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3. INVESTIGATOR'S RESPONSIBILITIES

4.1.3 The investigator should be aware of, and should comply with, GCP and the applicable regulatory requirements.

INTEGRATED ADDENDUM TO ICH E6(R1):
GUIDELINE FOR GOOD CLINICAL PRACTICE E6(R2)

Investigator’s Qualifications and Agreements

The investigator(s) should:

  • be qualified by education,training, and experience and meet regulatory requirements,




  • be familiar with the appropriate use of the investigational product(s),

  • be aware of, and should comply with, GCP and the applicable regulatory requirements,

  • permit monitoring and auditing by the sponsor, and inspection by the appropriate regulatory authority(ies),

  • maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties.

evidence through up-to-date curriculum vitae and/or other relevant
documentation (e.g ICH GCP certificate)

3. INVESTIGATOR'S RESPONSIBILITIES

The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).

A systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data were recorded, analyzed and accurately reported according to the protocol, sponsor's standard operating procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).

The act by a regulatory authority(ies) of conducting an official review of documents, facilities, records, and any other resources that are deemed by the authority(ies) to be related to the clinical trial and that may be located at the site of the trial, at the sponsor's and/or contract research organization’s (CRO’s) facilities, or at other establishments deemed appropriate by the regulatory authority(ies).

A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator

ADEQUATE RESOURCES

Potential for recruiting the required number of suitable subjects within the agreed period

Sufficient time to properly conduct and complete the trial

  • Adequate number of qualified staff for the duration of the trial
  • Staff adequately trained about the protocol, investigation product(s) and their trial-related duties & functions
  • Principal Investgator oversight:
    • Appropriate supervision of any individual or group to whom the investigator assigns trial-related duties at the trial site before beginning of the activities
    • Assurance that any person or party retained to perform trial-related duties is suitably qualified to perform duties. Systems should be implemented to ensure the integrity of trial-related duties performed and any data generated

Facilities

Suitable facilities for the duration of the trial

Patients

Time

Personnel

# CSP - Article R1124-1
# Arrêté du 14 novembre 2006 relatif aux données constitutives du fichier national des personnes qui se prêtent à des recherches biomédicales

Fichier national des personnes qui se prêtent à des recherches biomédicales => respect de la période d'exclusion entre 2 participations

3. INVESTIGATOR'S RESPONSIBILITIES

# CSP - Article L1121-16
Etude 'First-In-Human'
=> Autorisation de Lieu de Recherche Impliquant la Personne Humaine valide

Medical Care of Trial Subjects

The investigator has responsibility for the medical care of trial subjects.

Ascertain reason for subject withdrawal.

Ensuring adequate medical care.

Informing subject's primary physician (if subject agrees).

Making medical decisions.

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# BPC - 4.3.6 'L’investigateur s’assure que la personne qui participe à une recherche biomédicale est affiliée à un régime de sécurité sociale ou bénéficiaire d’un tel régime conformément à l’article L. 1121-11 du code de la santé publique.'

3. INVESTIGATOR'S RESPONSIBILITIES

Although a subject is not obliged to give his/her reason(s) for withdrawing prematurely from a trial, the investigator should make a reasonable effort to ascertain the reason(s), while fully respecting the subject’s rights.

During and following a subject’s participation in a trial, the investigator/institution should ensure that adequate medical care is provided to a subject for any adverse events, including clinically significant laboratory values, related to the trial. The investigator/institution should inform a subject when medical care is needed for intercurrent illness(es) of which the investigator becomes aware.

It is recommended that the investigator inform the subject’s primary physician about the subject’s participation in the trial if the subject has a primary physician and if the subject agrees to the primary physician being informed.

A qualified physician (or dentist, when appropriate), who is an investigator or a subinvestigator for the trial, should be responsible for all trial-related medical (or dental) decisions.

