FRENCH REGULATION OF BIOMEDICAL RESEARCH INVOLVING HUMAN BEINGS Judge Christian Byk, Secr.Gl Internat.l Assoc.of Law, Ethics and Science

FRENCH REGULATION OF FRENCH REGULATION OF BIOMEDICAL RESEARCH BIOMEDICAL RESEARCH

INVOLVING HUMAN INVOLVING HUMAN BEINGSBEINGS

Judge Christian Byk, Secr.GlJudge Christian Byk, Secr.Gl

Internat.l Assoc.of Law, Ethics Internat.l Assoc.of Law, Ethics and Scienceand Science

The Historical ContextThe Historical Context

A recent legislation (incorporated in A recent legislation (incorporated in the Publ.Health Code)the Publ.Health Code)

- The 20th Dec.1988 Act on Biomedical The 20th Dec.1988 Act on Biomedical researchresearch

- The modification of 9th Aug.2004The modification of 9th Aug.2004 A necessary regulationA necessary regulation- For the protection of human subjectsFor the protection of human subjects- For the quality and competivity of the For the quality and competivity of the

drug industrydrug industry

The International ContextThe International Context

Main international sourcesMain international sources

-The Nuremberg Code(1947)-The Nuremberg Code(1947)

-The HelsinkiDeclaration (WMA,1964 modif.)-The HelsinkiDeclaration (WMA,1964 modif.)

-The ManillaDeclaration(CIOMS,1982,modif.)-The ManillaDeclaration(CIOMS,1982,modif.) Main European SourcesMain European Sources

-The Oviedo Convention(CofEur,1997) and -The Oviedo Convention(CofEur,1997) and its Protocol on Biomedical Research,2005)its Protocol on Biomedical Research,2005)

-The European Union Directive 2001-The European Union Directive 2001

The Main Features of the The Main Features of the French RegulationFrench Regulation

Definition of Biomedical ResearchDefinition of Biomedical Research Prerequisite Conditions that must be Prerequisite Conditions that must be

fulfilled in order to conduct a fulfilled in order to conduct a biomedical researchbiomedical research

Conducting a biomedical researchConducting a biomedical research SanctionsSanctions

Definition of Biomedical Definition of Biomedical ResearchResearch

A Positive Definition: it includesA Positive Definition: it includes

-Research on drugs-Research on drugs

-Research on medical devices-Research on medical devices

-Other researches are listed and -Other researches are listed and defined by a decision of the health defined by a decision of the health MinisterMinister

Definition of Biomedical Definition of Biomedical ResearchResearch

A negative definition(lower risks research A negative definition(lower risks research are excluded)are excluded)

-Non invasive research:those with products -Non invasive research:those with products used in current practice in conformity with used in current practice in conformity with their therapeutical indications their therapeutical indications

-Research aiming to evaluate current health -Research aiming to evaluate current health care (except drugs and research on care (except drugs and research on innovative techniques or comparing the innovative techniques or comparing the safety of medical strategies) . But they can safety of medical strategies) . But they can only be conducted after an ethics review only be conducted after an ethics review committee approved them.committee approved them.

Conditions to be fulfilled prior Conditions to be fulfilled prior to any researchto any research

Subjective conditionsSubjective conditions-conditions related to those who initiate the -conditions related to those who initiate the

researchresearch-conditions related to the research subjects-conditions related to the research subjects

Objective conditionsObjective conditions-conditions related to the research protocol-conditions related to the research protocol-conditions related to the premises where -conditions related to the premises where

the research is conductedthe research is conducted-specific conditions for drug research-specific conditions for drug research

Subjective ConditionsSubjective Conditions

Conditions related to those who Conditions related to those who initiate the researchinitiate the research

-the Promotor:-the Promotor:An individual or an entity that intitiates An individual or an entity that intitiates

the research and assumes its the research and assumes its management and financingmanagement and financing

The promotor (or a representative) The promotor (or a representative) should be established in the European should be established in the European UnionUnion

Conditions related to those Conditions related to those who initiate the researchwho initiate the research

The Investigator The Investigator - An individual appointed by the Promotor An individual appointed by the Promotor

to conduct the research on specified to conduct the research on specified premises.premises.

