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Accidents During
Clinical Trials
Houria Chikhi
Juliette Paillard
27 février 2017
Séminaire Réglementaire
Clémence Patte
Augustine Screpel
1
Key points of CT Regulation
TGN-1412 (2006)
BIA 10-2474 (2016)
Conclusion
2
Key Points of Clinical
Trials Regulation
3
Life Cycle of Medicine
4
Preclinical Studies
ICH M3: “Note for guidance on non-clinical safety studies for the
conduct of human CT and MA for pharmaceuticals”
ICH S6: “Preclinical safety evaluation of biotechnology-derived
pharmaceuticals”
 Aim : to determine the 1st dose to administrate to humans
Pharmacodynamic
MOA, target affinity, primary and secondary effect(s)
Pharmacokinetic
ADME
Acute
-4 to 5 doses
-observation: 14 days
-mice+rats
Subacute
-2 species, 2 genders, several doses
-90 days
Chronic
-2 species, 2 genders, several doses
-6 to 12 months
Toxicology
-DL0, MTD, LD100, LD50
-Reprotoxicity,
cancerogenesis,
mutagenesis
5
NOAEL or MABEL ?
NOAEL
MABEL
• Non Observable
Adverse Event
Level.
• Minimal
Anticipated
Biological Effect
Level
• Based on
toxicology
• Justify based on
pharmacology
• Dependant of
animal species
• Include
anticipation
duration effect
6
Clinical studies
1) UE Legislation
• Directive 2001/20/CE: Applied in 2004(UK) and 2006 (FR)
Requirements :
 Protection of trial participants
 Competent authority + Ethic Committee Approval
 Safety Requirements Reports
 Registration of the Clinical Trial (EudraCT)
 Reinforcement people protection involved in Clinical Trial
• Regulation 536/2014 : Applicable in 2018
7
Clinical Studies
2) FR legislation
• Law 2012-300 = Loi Jardé with decree n° 2016-1537
of 16/11/2016
3) UK legislation
• SI 2004/1031 The Medicines for Human Use (CT)
Regulations 2004 with numerous amendments.
8
Clinical Trial : Actors
SPONSOR
•
Ethic
Competent
Authorities
Sponsor:
an individual, company,
institution
or organisation
Committee
CRO
which takes responsibility for the initiation, for
management and for setting up the financing of the CT.
Authorisation
the
Favorable
Opinon
• • Contract
ResearchIndependent
Organization
(CRO):
A person
or an
Ethic Committee:
body.
Responsible
to protect
organization
contracted
the ofsponsor
perform
one or
the rights, safety
and wellby
being
human to
subjects
involved
more
sponsor’s
trial-related
duties andof
functions.
in CT,ofand
to provide
public assurance
that protection
9
Clinical Trial : Actors (3/3)
SPONSOR
Competent
authorities
CRO
Investigator:
an individual
responsible for the
conduct of a CT at a
CT site.
Ethic
Committee
Favorable
Opinon
Authorisation
Investigator
Start of CT
10
TGN-1412
13
Actors
Role
Name
Location
Sponsor
Germany
Manufacturer
Germany
CRO
Investigator
Northwick-UK
Competent
Authority
London-UK
14
1. The study
TGN-1412
15
Molecule
• Humanized IgG4κ mAb
• Superagonist binding CD28
16
Medical need
Autoimmune disease: Cellular mechanisms
Autoreactive
CD4+ Th
lymphocytes
CD4+ Treg and
CD8+ supressor
Loss of selftolerance
Dysregulated
signaling
3% people
worldwide
75% women
Comparable
structure selfAG foreign
molecules
17
Medical need
B Cells Chronic lymphocytic leukemia:
• Leukemic B cells accumulation
• T cell abnormalities
TOLERANCE
VS
LEUKEMIC B CELLS
18
Preclinical studies
• Mice :
 Healthy mice : to determine and select Treg
 Unwell mice : to determine the DME
• Monkeys
 Safety and toxicology studies done on Rhesus
and Cynomolgus Monkeys
 TGN-1412 induces activation and expansion of T
cell only in Cynomolgus Monkey → studies
conducted on them
19
Preclinical studies
• NOAEL: 50mg/Kg per week (4 weeks max)
 Determined by a repeat dose study : IV - 5
doses up to 50 mg/Kg
 TGN-1412 well tolerated up to 50mg/Kg
• PK :
 Half life : 8 hours (Monkeys)
 Full removal : 1 month
20
How the started dose was
calculated ?