Communication with IRB/IEC

As part of the investigator's written application, the investigator* should provide the IRB/IEC with a current copy of the Investigator's Brochure.

During the trial, the investigator* should provide to the IRB/IEC all documents subject to review.

En France, le rôle de l'investigateur décrit ci-dessus est de la responsabilité du promoteur.
# BPC- '5.10. Autorisation par l’Agence française de sécurité sanitaire des produits de santé' & '5.11. Avis du comité de protection des personnes'
Le promoteur est chargé de soumettre :
- à l'Agence Nationale de Sécurité du Médicament et des produits de santé (ANSM) pour obtention d'une autorisation,
- et au Comité de Protection des Personnes pour obtention d'un avis favorable.

3. INVESTIGATOR'S RESPONSIBILITIES

Before a trial begins, the investigator* should have written and dated approval/favorable opininion from the IRB/IEC for the:
- protocol/amendments,
- informed consent form (initial and updates),
- subject recruitment procedures (e.g. advertisements)
- and any other written information to be provided to subjects.

*

COMPLIANCE WITH THE PROTOCOL

The investigator should conduct the trial in compliance with the approved protocol (regulatory authorities and IRB/IEC), ex. sufficient documentation to support subject meeting inclusion/exlusion criteria.

To confirm agreement, signature of the protocol by the investigator and the sponsor (or an alternative contract)

No deviation or changes of the protocol without prior:
- agreement by the sponsor,
- and review and documented approval/favourable opinion from the IRB/IEC (amendment).

Unless to eliminate immediate hazard(s) to trial subjects or when the change(s) involves only logistical or administrative aspects of the trial (ex. change in monitor, change of phone number).

In case of deviation, the investigator should document and explain any deviation from the approved protocol.

3. INVESTIGATOR'S RESPONSIBILITIES

The investigator should follow the trial's

randomization

process, if any, and should ensure that the code is broken only in accordance

with the protocol. If premature

unblinding

Blinding/Masking: A procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s). Single-blinding usually refers to the subject(s) being unaware, and doubleblinding usually refers to the subject(s), investigator(s), monitor, and, in some cases, data analyst(s) being unaware of the treatment assignment(s).

occur, the investigator should promptly document and explain this to the sponsor.

INVESTIGATIONAL PRODUCT(S) (IP)

Definition: A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use.

Responsible for IP management at site = Principal Investigator

Delegation: The investigator may assign some or all duties for IP management to an appropriate pharmacist or another appropriate individual who is under the supervision of the investigator.

  • Storage: The IP should be stored per requirement.

  • Usage: The investigator should ensure the IP is used in accordance with the approved protocol.

  • Instructions: The investigator should explain the correct use of the IP to each subject and should check, at intervals appropriate for the trial, that each subject is following the instructions properly/compliance.

  • Records: The investigtor (or delegated personnel) should maintain records of the delivery, inventory, dispensation, usage, disposal or return and reconciliation of IP(s) and other study medication provided by the sponsor.

3. INVESTIGATOR'S RESPONSIBILITIES

RANDOMIZATION PROCEDURES AND UNBLINDING

3. INVESTIGATOR'S RESPONSIBILITIES

Definition: The process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce bias.

The investigator should follow the trial's randomization procedures.

If the trial is blinded, the investigator should promptly document and explain to the sponsor any premature unblinding (e.g., accidental unblinding, unblinding due to a serious adverse event) of the investigational product(s).

INFORMED CONSENT

3. INVESTIGATOR'S RESPONSIBILITIES

A process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject's decision to participate.

Informed consent is documented by means of a written, signed and dated informed consent form.

Both, the written informed consent form and discussion, must include information specified in ICH E6 (R2) - Section 4.8.10

INFORMED CONSENT

3. INVESTIGATOR'S RESPONSIBILITIES

Informed consent should be obtained prior to subject's participation in a trial (before any study procedures are performed).