- A Coordinator must be nominated when A Coordinator must be nominated when several investigators have been several investigators have been appointedappointed

- The law does not prohibit an individual to The law does not prohibit an individual to be both a promotor and an investigatorbe both a promotor and an investigator

The InvestigatorThe Investigator

In general, the investigastor must be a In general, the investigastor must be a physician but:physician but:

-in research in the field of psychology,a -in research in the field of psychology,a psychologist can also be designated as psychologist can also be designated as investigatorinvestigator

-in the field of odontology,both a dental -in the field of odontology,both a dental surgeon and a qualified physician must be surgeon and a qualified physician must be appointedappointed

-in research aimming at evaluating current -in research aimming at evaluating current health care, the investigator can be a health care, the investigator can be a « qualified person »« qualified person »

Conditions related to the Conditions related to the Research SubjectsResearch Subjects

DefinitionDefinition

Only born and living human beings can be Only born and living human beings can be subjects to biomedical research (under the subjects to biomedical research (under the 1988 Act)1988 Act)

Consequently are excluded:Consequently are excluded:

-Dead persons except if they have consented -Dead persons except if they have consented when alivewhen alive

-Fœtus and embryos:they are covered by -Fœtus and embryos:they are covered by specific legislationsspecific legislations

Common RulesCommon Rules

Prerequisite conditions:Prerequisite conditions:-biomedical research shall be based on strong -biomedical research shall be based on strong

scientific knowledge and preclinical scientific knowledge and preclinical experimentationexperimentation

-biomedical research shall be aimed at -biomedical research shall be aimed at developing scientific knowledge on human developing scientific knowledge on human beingbeing

-the expected risk should not be -the expected risk should not be disproportionnate with the interest of the disproportionnate with the interest of the sujects or the researchsujects or the research

-the trouble that may result from the research -the trouble that may result from the research must be limited as much as possiblemust be limited as much as possible

Common RulesCommon Rules

Other conditions:Other conditions:-All the subjects must be clinically examined -All the subjects must be clinically examined The results have several functions: to The results have several functions: to

determine the eligiblity of the person as a determine the eligiblity of the person as a subject, to bring him/her appropriate subject, to bring him/her appropriate information and to serve as an evidence in information and to serve as an evidence in case the subject will have to claim for case the subject will have to claim for damagesdamages

-Other preventive measures: a person who -Other preventive measures: a person who has no social security cannot become a has no social security cannot become a subject and the participation of subjects in subject and the participation of subjects in different biomedical research is limited.different biomedical research is limited.

Specific RulesSpecific Rules

Categories of persons concerned:Categories of persons concerned:-pregnant and breast-feeding women,inmates -pregnant and breast-feeding women,inmates

(prisonners, mental (prisonners, mental patients…),minors,uncapacitated adults and adults patients…),minors,uncapacitated adults and adults not able to expresstheir own consentnot able to expresstheir own consent

Conditions required:Conditions required:

-the expected benefit for the persons concerned -the expected benefit for the persons concerned justifies the risk ORjustifies the risk OR

-there is an expected benefit for other persons in the -there is an expected benefit for other persons in the same category ANDsame category AND

-expected risks should be minimal-expected risks should be minimal

Informed Consent-Common Informed Consent-Common RulesRules

ConsentConsent.No one can be involved in a .No one can be involved in a

biomedical research without being biomedical research without being asked to give a free informed asked to give a free informed consent prior to the researchconsent prior to the research

.In principle, the consent is written but .In principle, the consent is written but it can be exceptionnally given orally it can be exceptionnally given orally in the presence of an independant in the presence of an independant witness.witness.

Informed Consent-Common Informed Consent-Common RulesRules

Information: written document (summary)Information: written document (summary)

.scope:objective, methodology, .scope:objective, methodology, length,expected benefits and risks,decisions length,expected benefits and risks,decisions of the ethics committee and competent of the ethics committee and competent authority,information on the right to authority,information on the right to withdraw consent… withdraw consent…

.limits:research in psychology may and .limits:research in psychology may and exceptionnally information concerning the exceptionnally information concerning the diagnosis of a person may not be revealed diagnosis of a person may not be revealed when it is the interest of the person when it is the interest of the person concerned.concerned.

Informed Consent-Specific Informed Consent-Specific RulesRules

Uncapacitated personsUncapacitated persons-consent is given by the legal -consent is given by the legal

representatives (in principle both parents representatives (in principle both parents for a minor) or by a member of the family for a minor) or by a member of the family or a proxy (for those who have not or a proxy (for those who have not declared uncapacitated). In all cases, the declared uncapacitated). In all cases, the refusal of the person should be respectedrefusal of the person should be respected

-information-informationThey received information appropriate to They received information appropriate to

their capacity of understanding and are their capacity of understanding and are consulted as much as possibleconsulted as much as possible

Informed Consent-Specific Informed Consent-Specific RulesRules

Biomedical research in emergency situationsBiomedical research in emergency situations

