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Early safety signal MS Bad Homburg 07 1
Interpretation of early safety signals
• Do early safety signals exist ?Drawing the picture
• Why and how are they searched for ?The MTD story
• Making interpretation ? Questions and practice
Early safety signal MS Bad Homburg 07 2
Interpretation of early safety signals
• Do early safety signals exist ?Drawing the picture
• Why and how are they searched for ?The MTD story
• Making interpretation ? Questions and practice
Early safety signal MS Bad Homburg 07 3
Drawing the picture !
1 Sanofi-Aventis survey11 y (95-2005)101 compounds
2 Data from other originsPublished articles on adverse eventsData from registers
Early safety signal MS Bad Homburg 07 4
Sanofi Aventis Survey11 years (95-2005)101 compounds Phase I – FIMs• all the compounds
* if available data from reports (SD&MD)* excepted oncology and insulins
• 101 single dose (SD) studies87 multiple doses (MD) studies
. (14 stop)
Early safety signal MS Bad Homburg 07 5
Sanofi Aventis SurveyEarly safety signals: TypesTypes
• Clinical AE• Potentially clinically significant
abnormality (PCSA)ie ECG, lab, vital signs ….
using predefined threshold based on . value and/or variation from baseline
Early safety signal MS Bad Homburg 07 6
Sanofi Aventis Survey
Early safety signals: CharacteristicsCharacteristics
n°1 Directly and immediatelyDirectly and immediately… … ….….safetysafety relevantrelevant:
AEs or abnormalities « PCSAs »For ex: vomiting, orthostatic hypotension,
ALT increase…
Early safety signal MS Bad Homburg 07 7
Sanofi Aventis Survey: Early safety signals: CharacteristicsCharacteristics
Not Not directly safetydirectly safety relevantrelevant: n°2&3: n°2&3**2 Result predicting risk
For ex: aPPT baseline x 2, 5 and anticoagulant
**3 Result limiting riskFor ex: Cmax limitation when expectedconvulsions from preclinical data
Early safety signal MS Bad Homburg 07 8
Survey: a big VarietyVariety of early safety signals
The most frequent examples:Mainly GI AEs 17 compounds
CNS AEs 17 c. .
PCSAs: Liver enzymes 11 c.QTc increase 7 c.
Early safety signal MS Bad Homburg 07 9
Ex Gastro Intestinal Early Safety Signals
Digestive Event Nausea VomitAbdominal pain
100 mg 1150 mg 1225 mg 3 2 1300 mg 7 2 1 4
Early safety signal MS Bad Homburg 07 10
Triglycerides (mmol/L) - Individual data
0
2
4
6
8
10
12
Day-1 Day 3 Day 5 Day 7 Day 10 Day 13 Day 15 END
TIME (D)
Early safety signal MS Bad Homburg 07 11
Survey: ESS SeriousnessSeriousness ?12 SAEs (12%)
no death all, complete reversibility
• 3 in SD studies: 3 syncopes from 3 compounds • 9 in MD studies:
* Drug induced liver injury. 6 reports from 3 compounds
* Rhabdomyolysis . . 2 reports from 2 compounds
* Rash, fever and bicytopenia
Early safety signal MS Bad Homburg 07 12
Cytolytic hepatitis
0
100
200
300
400
500
600
700
800
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
ALATASATGamma GTBilirubin (total)Alkalin phosphatase
Early safety signal MS Bad Homburg 07 13
Cholestatic hepatitis
0
50
100
150
200
250
300
Screen
ing D-1 D3 D7
D13
D14
D15 (unsch
eduled
)
D16
D17 (unsch
eduled
)
D18 (unsch
eduled
)Gamma GTAlkalin phosphataseALATASATBilirubin (total)
Early safety signal MS Bad Homburg 07 14
B Other early safety signalsB Early safety signals: other origins
Incidences - related to tested compound: AEs 15 %SAEs 0,4 %o
Survey # 0,2 %o
Deaths 5 / 30 years / worldwide
® Rosenzweig Br J Clin Pharm 1999, 45: 19® Sibille Eur J Clin Pharm 1992, 42: 389 & 1998, 54: 13® Luftullin Int J Clin Pharm & Ther 2004; 43: 217® Sibille Br J Clin Pharm 2006; 62:503® Japan Clin Pharm & Therap 2006; 79:P71® Club phase I www.clubphase1.org
Early safety signal MS Bad Homburg 07 15
Interpretation of early safety signals• Do early safety signals exist ?
