche Thérapeutique, Lyon, France), and from young male healthy subjects (YMHS) only, under phase I study conditions [11]. Such parameter variations are then applied to upper or lower limits of normal ranges (ULNR or LLNR), as appropriate.…”

mentioning

confidence: 99%

See 3 more Smart Citations

A safety grading scale to support dose escalation and define stopping rules for healthy subject first‐entry‐into‐man studies

Sibille

Patat

Caplain

et al. 2010

Brit J Clinical Pharma

View full text Add to dashboard Cite

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • After the TGN1412 incident in London, the European authorities reinforced the safety requirements for first‐entry‐into‐man (FIM) studies. Their recommendations on risk management included a risk minimization strategy based on clearly defined stopping rules. However to date, there are no approved grading scales for clinical adverse events or safety findings to support dose escalation and to define stopping rules in order to mitigate the risks for healthy subjects participating in FIM trials. WHAT THIS STUDY ADDS • This paper proposes standardized methods for the grading of safety data (adverse events, laboratory tests, electrocardiogram and vital sign findings) based on relevant criteria. The proposed grading scale provides support both for dose escalation and the design of stopping rules. The derived safety thresholds are applicable at either an individual subject level or at a cohort level, and are specifically adapted to young male healthy subjects, who represent the majority of the subjects participating in FIM trials. AIM To propose a relevant grading scale for clinical adverse events or laboratory results, electrocardiogram (ECG) and vital sign findings supporting both dose escalation and stopping decisions in first‐entry‐into‐man (FIM) studies conducted in young healthy subjects. METHODS A three‐level scale was used for the proposed grading system. The grading is directly derived from the observed severity of discontinuous variables, as are most of clinical adverse events. A ‘combined method’ based on normal ranges and spontaneous variation is suggested for grading the findings which are continuous variables mainly numerical in nature. One grade, at the subject level, and one algorithm, at the cohort level, support the proposed decision rules. This work was managed by a Club Phase I working group. RESULTS Examples of grade 1, 2 and 3 limits are given for the most frequent clinical adverse events and laboratory tests, ECG and vital sign findings. When available, the proposed NIH and FDA limits are also provided. The safety recommendation is to use the grade 2 at least as an alert for caution and the grade 3 as a maximum for stopping, applying the algorithm at the cohort level. CONCLUSIONS This paper proposes a safety grading system based on relevant criteria which might be used by investigators and sponsors to support and rationalize dose escalation decisions in healthy young subject FIM studies. These proposals are designed not to be a guideline but some ‘points to consider’ helping the dose escalation process. This paper supports the recent reinforcement of the safety requirements for FIM studies by European authorities.

show abstract

“… ¶ Un‐published data from the same healthy male population (same clinical pharmacology unit, see ref. [11].). …”

Section: Resultsmentioning

confidence: 98%

“… * Young male healthy subject data. Normal range values determined by non‐parametric procedure (2.5–97.5% of the distribution of data) [11]. …”

Section: Resultsmentioning

confidence: 99%

“… † Young male healthy subject data. Spontaneous variation limits (changes) determined by the 2.5–97.5% interval of variation in phase I conditions [11]. …”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

A safety grading scale to support dose escalation and define stopping rules for healthy subject first‐entry‐into‐man studies

Sibille

Patat

Caplain

et al. 2010

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…Likewise, in human populations from different countries variability of laboratory values was observed (MiriDashe et al, 2014;Zeh et al, 2011). In studies in human volunteers, unwanted variations can be reduced by setting of appropriate selection criteria (Sibille, 1990;Sibille et al, 1999). Depending on the disease and parameters studied, interindividual variation in controls can be larger than in patients (Wagener et al, 2013).…”

Section: Discussionmentioning

confidence: 92%

Integrated analysis of toxicity data of two pharmaceutical immunosuppressants and two environmental pollutants with immunomodulating properties to improve the understanding of side effects—A toxicopathologist׳s view

Kuper

Vogels

Kemmerling

et al. 2015

European Journal of Pharmacology

View full text Add to dashboard Cite

Clinical Trials—Collecting Safety Data and Establishing the Adverse Drug Reactions Profile

Talbot

Keisu

Ståhle

2011

Stephens' Detection and Evaluation of Adverse Drug Reactions

View full text Add to dashboard Cite

Laboratory data in healthy volunteers: reference values, reference changes, screening and laboratory adverse event limits in Phase I clinical trials

Cited by 15 publications

References 9 publications

A safety grading scale to support dose escalation and define stopping rules for healthy subject first‐entry‐into‐man studies

A safety grading scale to support dose escalation and define stopping rules for healthy subject first‐entry‐into‐man studies

Integrated analysis of toxicity data of two pharmaceutical immunosuppressants and two environmental pollutants with immunomodulating properties to improve the understanding of side effects—A toxicopathologist׳s view

Clinical Trials—Collecting Safety Data and Establishing the Adverse Drug Reactions Profile

Contact Info

Product

Resources

About