The 'informed consent' process must cover following topics:

Behaviour/Attitude

Language

Information

Documentation

Signature and date

Time

Click on each requirement to learn more

ICH E6 (R2) provides guidance on how to consent

Vulnerable subjects

Vulnerable Subjects: Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.


When a subject (e.g. minor, incapacitated) can only be enrolled with the consent of the legal representative, the subject must be informed to the level of their understanding, provide assent (where this is feasable) and personally sign and date the consent form.
In emergency situations where the subject and legal representative are unable to consent, enrollment requires protective measures to be described in protocol or other IRB/IEC approved documents. Subject or legal representative should be informed as soon as possible and consent to continue and other consent as appropriate.
If the subject/legal representative are unable to read, an impartial witness must be present during the consent discussion and sign and date the consent form.

Version of the ICF

Neither the investigator, nor the trial staff, should coerce or unduly influence a subject to participate or to continue to participate in a trial.

Subject should not be asked to waive legal rights or release investigator or sponsor from liability for negligence.

The investigator, or a person designated by the investigator, should fully inform the subject or, if the subject is unable to provide informed consent, the subject's legally acceptable representative, of all pertinent aspects of the trial including the written information and the approval/ favourable opinion by the IRB/IEC.

All explanations that have to be given to the subject during the informed consent discussion and be present in the written informed consent form (and any other written information to be provided to subjects) are listed in the ICHE6 R2 section 4.8.10. :

- the purpose of the trial,

- the trial procedures to be followed, including all invasive procedures,

- that the subject's participation in the trial is voluntary and that the subject may refuse to participate or withdraw from the trial, at any time, without penalty or loss of benefits to which the subjects is otherwise entitled,

- the expected duration of the subject's participation in the trial. ...




The language used in the oral and written information about the trial, including the written informed consent form, should be as non-technical as practical and should be understandable to subject or legal representative and impartial witness (if applicable).

The investigator, or a person designated by the investigator, should provide the subject or the subject's legally acceptable representative ample time and opportunity to inquire about details of the trial and to decide whether or not to participate in the trial. All questions about the trial should be answered to the satisfaction of the subject or the subject's legally acceptable representative

Prior to a subject’s participation in the trial, the written informed consent form should be signed and personally dated by the subject or by the subject's legally acceptable representative, and by the person who conducted the informed consent discussion.

A signed & dated copy of the ICF should be given to the subject or the legal representative (including any other written information provided to the subject).

The informed consent process should be documented in the medical record/source file, as well as communication of any new information relevant to a subject's willingness to continue participation in the trial.

Prior to the beginning of the trial, the investigator should have the IRB/IEC's written approval/favourable opinion of the written informed consent form and any other written information to be provided to subjects.

The written informed consent form and any other written information to be provided to subjects should be revised whenever important new information becomes available that may be relevant to the subject’s consent. Any revised written informed consent form, and written information should receive the IRB/IEC's approval/favourable opinion in advance of use.

The subject or the subject’s legally acceptable representative should be informed in a timely manner if new information becomes available that may be relevant to the subject’s willingness to continue participation in the trial. The communication of this information should be documented.


RECORDS AND REPORTS

3. INVESTIGATOR'S RESPONSIBILITIES

The investigator/institution should maintain adequate and accurate source documents and trial records that include all pertinent observations on each of the site’s trial subjects

Definitions:

Source Documents:

Original documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects' diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical trial).

All information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies).

Source Data:

CRF entries should be consistent with data contained in source documents.

RECORDS AND REPORTS

3. INVESTIGATOR'S RESPONSIBILITIES

To ensure data integrity, ALCOA+ principles should be applied to source documents and essential documents (including CRF)

RECORDS AND REPORTS (ctd)

3. INVESTIGATOR'S RESPONSIBILITIES

To ensure data integrity, ALCOA+ principles should be applied to source documents and essential documents (including CRF)

RECORDS AND REPORTS

3. INVESTIGATOR'S RESPONSIBILITIES

Trials documents should be maintained as specified in:

  • Sponsor requirements.

