pr boris jung critical care medicine montpellier · kraut et madias, nat rev nephro 2010 metabolic...
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Pr Boris JungCritical Care Medicine
Montpellier
Research Protocols Implying Human Beings,
Constitution Of Collections Of Human Biological Samples
Sep, 15Th 2020
1.The timeline of a study design
2.The consent to human research
3.The specifics of human research in the critically ill
4.How to constitute a human biological collection
1.The timeline of a study design
2.The consent to human research
3.The specifics of human research in the critically ill
4.How to constitute a human biological collection
Idea
Literature check ;-)
Quantitative hypothesis
Population of Interest
Measured Parameters
Fact
5Berend Et Al, N Engl J Med 2014
One example: Acidemia
Kraut Et Madias, Nat Rev Nephro 2010
Metabolic Acidosis Is Associated With Physiological Disturbances
Sodium Bicarbonate
Idea
Good ? Bad ?
NS ?
Should We Administer Sodium Bicarbonate To Correct Severe Metabolic Acidosis
81999 French Guidelines
Idea
9Jung Et Al, Crit Care 2011
Sodium Bicarbonate is used in French ICUs to treat severe metabolic acidosis
Fact
Sodium Bicarbonate
Idea
Good ? Bad ?
NS ?
2011
Ph < 7.20
MortalitY = 57%
Jung Et Al, Crit Care 2011
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Jung Et Al, Crit Care 2011
Observational Studies : Controversial
Physiological Studies : Ns
Prospective Trial: None
Literature check
Inclusion Criteria
Exclusion Criteria
Design Of The Study
• Prospective Vs Retrospective• Interventional Vs Observational • Single Intervention Vs Bundle• Randomized Vs Before-After• Single Center Vs Multiple Center
Literature check
Better outcome =
More survivors at D28 and/or less patients with at least 1 organ failure at D7
1) Day 28 Mortality and/or 2) Number of patients with at least one organ failure at D7 (defined by SOFA ≥ 3)
Quantitative hypothesis: Main endpoint
Hypothesis
http://marne.u707.jussieu.fr/biostatgv/?module=etudes/sujets#
“Sample
Size”
Lancet 2018; 392: 31–40
PRIMARY (Composite) ENDPOINT
D28 Mortality OR Day 7 Organ Failure
Control arm
P-value = 0.089
A. Time to Death in Overall Patients
Control arm Bicarbonate arm
Bicarbonate arm 45%
54%
D-28 Mortality
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Lancet 2018; 392: 31–40
P-value = 0.028
Control arm
Bicarbonate arm
Control arm Bicarbonate arm
B Time to Death in Patients with pre-specified Acute Kidney Injury
46%
63%
D-28 Mortality
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Lancet 2018; 392: 31–40
BICARICU-2: PHRC-N 2018
Mortality D90
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Speeding Up Research !
Un SDRA comme un autre ?
Gattinoni et al, ICM 2020
“Based on detailed observation of several cases and discussions with colleagues treating these patients,
we hypothesize.. “
Marini & Gattinoni, JAMA 2020
In this large series (n=742), COVID-19 ARDS patients have features similar to other causes of
ARDS, compliance with lung-protective ventilation was high, and the risk of 28-day mortality increased with the degree of ARDS
severity
Ferrando et al, ICM 2020
Res
pira
tory
Sys
tem
C
ompl
ianc
e (m
l/cm
H2O
)
“Human intuitions are simply too fallible – and clinical experience too contingent and heterogenous –
to reliably identify phenotypes without sufficient data”
Bos et al, ERJ 2020
“Détecter Une Anomalie Et Se Persuader Qu’il S’agit D’une Nouvelle Norme”
“Rejeter L’observation Usuelle Car Une Nouvelle Norme Est Désormais Définie”
Departement De L’information Clinique (Dim)
1. Methodological Help
2. Statistical Plan
3. Analysis
Methodology
IRB = Institutional Review Board (Comité de Protection des Personnes)
✦ Doctors, Nurses And Research Technicians With A
Strong Experience In Research✦ People With An Experience In French Law✦ People From Patients Associations✦ With No Conflicts Of Interest With The Protocol✦ Sometimes Experts Can Be Invited To Review The
Scientific Aspect Of The Protocol
✦ Examine The Scientific Content Of The Protocol✦ Examine The Researchers’ Curriculum✦ Examine The Information To The Patients Content✦ Make Sure The Protocol Fits With French Law✦ Check Whether Insurances, Declarations To The
Authorities Have Been Made✦ Protects The Patients And The Society
IRB = Institutional Review Board (Comité de Protection des Personnes)
If The Research Involves Any Medication
The Ansm Will Review The Protocol
✦ Safety
✦ Indication
✦ Surveillance Of Any Side Effect
Safety
Data Management ?