Security Factor /10
•50 mg/kg
•Non Observed
Adversed Event
HED
•Human
Equivalent dose
•16 mg/kg
NOAEL
Surface area
allometric
correction factor
•Maximum
Recommended
Starting Dose
•1,6 mg/Kg
MSRD
Starting
dose
• 0,1 mg/kg
• First human
dose
Safety Margin
21
Design
•
•
•
•
•
•
•
Phase I
Single-centre
Double-blind
Randomized
Placebo
Controlled
Single escalating dose study
 To assess safety, pharmacokinetics,
pharmacodynamics and immunogenicity of TGN-1412
22
Design
Only Men (18-40 yo)
0,1
mg/kg
0,5
mg/kg
2,0
mg/kg
5,0
mg/kg
Dose escalation schema
x4
TGN-1412
Placebo
23
2.What happened ?
TGN-1412
24
Chronology
Multiorgan
failure
Patient 6
Start of
Clinical
Trial
13th
March
2006
Multiorgan
failure
All patients
Within
5 hours
“Cytokin
storm”
Incident
reported to
MHRA
14th
March
2006
Within 20
hours
+ Methyl
Prednisolone
ICU
25
What happened ?
26
3. Investigations
TGN-1412
27
 Inspections:
- Dosing error ?
- Error in the formulation or dilution ?
- Contamination ?
- Unknown biological effect ?
Disapproved
hypothesis
• Appointment of an ESG (Expert Scientific Group)
28
ESG
 “Pre-clinical development studies performed with
TGN-1412 did not predict a safe dose for use in
humans, even though current regulatory
requirements were met”
 In vitro assays : dose of TGN-1412 given to volunteers
was close to the maximum immunostimulatory dose.
• “Differences of up to 4% existed in the amino-acid
sequences of the C”D loop of CD28 receptor in
rhesus and cynomolgus with that of humans”
29
OKT3 case
• With OKT3, similar effects on animals and humans
to those observed with TGN-1412
• In brochure: “Precautions”
“Cytokine release: (…) The anti-CD3 monoclonal
antibody OKT-3, elicits a “cytokine-storm”
characterized by an increase in systemic
inflammatory mediators. In the unlikely event that
TGN-1412 also induces massive cytokine release,
appropriate counter-measures must be taken.”
30
Investigator’s brochure failure
• “100% homology exists between the CD28 TGN1412
binding site in human beings and monkeys,
restricted to the so-called C”D loop.” => However,
no sequence comparison was included in the
disclosed information.
• Only provides information on the affinity of TGN1412
to the human CD28 molecule (1·88×10−9 mol/L), not
for its monkey counterpart.
31
Doses administered and timing
Subjects
1
2
3
4
5
6
Body
weight
(kg)
84.4
69.9
88.5
82.4
72.1
81.8
Dosing
TGN1412
(mg)
8.4
6.8
8.8
8.2
7.2
8.2
Dosing
time
(AM)
08:00
08:20
08:30
08:40
08:50
09:00
Only 10 minutes between administrations
32
4. Measures/Recommandations
TGN-1412
33
Management and reduction of risk :
• FIH trials of mAb or new biologic would not be
sanctioned by the MHRA without having received
the benefit of additional expert opinion
34
ESG
Experts
Recommandations to optimize security :
•
Assessment of 1st in man trial should be sciencesbased made and a justified on a case by case
basis on individuals
•
Determining and administering the initial doses in
man
•
Structured approach needed for the evaluation
of pre-clinical and clinical experiments
35
EMA
New regulatory environment :
“Guideline on strategy to identify and mitigate risk for
first in-man Clinical trial with investigational
medicinal products”
•Conduct of the CT : case by case science driven
approach
•Estimating FIH starting doses and dose escalation
•Understanding and projecting the likely effects of the first
pharmacologically active dose administered to humans.
