Sponsor Oversight &

Investigator Supervision,from an auditor’s point of view

Birthe Emilie Nielsen

Senior Principal Quality Auditor, LEO Pharma A/S

Topics to be addressed today

Sponsor Oversight of CROs

Investigator Supervision

Major points to consider during audit and monitoring

A few new issues to consider…

References

Sponsor oversight

Oversight

Meaning

Sponsor oversight

When outsourcing activities the ultimate responsibility resides with Sponsor; The CRO should implement QC and QA (5.2.1)

• QA has a process for assessing potential CROs, as part of the Request for Proposal Process

Outsourced tasks should be specified in writing (contract) (5.2.2)

• Clinical Operations works closely together with Legal and QA

Sponsor should ensure oversight of any duties, -including subcontracted activities

• Contracts & Audits

Sponsor Oversight

Clinical Operation manages CROs by detailed

plans and routine meetings

Escalations plans are of overall importance

Deliverables may be measured by KPIs during

the trial and after the Services have been

terminated

The oversight is risk-based; depending on the

number of services outsourced, - the criticality

and complexity of the services

Audits are part of the oversight

Audits are defined as an independent quality assessment

The reference documents are ICH GCP; the trial protocol

incl. associated documents and the contract

Audits are risk-based

Quality Agreement might be part of the oversight approach

Audit findings

Lack of critical processes

Lack of Signed Contract

Timelines not met

Staff not qualified or trained

Lack of resources allocated

Lack of escalation to Sponsor

Clinical Research -

Subject’s rights, safety and data integrity

Investigator Supervision - Background

Fundamental parts of ICH GCP

FDA form 1572, (Section 9, first paragraph)

FDA guidance document: Investigator Responsibilities —

Protecting the Rights, Safety, and Welfare of Study

Subjects, - October 2009

EMA Reflection paper on expectations for electronic

source data and data transcribed to electronic data

collection tools in clinical trials

ICH GCP E6 (R2)

And additional quotations

Investigator Supervision, - Risks

Cultural background

Trial Duration

Trial Complexity

Site Setting

Major Points

Primary Study

Endpoint Data

Safety

Assessments

Eligibility

criteria

Protocol

Compliance

Staff

Qualifications

Training

Staff

Meetings

Adequate

Resources

Informed

Consent

Delegation of

responsibilities,

Approval of

eCRF

Review

of ePRO

Available for

CRA

TimingLab Data

ALCOA

++

Examples from audits….

Eligibility, safety and endpoint data

4.9.0

Investigator should maintain adequate source

documents, including all pertinent observations on each

subject. Source data should be attributable, legible,

contemporaneous, original, accurate and complete

A common challenge; often findings in this category

ALCOA

Delegation of responsibilities

4.1.5

The investigator should maintain a list of appropriately

qualified persons to whom the investigator has delegated

significant trial-related duties.

Investigator is responsible for demonstrating that staff

are qualified by training and education

Delegation of responsibilities,

Adequate Resources

4.1.3 & 4.1.4

Investigator should have adequate resources and

sufficient time to properly conduct and complete the trial

Should be able to demonstrate that subjects were seen

according to the protocol requirements

Adequate

Resources

IMP

4.5.6

Investigator should ensure that IMP is administered

according to the protocol

Sometimes cultural differences means that procedures

are carried out in a different way

IMP

Supervision and monitoring

4.2.5

The Investigator is responsible for supervising any

individual or party to whom the investigator delegates

trial related duties

This includes being available for the monitor; compliance

issues, questions

Available for

the CRA

New Initiatives/issues to considerGXP’ Data Integrity Guidance and Definitions

5.2 The use of scribes to record activity on behalf of another operator can be considered where justified, for example:

• The act of contemporaneous recording compromises the product or activity e.g. documenting line interventions by sterile operators.

• Necropsy (GLP)

• To accommodate cultural or literacy/language limitations, for instance where an activity is performed by an operator but witnessed and recorded by a second person.

Consideration should be given to ease of access, usability and location whilst ensuring appropriate control of the activity guided by the criticality of the data.

In these situations, the recording by the second person should be contemporaneous with the task being performed, and the records should identify both the person performing the task and the person completing the record. The person performing the task should countersign the record wherever possible, although it is accepted that this countersigning step will be retrospective. The process for supervisory (scribe) documentation completion should be described in an approved procedure that specifies the activities to which the process applies.

New Initiatives/issues to considerCentral Authority of the Laender for Health Protection with Regard to

Medicinal Products and Medical Devices

The members of the expert group 05 consider that the requirement pursuant to 4.9.1 ICH-GCP according to which the investigator has to ensure the accuracy, completeness, readability and up-to-dateness of data in the (e)CRF at the time of forwarding such data to the sponsor is not fulfilled.

The consequence of this is, that also if the CRF is available in an electronic form the investigator or a medical trial staff member needs to verify at regular intervals that the entered data comply with the above mentioned criteria. This can reasonably only be done by a signature or an electronic signature after each visit, for which the requirement for timely input and thus transmission to the sponsor exists.

Regular verifications are all the more important when serious adverse events are documented as reporting has to be made by the investigator pursuant to ICH-GCP 4.11 and it is mandatory that the assessment of causality is made by him/her.

New Initiatives/issues to considerCentral Authority of the Laender for Health Protection with Regard to

Medicinal Products and Medical Devices

Result

The members of the expert group 05 consider, also after consultation with the representatives of the competent supreme federal authorities in the expert group 05, that data verification of data entered in eCRFs has to be made by an investigator or by medical trial staff members delegated by him/her regularly and in close temporal relation to the visits in order to comply with the requirement directed to the investigator pursuant to ICH-GCP 4.9.1.

The missing implementation of electronic signatures for regular data verification in the eCRF is therefore considered a major deficiency the sponsor is accounting for (ICH-GCP 5.1.1 and 5.1.3).

The classification of the deficiency the investigator is accountable for, with regard to the proof of a regular data verification in the eCRF(ICH-GCP 4.9.1) should be taken under consideration of the circumstances encountered during the inspection.

References

2.7 The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.

2.8 Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s).

4.2.3 The investigator should have available an adequate number of qualified staff and adequate facilities for the foreseen duration of the trial to conduct the trial properly and safely.

4.2.4 The investigator should ensure that all persons assisting with the trial are adequately informed about the protocol, the investigational product(s), and their trial-related duties and functions.

4.2.5 The investigator is responsible for supervising any individual or party to whom the investigator delegates trial-related duties and functions conducted at the trial site.

References

4.5.1 The investigator/institution should conduct the trial in

compliance with the protocol agreed to by the sponsor and, if

required, by the regulatory authority(ies) and which was given

approval/favourable opinion by the IRB/IEC. The

investigator/institution and the sponsor should sign the protocol, or

an alternative contract, to confirm agreement.

4.5.3 The investigator, or person designated by the investigator,

should document and explain any deviation from the approved

protocol.

References

4.9.0 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. Source

data should be attributable, legible, contemporaneous, original,

accurate, and complete. Changes to source data should be

traceable, should not obscure the original entry, and should be

explained if necessary (e.g., via an audit trail).

4.9.1 The investigator should ensure the accuracy, completeness,

legibility, and timeliness of the data reported to the sponsor in the

CRFs and in all required reports..