Patat Alain Yes Donazzolo Stopping Rules APA BERLIN 2

55 Pages·2011·0.51 MB·English

STOPPING RULES
IN FIRST ENTRY INTO HUMAN STUDIES
Club Phase 1 Working Party:
Alain Patat, Yves Donazzolo, Henri Caplain, Stephan Chalon,
Michel Sibille
Joint Conference of European Human Pharmacological Societies and 20th
Anniversary of AGAH
AGAH, CLUB PHASE I, AHPPI & BAPU
BERLIN, 31 Mar - 01 APR 2011
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Joint conference AGAH - BAPU - Club Phase I - AHPPI - Berlin - 31 March to 1st April 2011
WHY
French Club Phase I Working group : Br J Clin Pharmacol 2010 70:5 736–748
French Club Phase I Working group: A safety grading

scale to support dose escalation and define stopping rules
for healthy subjects first-entry-into-man studies. Br J Clin
Pharmacol 2010 70:5 736–748
New requests by regulatory authorities after TGN 1412

tragedy – London 2006
 Improve and facilitate decision making in dose escalation
studies as requested by EMA guideline on Strategy to
Identify Mitigate Risks for First in Human Clinical trials
with Investigational Medicinal Products
 Using risk assessment & minimization strategy
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Joint conference AGAH - BAPU - Club Phase I - AHPPI - Berlin - 31 March to 1st April 2011
HOW & SCOPE
Needs:
 Standardisation of methods for an accurate and relevant
grading of adverse events & clinical findings
 Clinically relevant & accepted «Stopping rules»
• Individual level
• Group/cohort level
 Applicable to FIH studies conducted in young male subjects
• First-in-Human dose escalation studies (single & multiple
dose)
• Healthy subjects
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AP 3
Joint conference AGAH - BAPU - Club Phase I - AHPPI - Berlin - 31 March to 1st April 2011
CURRENT AVAILABLE GUIDELINES
Nothing relevant and accepted fitting well to healthy
subject participating in FIHs
WHO Recommendations for grading Acute & subacute toxic
1.
effects WHO Handbook for reporting results of cancer
treatment (1981)
NCI Common Terminology Criteria for Adverse Events (CTCAE
2.
v4 Sept 2009)
(cid:31) Only applicable to oncology
NIH Division of AIDS (Dec 2004) : Table for grading the
3.
severity of adult and paediatric adverse events
FDA Guidance for Industry (Sept 2007) : Toxicity grading scale
4.
for adult and adolescent volunteers enrolled in preventive
vaccine clinical trials.
(cid:31) controversy in-between organizations (2005)
(cid:31) not relevant enough to healthy subjects
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Joint conference AGAH - BAPU - Club Phase I - AHPPI - Berlin - 31 March to 1st April 2011
NEED OF RELEVANT PROPOSALS
CPI proposals .../...
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Joint conference AGAH - BAPU - Club Phase I - AHPPI - Berlin - 31 March to 1st April 2011
PREAMBULE : DEFINITION & WORDING
ADVERSE EVENT OR FINDING
Adverse Event (ICH definition):
« any untoward medical occurrence in a patient or clinical

investigation subject administered a pharmaceutical
product and which does not necessarily have to have a
causal relationship to this treatment ».
Any spontaneously reported or observed AE (cid:31) to be

collected
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Joint conference AGAH - BAPU - Club Phase I - AHPPI - Berlin - 31 March to 1st April 2011
PREAMBULE : DEFINITION & WORDING
ADVERSE EVENT OR FINDING
Clinical event = ADVERSE EVENT

Non-clinical (vital signs, ECG, routine laboratory tests…) event =

FINDING
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Joint conference AGAH - BAPU - Club Phase I - AHPPI - Berlin - 31 March to 1st April 2011
IS THE EVENT RELATED ?
Investigator judgement: « unrelated, unlikely, possible,

probable, (likely) or definite »
Final judgement / coding : binary process (related or not

related )
Low imputability power due to small number of subjects (cid:31)

 Clear proof of intercurrent disease: non-related
 If not => related
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Joint conference AGAH - BAPU - Club Phase I - AHPPI - Berlin - 31 March to 1st April 2011
QUOTATION?
USE OF THE NIH / FDA GRADING
Grading: use NIH/FDA 4-level scales of intensity:
1. Grade 1 : mild : Does not interfere with daily activity
2. Grade 2 : moderate : Interferes with daily activity; no
treatment excepted acetaminophen (limited amount)
3. Grade 3 : severe : Prevents daily activity or requires
treatment (or medical intervention - FDA)
4. Grade 4 : life-threatening : Emergency room visit or
disabling or hospitalization
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Joint conference AGAH - BAPU - Club Phase I - AHPPI - Berlin - 31 March to 1st April 2011
FIRSTLY
Application to clinical AEs
quotation directly derived
à
from observed severity/intensity
or
from daily life consequences
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Joint conference AGAH - BAPU - Club Phase I - AHPPI - Berlin - 31 March to 1st April 2011