36
What about today ?
- TeGenero went
into insolvency in 2007
-
TGN1412 commercials
rights were acquired by a
Russian Company
-
TAB08
-
Indication : Rheumatoid
Arthritis
-
Phase II
“A sophisticated product could be destroyed by inadequate
development.”-Adam Cohen
37
BIA 10-2474
38
Actors
Role
Name
Location
Sponsor
Portugal
Manufacturer
Portugal
CRO
Investigator
RennesFrance
Competent
Authority
Paris-France
39
1.The study
BIA 10-2474
40
Molecule : BIA 10-2474
 Inhibitor of fatty acid amide hydrolase (FAAH)
 Indication : Neuropathic Pain
(According to Bial , Reversible Inhibitor)
41
FAAH : Fatty Acid Amid Hydrolase
• Serine hydrolase with an unusual SerSer-Lys catalytic triad
• After release of Anandamid, cause
its hydrolysis
• Anandamid + H20 ← → arachidonic
acid + ethanolamin
42
Anandamid
- ⅓ Endocannanabinoid
- Inhibition by FAAH →
Anandamid degradation
inhibition → 
Anandamid
- High affinity for CB1
receptor and low affinity
for CB2
Anandamid
- Retrograde action
43
Mechanism of action
44
Preclinical studies
Species
NOAEL (mg/kg)
NOEL (mg/kg)
Mice
100
25
Rats
30
10
Dogs
50
20
Monkeys
100
75
 4 species instead of 2
45
Preclinical studies
46
Protocol
•
•
•
•
•
•
Phase I
Single-centre
Double-blind
Randomized
Placebo-controlled
Including additional FI and PD part
 To assess safety and tolerability of BIA 10-2474 after
SAD and MAD
 To characterize the PK and PD and assess several
potential PD effects.
47
Dose escalation
SAD Cohort
•
5 fold increase from
the first dose 0,25 mg
to the second
•
2-fold until 100 mg
MAD Cohort
Once daily D1 to D10
Dose levels: after
evaluation of safety ,
tolerability and
available PK results of
previous of SAD and
MAD dose groups
• PK and PD assessment
•
•
48
Inclusion/Exclusion Criteria
Inclusion Criteria
• Male or female (only
male for the PD part)
• BMI between 19 and
30 kg/m²
• Healthy, negative
tests for virus
• Negative screen for
alcohol and drugs
Exclusion criteria
• Subjects with surgery
history,
• History of hyperemesis,
atopy, alcoholism or
drug abuse
• Significant infection or
known inflammatory
process
49
2. What happened ?
BIA 10-2474
50
Chronology
1st subject
declared
brain dead
1st subject was
hospitalized
06/01
50 mg dose
Cohort 5
10/01
11/01
1st
subject slips
into coma
Study stopped
12/01
Authorities
notified
13/01
5 subjects were
hospitalized
14/01
17/01
1st subject
died
51
3. Authorities
Investigations
BIA 10-2474
52
IGAS
Cohort
50mg
« The participants weren’t protected enough »
 3 importants failures :
1. Failure to provide information to other
volunteers and to confirm their consent.
2. Responsibility for failing to halt the trials after
the first hospitalisation
3. Delay in informing the ANSM.
53
Appointment of TSSC (Temporary Specialized
Scientific Committee)
•
On BIA 10-2474
Cohort
50mg
• On clinical data and MRI of healthy
volunteers
Other
cohorts
54
TSSC’report BIA 10-2474
« Accident clearly linked to the tested molecule »
• About the molecule : low efficiency, low specificity
and concentration-effect curve steep
• Molecule capacity to set other cerebral structure
 off target
• High risk molecule with minor interest
 Important role of the dose escalation in the
accident
Cohort
50mg
55
TSSC Review of clinical data &
MRI
• Nature and frequency of symptoms reported
by volunteers receiving BIA10-2474 were unlike
those seen in hospitalized volunteers in the 50mg
cohort.