The ethics committe may authorize the The ethics committe may authorize the consent to be collected after the research consent to be collected after the research has started when the person is able to has started when the person is able to express a consent. But the prior consent of express a consent. But the prior consent of the family or a proxy is required if presentthe family or a proxy is required if present

Dead persons a biomedical research is Dead persons a biomedical research is possible if the person has consented when possible if the person has consented when alivealive

Objective ConditionsObjective Conditions

The existence of a protocolThe existence of a protocol The necessity of a positive decision The necessity of a positive decision

of an ethics committeeof an ethics committee The authorisation of the competentThe authorisation of the competentauthorithyauthorithy Conditions related to the premises Conditions related to the premises

where research are conductedwhere research are conducted Conditions concerning drug researchConditions concerning drug research

The Protocol and other related The Protocol and other related informationinformation

The research protocol should fully The research protocol should fully described the objective, described the objective, conception,methodology and conception,methodology and organisation of the researchorganisation of the research

The other related informationThe other related information- The brochure for the investigatorThe brochure for the investigator- The financial information:specific The financial information:specific

taxes must have been paid to the taxes must have been paid to the Drug AgencyDrug Agency

The role of the Ethics Review The role of the Ethics Review CommitteeCommittee

Every research protocol shall be submitted to Every research protocol shall be submitted to the review of a Committee for the protection the review of a Committee for the protection of personsof persons

Documents to be submitted: protocol, Documents to be submitted: protocol, brochure for the investigator,information brochure for the investigator,information summary for the subjects, consent summary for the subjects, consent forms,insurance…forms,insurance…

The committee ensures that legal The committee ensures that legal requirements are respected and controls the requirements are respected and controls the scientific pertinence of the research scientific pertinence of the research

The Decison of the Ethics The Decison of the Ethics Review CommitteeReview Committee

No research can be initiated if the decision No research can be initiated if the decision is negativeis negative

In case of a negative decision, the In case of a negative decision, the promotor can however ask for a second promotor can however ask for a second review by another committeereview by another committee

A final decison by a committee can be A final decison by a committee can be appealed in an administrative courtappealed in an administrative court

If the research has not begun a year after If the research has not begun a year after a positive decision, the review process a positive decision, the review process shall be started againshall be started again

The Authorisation of the The Authorisation of the Competent AuthorityCompetent Authority

The competent authority: the Drug Agency The competent authority: the Drug Agency (AFSSAPS)or the Health Minister(AFSSAPS)or the Health Minister

Main documents to be submitted:protocol, Main documents to be submitted:protocol, brochure for the investigator,decision of brochure for the investigator,decision of the ethics committee,insurance,scientific the ethics committee,insurance,scientific data concerning the products…data concerning the products…

Criteria: protecting the subjects by taking Criteria: protecting the subjects by taking into account the safety and quality of the into account the safety and quality of the products, the methodology and products, the methodology and organisation of the researchorganisation of the research

Instruction: no longer than 60 daysInstruction: no longer than 60 days

The Authorisation of the The Authorisation of the Competent AuthorityCompetent Authority

The authority may raise objectionsThe authority may raise objections If the protocol is not modified, the If the protocol is not modified, the

autorisation is refusedautorisation is refused The granted autorisation is valid for The granted autorisation is valid for

one yearone year The decision may be appealed in an The decision may be appealed in an

administrative courtadministrative court

The Premises where the The Premises where the Research are conductedResearch are conducted

Common rulesCommon rules- a biomedical research can only be a biomedical research can only be

conducted in place benefiting of conducted in place benefiting of appropriate staff and technical materialappropriate staff and technical material

- When the subject is a patient who When the subject is a patient who needs hospital services, the research needs hospital services, the research shall be done in the hospital premisesshall be done in the hospital premises


Premises submitted to an agreement :Premises submitted to an agreement :

-premises which are based outside -premises which are based outside hospitalshospitals

-health care premises when they are not -health care premises when they are not currently suited for the researchcurrently suited for the research

The agreement is delivered by the The agreement is delivered by the representative of the State in the regionrepresentative of the State in the region


Conditions required:Conditions required:

- capacity in an emergency situation to - capacity in an emergency situation to treat the subject immediatelytreat the subject immediately

-appropriate staff and material as well -appropriate staff and material as well as a good organisationas a good organisation

-quality insurance control-quality insurance control

-protecting confidentiality-protecting confidentiality

Conditions related to DrugsConditions related to Drugs

Good Production PracticesGood Production PracticesAccording to the European directive of 8th According to the European directive of 8th