Drawing the picture• Why and how are they searched for ?
The MTD storymaximal tolerated dose
• Making interpretation ? Questions and practices
Early safety signal MS Bad Homburg 07 16
The MTD story
Phase I = first step of drug development Phase I goal = jump to second step, by the
way of Phase 2 dose selectionActive search of early safety signals to determine
MTD MTD -- Maximal Maximal ToleratedTolerated DoseDose
Early safety signal MS Bad Homburg 07 17
MTD definition
® CUTLER et al.Defining the maximum tolerated dose
J Clin Pharmacol 1997;37:767 & 2000;40:1184
« TheThe highesthighest safesafe dose dose and and
maximal usable dosemaximal usable dose »»
Early safety signal MS Bad Homburg 07 18
Survey: MTD rate of determination
MTD was defined in 58 out of the 101compounds 58%
from SD st. 39% . from MD st. 31% . from both 12 %in this last circumstance the MTD of MD
study was identical (7) or lower (5)
Early safety signal MS Bad Homburg 07 19
MTD: 4 possible applications• From DirectDirect safety signalsN° 1 « Genuine MTD »• From IndirectIndirect safety signals:N° 2 * predicting risk – biomarkerN° 3 * limiting risk – PK concentration
« Analogic MTDs »•• NoNo safety signal: inhaled compound
n.of actuations N° 4 « Derived MTD »
Early safety signal MS Bad Homburg 07 20
MTD: 4 types• From Direct safety signalsN° 1 « Genuine MTD » : 45/58 78%• From Indirect safety signals:N° 2 * predicting risk – biomarker: 5N° 3 * limiting risk – PK concentration: 3
« Analogic MTDs »: (5+3) 8 14%• No safety signal: inhaled compound
n.of actuations N° 4 « Derived MTD »: 5 8%
Early safety signal MS Bad Homburg 07 21
Survey: Is MTD a securedsecured strategy ?
12 SAEs (12%) no death all, complete reversibility
Early safety signal MS Bad Homburg 07 22
Survey: MTD …a realistic timelinerealistic timeline
• Reaching MTD: median - 7 dose steps in SD
- 3 in MD studies
Early safety signal MS Bad Homburg 07 23
Survey: Is the choice of the firstfirst dose…
…of SDSD study accurate ?
Early safety signal MS Bad Homburg 07 24
Survey: Is the choice of the firstfirst dose…
…of SDSD study accurate ?
Criteria of accuracy : No ESS, No activity > LOQ
Early safety signal MS Bad Homburg 07 25
Survey: Is the choice of the firstfirst dose…
…of SDSD study accurate ?
Criteria of accuracy : No ESS, No activity > LOQ
Results: 96% no ESS, no activity67% concentration > LOQ
Early safety signal MS Bad Homburg 07 26
Survey: Is the firstfirst dose of SDSD study…safe?
A major question after the London story …
Early safety signal MS Bad Homburg 07 27
Survey: Is the firstfirst dose of SDSD study…safe?
A major question after the London story …101 SD studies: no SAE
only 4 related safety issuesall mild & reversible AEs
• Orthostatic hypotension 2 (CV&CNS area)• Digestive low tolerability (antibiotic)• Local irritation (infused vein)
Early safety signal MS Bad Homburg 07 28
Survey: Is the firstfirst dose of SDSD study…safe?
A major question after the London story …
If * rules and regulations* prudence on choice of doses
…an answer far from the tragedy !
Early safety signal MS Bad Homburg 07 29
Survey: Is the firstfirst dose of MDMD…safe ?
….MD could be more at risk!
2 SAEs1. Rhabdomyolysis2. Hepatitis
Early safety signal MS Bad Homburg 07 30
Survey:Exceeding the NOAEL NOAEL Human Equivalent Human Equivalent DoseDose
Is it …usefuluseful ?• Actual frequency: 42 compounds in SD
. 21 in both SD and MD
Early safety signal MS Bad Homburg 07 31
Survey:Exceeding the NOAEL NOAEL Human Equivalent Human Equivalent DoseDose
Is it …usefuluseful ?• Actual frequency: 42 compounds in SD
. 21 in both SD and MD• Results: improving MTD determination ?