RGPD 2018“Règlement Général sur la Protection des
Données à caractère personnel “
Data ManagmentRGPD 2018
“Règlement Général sur la Protection des Données à caractère personnel “
1.The timeline of a study design
2.The consent to human research
3.The specifics of human research in the critically ill
4.How to constitute a human biological collection
Patient’s CONSENT
✦ Information As Clear As Possible
✦ Need Time To Think Before Signing
✦ Can Be Retracted Anytime With No Consequences
✦ Formal Meeting Between The Investigator / Patient
✦ Study With Or Without Direct Clinical Benefit
Recherche prospective avec un
accès direct à la personne
Etude Non interventionnelle
3° (RIPH 3)
Etude Interventionnelle
1° ou 2° (RIPH 1 ou RIPH 2)
Recherches 2°
DM ou HPS 1°
Médicament 1°
Avis CPP MR003 (MR002)
ou CNILAvis CPP
MR001 ou CNILCPP + ANSM
MR001 ou CNIL
SignedConsent
Non-Opposition Consent
1.The timeline of a study design
2.The consent to human research
3.The specifics of human research in the critically ill
4.How to constitute a human biological collection
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✦ Patients With At Least 2 ‘Organ Failure” Or With 1
Organ Failure And At High Risk ✦ Often Needing Organ Suppleance (Mechanical
Ventilation, Dialysis, Heart Assistance…)✦ Constant Monitoring ✦ Multiple Specialities (Cardiology, Nephrology,
Anesthesia,…)✦ High Tech ✦ Mortality Ranges: 10-30%
What Is Critical Care Medicine ?
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Renal Replacement Therapy
Plasma Exchange Therapy
Mechanical Ventilation
Nitric Oxide Inhalation
Multiples Drugs
Patients Often Unable To Consent To Research
✦ Inclusion With No Consent✦ Need Efforts In Trying To Reach The Patient’S Legal Representative✦ Legal Representative Consent Asap✦ Follow-Up Consent By The Patient Asap (Sometimes Tricky…)
LIFE THREATENING CONDITION
NON-LIFE THREATENING CONDITION
✦ Inclusion Needs Consent By LEgal Representative✦ Follow-Up Consent By The Patient Asap (Sometimes Tricky…)
Patient’s CONSENT in the ICU
Avis Comité d’éthique
Recherche prospective avec un
accès direct à la personne
Etude Non interventionnelle
3° (RIPH 3)
Etude Interventionnelle
1° ou 2° (RIPH 1 ou RIPH 2)
Recherches 2°
DM ou HPS 1°
Médicament 1°
Avis CPP MR003 (MR002)
ou CNILAvis CPP
MR001 ou CNILCPP + ANSM
MR001 ou CNILAvis CEREES (ex CCTIRS)
et/ou Autorisation CNIL
Recherche sur données Pas d’accès à la personne - Recueil rétrospectif ou prospectif et l’exploitation de données issues de dossiers médicaux ou d’autres bases de données - Echantillons biologiques - Banque d’images - Bases médico-administratives
Recherches qui bien qu’organisées et pratiquées sur l’être humain n’ont pas pour finalité la production de connaissances biologiques ou médicales - Produits cosmétiques - Enquêtes de satisfaction du consommateur (produits cosmétiques
ou alimentaires) - Enquête de satisfaction auprès des patients - Expérimentations en science humaine et sociale dans le domaine de
la santé - Évaluation des pratiques professionnels de santé ou pratiques
d’enseignement dans le domaine de la santé
Différents types de recherches
Avis Comité de Protection de Personnes (CPP)
Nct02476253
The Protocol’s Abstract Is Declared On A Public Network Before The First Patient Inclusion
Advertising the Protocol
The Full Extent Protocol And The Statistical Plan Can Be Published In Peer-Reviewed Journals
Steering Committee
✦ Independent Researchers With No Role In The Protocol✦ Clinicians, Statisticians, (Pharmacologists)✦ Interim Analysis✦ Examine Safety Of The Study And Protocol Arms✦ Avoid Futility ✦ Can Recommend The Study’s Interruption (Safety/Futility)
N Engl J Med 2018
N Engl J Med 2018
1.The timeline of a study design
2.The consent to human research
3.The specifics of human research in the critically ill
4.How to constitute a human biological collection
Biobank - Human samples
• Human samples = cells, blood, plasma,….
• Aims of a biobank = Science
✦ Needs consent or non opposition (If “soins courants”) ✦ Needs declaration to Research Authorities / ARS ✦ Needs IRB/CPP approval✦ If any potential risk related to patient sampling, need full approval and sometimes €€ compensation✦ Can be an additional blood tube or even “tubes leftover” after routine of care phlebotomy✦ Can need super-qualified skills to prepare and store the samples (ex: RNA)
Biobank - Human samples
Conclusion
✦ An idea is rarely that original but a non-sense protocol is useless and non ethic✦ Checking the literature is a big issue in ethic assessment ✦ Methodology avoiding insufficient power is highly recommended ✦ Consent in the critically ill is not an easy process ✦ Several agencies, local and national watch the process