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

18

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

19

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 ?

38

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