YES:if not, MTD score is 39%39%if yes, MTD score increased to 58%58%
Early safety signal MS Bad Homburg 07 32
Survey:Exceeding the NOAEL Human Equivalent Dose
Is it ….safesafe ?
Early safety signal MS Bad Homburg 07 33
Survey:Exceeding the NOAEL Human Equivalent Dose
Is it ….safesafe ?• SD studies42 SD studies: YES - no SAE up the top dose
Early safety signal MS Bad Homburg 07 34
Survey:Exceeding the NOAEL Human Equivalent Dose
Is it ….safesafe ?MD studies• 21 MD studies: Mild over-risk
*** 3 SAEs 14%Hepatitis (2 reports 1 compound)Rhabdomyolysis (1 report)
*** versus 6/66 rest of cohort 9%
Early safety signal MS Bad Homburg 07 35
Interpretation of early safety signals
• Do early safety signals exist ?Drawing the picture
• Why and how are they reached and collected ?
The MTD story• Making interpretation ?
Questions and practices
Early safety signal MS Bad Homburg 07 36
In fact, three scenarios:
1. High frequency/intensity of ESS 2. Dose dependent occurrence of
ESS 3. Low frequency of ESS
Early safety signal MS Bad Homburg 07 37
Scenarios and ……decision process
1. High frequency/intensity of ESS 2. Dose dependent occurrence
CLARITY
Early safety signal MS Bad Homburg 07 38
1st Ex. Digestive Event Nausea Vomit
Abdominal pain
100 mg 1150 mg 1225 mg 3 2 1300 mg 7 2 1 4
2d Ex Digestive Event Nausea Diarrhea Meteorism
400 mg 0600 mg 2 2800 mg 5 2 1 2
1000 mg 12 2 5 5
Early safety signal MS Bad Homburg 07 39
Multiple dose - 14 days 12 subjects per doseRash: Acnea-like syndrom
Dose Men Women
20 mg 0 ND
50 mg 3 mild 6 mild
80 mg 5 (3mild/2moderate) ND
Early safety signal MS Bad Homburg 07 40
Dose Escalation Process
Early Safety
Signalss?No
Relevance to support MTD?
Risk?
STOPQUALIFY MTD
Yes
NoNo
Yes Yes
Early safety signal MS Bad Homburg 07 41
Scenarios and ……decision process
1. High frequency/intensity of ESS 2. Progressive dose dependent occurrence
CLARITY
3. Low frequency of ESSLow frequency of ESSPERPLEXITYPERPLEXITY
Early safety signal MS Bad Homburg 07 42
Perplexity: 1verum - 1placebo
05000
100001500020000250003000035000400004500050000
Scr
eeni
ng
Day
- 1 4 8 12
CO
NTR
OL 13 15 18 28 32
CPKCPK 2
POST meeting 43
STUDY ON GOING
ES Signal: 1 + 1 + riskrisk
Placebo? Yes
Dose adaptation- SAME- LOWER
No No
No
Is AE- Expected?- Specific?
Acceptable Decision ?
Is- An other cause?
- Rare in HV?
STOP
No
Yes Yes
Yes
Support from PK and/or
PD
Early safety signal MS Bad Homburg 07 44
Conclusions (1)
1. ESS do exist,thus MTD determination is:
• Realistic• Safe• Even if, NOAEL HED exceeded in
SDSD study
Early safety signal MS Bad Homburg 07 45
Conclusions (2)
2. ESS interpretation is supported by simple algorithms:
• If Several ESSSeveral ESS: Intensity and number of early safety signals MTD
• If Unique ESSUnique ESS: More difficult decision making process
Early safety signal MS Bad Homburg 07 46
Conclusion (3):a subtle balanced strategy between…
1. Minimizing risk and keeping priority to subject protection
2. Testing the highest possible dose on the biggest number of subjects
toObtain Early Safety Signals
Have significant intensityHave significant frequency
Support MTD relevance