Other
cohorts
 Irrelevant
56
4. Transparency
BIA 10-2474
57
CPP
CPP
Rennes
A.Patat
Rennes CPP’s Member
A.Patat
Biotrial Direction Member
58
Disclosure rules
• Protocols and preclinical files are
made available only well after the
completion of the trial
 Data protection because of individual
privacy requirements should be
balanced with public health interests.
59
5.Scientific Discussion
BIA 10-2474
60
Molecule
Leaving
group
PF-04457845
Give the specificity
Molecule
Leaving
group
BIA 10-2474
Give a low
specificity
62
Molecule
• Low specificity
• High reactivity
• Covalent binding
 Evaluation failure
63
Preclinical failures
• The preclinical dossier wasn’t made public
• Brain damages in rats, mice and cynomolgus
monkeys should have been investigated further.
• 4 species
• Maybe due to poor tolerance results in the 1st
species
• Bial : Delay in the clinical development
64
Dose calculation failures
Highest
dose: 100
mg
High Risk
Molecule
Complete
inhibition :
5mg
MABEL ?
65
Pk and cumulative toxicity
Covalent
binding
Non AE in
SAD cohort
Non linear
PK for
D>40mg
½ life increase
with the dose
 elimination
saturation
Large
distribution
volume
Graduation
accumulation
in the brain
66
Consequences: Off-target
200 Serine
Hydrolase
Molecule with
Low
specificity
Off-target
effects
9 metabolites3 with same
intensity of
action
Brain lesions
don’t match
EC system
67
Protocol failures
SAD
MAD
Disrepect of
criteria
Evaluation
failure
68
6.Measures and
recommendations
BIA 10-274
69
Ministry of Health
 Biotrial must provide an action plan
regarding 3 majors failures, within 1 month.
 Examination of the 90 CT records
 Enforcement of CTA conditions
 FR will continue its European action
 Requested the ad hoc authority to reinspect
all authorized French research centers
 Any hospitalisation of a healthy volunteer in
any CT = suspension of the CT
70
France
Loi Jardé, Decree n°2016-1537 (16/11/2016):
71
France
Loi Jardé, Decree n°2016-1537 (16/11/2016):
72
EMA

New Phase I trial best practices paper

Incorporating findings from ANSM and IGAS
2 workings groups :
- Preclinical assessment and drug candidate
- Clinical Design
73
7.Personal injuries
compensation
BIA 10-274
74
Compensation for personal injuries
• Victims of drug disease link to CT
Drug taken in CT
Causal
Link
Existence of
damages
75
2 ways of actions for victims
Legal Process
• Compensation by
sponsor insurance.
• Medical expertise
by insurance
• Healthcare
product liability
regim
• Investigation by
ANSM to
determine
liabilities
Amicable Process
• Compensation
national solidarity .
• Medical expertise
by ONIAM (National
Office for the
Indemnisation of
Medical Accidents)
who suggested a
compensation
offer
76
Conclusion
77
Conclusion
• CT are the only tools to provide the
evidence needed for drug approval
• Regulation are theoritical and
administrative
• To limit risks:
 Case by case approach
78
Thank you for your
attention !
Questions ?
79
Bibliography (1)
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TGN1412 Study Protocol
TGN1412 Investigator Brochure
From TGN1412 to TAB08: the return of CD28 superagonist therapy to clinical development for the treatment of
rheumatoid arthritis
TGN1412: From discovery to disaster
Cellular and molecular mechanisms of autoimmune disease
The BIAL/Biotrial case of death of a human volunteer in the first-in-human study of BIA 10-2474: Are we missing the
fundamentals?
TGN 14-12 Interim Report. MHRA
Expert Scientific Group on phase one clinical trials. Final report.
Kenter et al, (2006). Establishing risk of human experimentation with drugs: lessons from TGN1412. The Lancet. 368 :
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Clinical Study Protocol N° BIA-102474-101
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