  • Regulation (local, european ...),

=> 'until at least 2-years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2-years have elapsed since the formal discontinuation of clinical development of the investigational product.'

# Bonnes Pratiques Cliniques :
4.9.4. L’investigateur conserve les documents et données relatifs à la recherche biomédicale, qui lui sont spécifiques et qui sont listés dans le chapitre 8 de la présente annexe, et dans le respect des dispositions législatives et réglementaires en vigueur, notamment l’arrêté du 8 novembre 2006 fixant la durée de conservation par le promoteur et l’investigateur des documents et données relatifs à une recherche biomédicale portant sur un médicament à usage humain.

# Règlement (UE) n° 536/2014 du parlement européen et du conseil du 16 avril 2014 relatif aux essais cliniques de médicaments à usage humain et abrogeant la directive 2001/20/CE
Archivage du dossier permanent de l'essai clinique À moins que d'autres dispositions du droit de l'Union n'exigent une durée d'archivage plus longue, le promoteur et l'in­vestigateur conservent le contenu du dossier permanent de l'essai clinique pour une période d'au moins vingt-cinq ans après la fin de l'essai clinique. Toutefois, les dossiers médicaux des participants sont conservés conformément au droit national.

  • ICH-E6 R2

The longest document retention period should be followed.

RECORDS AND REPORTS

3. INVESTIGATOR'S RESPONSIBILITIES

In the section 8. of the ICH E6(R2), the minimum list of essential documents which has to be archived is provided.

Essential documents are those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor and monitor with the standards of Good Clinical Practice and with all applicable regulatory requirements.

Some examples of essential documents:
- Signed protocol and amendments, if any, and sample CRF (to document investigator and sponsor agreement to the protocol/amendment(s) and CRF),
- Financial aspects of the trial (to document the financial agreement between the investigator and the sponsor of the trial),
- Investigator's brochure and updates (to document that relevant and current scientific information about the investigational product has been provided to the investigator),
- Source documents (to document the existence of the subject and substantiate integrity of trial data collected. To include original documents related to the trial, to medical treatment, and history of subject),
- Suspected Unexpected Serious Adverse Reaction (SUSAR)
- ...

PROGRESS REPORTS

3. INVESTIGATOR'S RESPONSIBILITIES

The investigator* is responsible for submitting written summaries of the trial status to the IRB/IEC annually, or more frequently, if requested by the IRB/IEC.
The investigator should promptly provide written reports to the sponsor, the IRB/IEC and, where applicable, the institution on any changes significantly affecting the conduct of the trial, and/or increasing the risk to subjects.

En France, le rôle de l'investigateur décrit ci-dessus est de la responsabilité du promoteur.

# BPC - '4.10. Informations disponibles au cours de la recherche'
L’investigateur notifie sans délai au promoteur tout fait nouveau intéressant la recherche ou le médicament expérimental susceptible de porter atteinte à la sécurité des personnes qui s’y prêtent ainsi que toute modification prise dans ce cadre, permettant ainsi au promoteur de respecter les dispositions législatives et réglementaires en vigueur.

*

SAFETY REPORTING

3. INVESTIGATOR'S RESPONSIBILITIES

The investigator is responsible for timely reporting of subject adverse events (AE) (all AE and/or laboratory abnormalities) to the sponsor, regardeless of wheteher the events are related to the investiagional product, within the time period defined in protocol.

Definitions:

Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.
An adverse event (AE) can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.

Adverse Event (AE):

Adverse events (AE) related to the investigational products:

Adverse Drug Reaction (ADR): all noxious and unintended responses to a medicinal product related to any dose. A causal relationship between an investigational product and an AE is a possibility.

Unexpected Adverse Drug Reaction: an adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator's Brochure for an unapproved investigational product or package insert/summary of product characteristics for an approved product).