Oct.2003, Good Production Practices of Oct.2003, Good Production Practices of drugs apply also to experimental drugsdrugs apply also to experimental drugs

LabellingLabellingThe GPP includes rules on labelling that The GPP includes rules on labelling that

are aimed to ensure the safety of the are aimed to ensure the safety of the subjects involved in biomedical researchsubjects involved in biomedical research

Conducting a Biomedical Conducting a Biomedical ResearchResearch

Duties towards the hospital where Duties towards the hospital where the research is conductedthe research is conducted

Duties towards the public authoritiesDuties towards the public authorities Duties towars the subjectsDuties towars the subjects

Duties towards the HospitalDuties towards the Hospital

The contract with the investigator The contract with the investigator organises:organises:

-the missions and duties of the -the missions and duties of the investigatorinvestigator

-the missions and duties of the promotor-the missions and duties of the promotor

-the financial arrangement-the financial arrangement The contract shall be approved by the The contract shall be approved by the

local colege of physicianslocal colege of physicians

Duties towards the HospitalDuties towards the Hospital

Delivering products free of chargeDelivering products free of charge in principle, the promotor delivers and in principle, the promotor delivers and

assumes the cost of experimented assumes the cost of experimented products (the social security pays for products (the social security pays for drugs when used in conformity with drugs when used in conformity with their agreement)their agreement)

Other products or exams are Other products or exams are assumed by the promotorassumed by the promotor

Duties towards the Public Duties towards the Public AuthoritiesAuthorities

During the researchDuring the research

-Respecting the Good Clinical Practices -Respecting the Good Clinical Practices issued by the Drug Agencyissued by the Drug Agency

-Requiring a new autorisation in case -Requiring a new autorisation in case of substantial modificationof substantial modification

-Notifying undesirable events to the -Notifying undesirable events to the Ethics Committee and Drug AgencyEthics Committee and Drug Agency


The Drug Agency may decide to:The Drug Agency may decide to:

-Interrupt the research when the -Interrupt the research when the promotor does not respect the legal promotor does not respect the legal conditions or when there is a risk for conditions or when there is a risk for the public healththe public health

-Impose specific measures-Impose specific measures

-Prohibit the research (same reasons as -Prohibit the research (same reasons as for interruption)for interruption)


At the end of the researchAt the end of the research-the promotor shall inform the Ethics Committe -the promotor shall inform the Ethics Committe

and the Authority that the research has and the Authority that the research has ended (witin 90 days) and, if necessary, ended (witin 90 days) and, if necessary, about the reasons of an earlier end (15 days)about the reasons of an earlier end (15 days)

-within a year a final report shall be produced -within a year a final report shall be produced with the results of the researchwith the results of the research

-research data shall be stored by the promtor -research data shall be stored by the promtor and the investigator during 15 yearsand the investigator during 15 years

Duties towards the Research Duties towards the Research SubjectsSubjects

CompensationCompensationNo payment is accepted but a limited No payment is accepted but a limited

compensation is allowed except for compensation is allowed except for minors,inmates and uncapacitated adultsminors,inmates and uncapacitated adults

DamagesDamages-the promotor is presumed responsible f-the promotor is presumed responsible f-in other cases, the State compensation -in other cases, the State compensation

system (ONIAM) may functionsystem (ONIAM) may function- An insurance is compulsory for the promotor - An insurance is compulsory for the promotor


Information of the subjectsInformation of the subjects

-during the research, all substantial -during the research, all substantial modification implies a new consentmodification implies a new consent

-after the research, the subject shall -after the research, the subject shall receive global information on the receive global information on the resultsresults


Information on the subjectsInformation on the subjects

-the national data bank of biomedical -the national data bank of biomedical research is accessible to patients’ research is accessible to patients’ groupsgroups

-the national register of research -the national register of research subjects is a mean to control that the subjects is a mean to control that the research subjects are not submitted research subjects are not submitted to undue experimentationto undue experimentation

SanctionsSanctions

PenaltiesPenalties a maximum of 3 years imprisonment for not asking a maximum of 3 years imprisonment for not asking

the consent or conducting research on vulnerable the consent or conducting research on vulnerable persons without respecting the legal conditionspersons without respecting the legal conditions

Entities are also submittes to penal lawEntities are also submittes to penal law Disciplinary sanctions are possible againstDisciplinary sanctions are possible againstthe investigator (as a physician) and the promotor the investigator (as a physician) and the promotor

(as a pharmacist )(as a pharmacist ) Administrative sanctions by the competent public Administrative sanctions by the competent public

authoritiesauthorities