SAFETY REPORTING

3. INVESTIGATOR'S RESPONSIBILITIES

Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR):

The investigator's responsibilites regarding the SAE:

Any untoward medical occurrence that at any dose:
- results in death,
- is life-threatening,
- requires inpatient hospitalization or prolongation of existing hospitalization,
- results in persistent or significant disability/incapacity, or
- is a congenital anomaly/birth defect..

SAFETY REPORTING

3. INVESTIGATOR'S RESPONSIBILITIES

All SAEs should be reported immediately to the sponsor except for those SAEs that the protocol or other document (e.g. Investigator’s Brochure) identifies as not needing immediate reporting.
Prompt follow up by detailed written reports. Subjects should be identified by unique code numbers.

Unexpected serious drug reactions have to be reported to regulatory authorities and IRB/IEC (in accordance with local requirements). Sponsor and IRB/IEC may need additional information for reported deaths (e.g. autopsy report).

# CSP - Article R1123-53
En France, c'est le promoteur qui déclare aux Autorités Compétentes et aux Comités de Protection des Personnes la survenue des SUSAR (Suspected Unexpected Serious Adverse Reaction).

The investigator must inform the co-investigators of the SUSARs notified and the updates of the Investigator's Brochure.

PREMATURE TERMINATION OR SUSPENSION OF A TRIAL

3. INVESTIGATOR'S RESPONSIBILITIES

If the trial is prematurely terminate or suspended for any reason, the investigator should promptly inform the trial subjects, should assure appropriate therapy and follow-up for the subjects. In addition, the following actions have to be performed (3 different ways to prematurely terminate a trial):

Decision taken
by the investigator

  • Promptly informs the institution (if applicable), the sponsor and the IRB/IEC and competent authorities,
  • Provides the sponsor and the IRB/IEC with a detailed written explanation of the termination or suspension.

  • Promptly informs the institution (if applicable), the IRB/IEC and competent authorities,
  • Provides the IRB/IEC with a detailed written explanation of the termination or suspension.

Decision taken by regulatory authorities

  • Promptly informs the institution (if applicable) and the sponsor and competent authorities/IRB/IEC,
  • Provides the sponsor with a detailed written explanation of the termination or suspension.

Decision taken by the sponsor

FINAL REPORT(S) BY INVESTIGATOR

3. INVESTIGATOR'S RESPONSIBILITIES

At the conclusion of a trial, the investigator* is responsible for providing:

  • The institution with information of trial completion (where applicable),
  • The sponsor with all required reports,
  • The IRB/IEC with a summary of the trial's outcome,
  • The regulatory authority(ies) with any reports required, according to local regulations.

# BPC - '4.13. Rapport final de la recherche'

Dans un délai d’un an suivant la fin de la recherche, un rapport final est établi et signé par le promoteur et l’investigateur, (si essai multicentrique, par tous les investigateurs ou si prévu par le protocole par l’investigateur coordonnateur).
Tous les investigateurs sont informés des résultats de la recherche par l’investigateur coordonnateur ou par le promoteur.

En France, le rôle de l'investigateur décrit ci-dessus est de la responsabilité du promoteur.

# CSP - Article L1122-1
A l'issue de la recherche, la personne qui s'y est prêtée a le droit d'être informée des résultats globaux de cette recherche, selon les modalités qui lui seront précisées dans le document d'information.

*

# Guidance on posting and publication of result-related information on clinical trials in relation to the implementation of Article 57(2) of Regulation (EC) No 726/2004 and Article 41(2) of Regulation (EC) No 1901/2006 - 4.3. Timing
Result-related information should be posted within the time­frames set out in the Regulation (EC) No 1901/2006 and the guidelines referred to under Section 1, i.e. (relating to paediatric clinical trials) within six months and otherwise within one year of the end of the trial.

Thanks!

Time for the quizz !

CTquality@gustaveroussy.fr