Inspection experience and interpretation of guidances · PDF fileInspection experience and interpretation of guidances ... Quality Management in Early Phase Clinical ... GCP inspectors

Inspection experience and

interpretation of guidances

on e-CRF and e-TMF

Heiner Gertzen

Sanofi - Paris / France

AGAH e.V. Workshop – 3 / 4 November 2016 – Bonn (Germany)

Quality Management in Early Phase Clinical Pharmacology Units

INSPECTION FINDING ON E-CRF

● Sponsor’s e-CRF system “gives the sponsor exclusive

access to the CRF”

● Inspectors (MPA) required “the possibility to confirm data

in the sponsor’s database versus CRF-data which have

never been under the exclusive control of the sponsor”

● Existence of an e-CRF site copy which “has never been in

the hands of the sponsor”

● Equivalence to paper copy of CRF which always remains

at the investigator site was requested

● First raised end-2013 - similar findings in other EU GCP

inspections (e.g., Germany, UK, Lithuania, Switzerland…)

AGAH Workshop – Bonn – 3 / 4 November 2016 | 2

AGAH QM Workshop - 04. November 2016 - No. 5 1

E-CRF SYSTEM PROPERTIES

● Data are entered and stored on a server residing at the sponsor site

● Investigator can review, enter, modify e-CRF data until database lock

● Any data change endorsed by investigator and recorded in audit trail

● Investigator confirms data (i.e., approves all CRF pages) prior to

database lock

● E-CRF system is validated to ensure traceability of data

● Audit trail includes original and changed values and information on

who made the entry, date and time

● After database lock the investigator keeps read-only access to the e-

CRF system until he receives a CD-ROM for archiving containing all

CRF reported data per patient and the audit trail

● Investigator is requested to verify and acknowledge he received PDR

for all his patients and to verify the contents for at least 3 patients prior

to removing site access to the e-CRF system


INSPECTION RESPONSE

● All key data reported in the e-CRF are transcribed data

based on independent source data under the exclusive

control of the investigator; this allows independent

confirmation of the data in the sponsor database

● Investigator has permanent full access and control of the

reported data up to database lock after which data cannot

be modified (neither by the investigator nor the sponsor)

● E-CRF copy is produced by a controlled and validated

process, contains all reported data, corrections and the

audit trail; server access maintained up to copy receipt



INSPECTORS’ EVALUATION

● Responses were not accepted (after direct discussion)

● Commitment requested to review system properties and

find ways to make system compliant

● E-CRF is considered as a source document

● Investigator copy of e-CRF needs to be generated● from data to which the sponsor has had no access

● by an entity which is independent from the sponsor

● Basis: EMA Reflection paper on expectations for electronic

source data and data transcribed to electronic data

collection tools in clinical trials (effective 1 AUG 2010)● E-system controls & security to be at least equivalent to paper


EMA - 09 June 2010 - EMA/INS/GCP/454280/2010: Reflection paper on expectations for electronic source data and data transcribed to electronic data collection tools in clinical trials

Section 4, page 6: Scope

● The scope of this reflection paper is electronic systems,(including instruments, software and services) used inclinical trials in the creation/capture of electronic clinicaldata, such as:

● Electronic Case Report Forms (e-CRFs) e.g. laptop / desktop,mobile device based programs or web based tools, which maycontain source data directly entered, transcribed data by re-keyingfrom other sources, or both.



Reflection paper on expectations for electronic source data and data transcribed to electronic data collection tools in clinical trials

Section 6.2, page 10: Specific Requirements – Topic 3: Control

● Source data should only be modified with the knowledge orapproval of the investigator● Requirement 6, ICH GCP 4.9.3, 4.9.4 and chapter 8)

● The sponsor should not have exclusive control of a sourcedocument● Requirement 10, ICH GCP 8.3.13

● The requirements above are not met if data are captured in anelectronic system and the data are stored on a central server underthe sole control of the sponsor. This is because the investigatordoes not hold an independent copy of the data and therefore thesponsor has exclusive control of the data. In order to meet therequirements a contemporaneous certified copy of the data shouldbe retained at the investigator site in addition to the recordmaintained on a central server.


Survey outcomes of e-CRF practices

● Majority of companies use 3rd party providers & systems

● InForm (Phase Forward, bought by Oracle)

● RAVE (Medidata) also used but to a lesser extent

● Fewer companies with internal systems developed and

maintained in-house

● OC / RDC (Oracle) as a basis / or purely internal

● Independent investigator copy of e-CRF easier to implement

with external systems - but this is not always the case,

practices appear to be variable

● Inspection experience is up to now quite variable, but

exchange of information and interpretation is growing

● EMA GCP Inspectors Working Group (EMA GCP IWG)



EMA GCP Inspectors’ Working Group - Inspectors’ expectations

● EMA GCP IWG joint meetings with interested parties● EDC data storage (e-CRF & e-source data) on the agenda

several times

● Do not necessarily require an independent EDCdatabase (e.g., trusted 3rd party)

● Sponsors to ensure investigators retain acontemporaneous copy of the CRF under their control(principles as applied to paper CRFs per ICH-GCP)

● As long as this is achieved: flexibility as to how it isrealized

● Inspectors acknowledge it is harder to achieve in web-based systems

● Inspectors also published their standpoint on EMAGCP Inspectors Q&A website


EMA/INS/GCP/454280/2010 TOPICS & REQUIREMENTS

● Topic 1: Creation and modification of systems

● An instrument used to capture source data shall ensure that the data are

captured as specified within the protocol. (Requirement 1, ICH GCP 2.6, 6.4.9)

● Topic 2: Creation, modification and transfer of data

● Source data shall be Accurate, Legible, Contemporaneous, Original,Attributable, Complete and Consistent. (Requirement 2, ICH GCP 1.51, 1.52,4.9.1 and 6.4.9)

● An audit trail shall be maintained as part of the source documents for theoriginal creation and subsequent modification of all source data. (Requirement3, ICH GCP 4.9.3 and 5.5.4)

● The location of source documents and the associated source data shall beclearly identified at all points within the capture process. (Requirement 11, ICHGCP Chapter 8)

● Topic 3: Control

● The investigator shall maintain the original source document or a certified

copy. (Requirement 5, ICH GCP 2.11, 5.15.1)



EMA/INS/GCP/454280/2010 TOPICS & REQUIREMENTS

● Topic 3: Control● Source data shall only be modified with the knowledge or approval of the

investigator. (Requirement 6, ICH GCP 4.9.3, 4.9.4 and Chapter 8)

● The sponsor shall not have exclusive control of a source document.(Requirement 10, ICH GCP 8.3.13)

● Source documents shall be protected against unauthorized access.(Requirement 9, ICH GCP 2.11, 5.15.1)

● Topic 4: Copying● The source document shall allow for accurate copies to be made.

(Requirement 8, ICH GCP 1.51)

● When source data are copied, the process used shall ensure that the copy isan exact copy preserving all of the data and metadata of the original.(Requirement 12)

● Topic 5: Storage

● The storage of source documents shall provide for their ready retrieval.

(Requirement 4, ICH GCP 2.11 and 5.15.1)

● Source documents and data shall be protected from destruction. (Requirement

7, ICH GCP 4.9.3, 4.9.4 and Chapter 8)


MHRA CRITICAL E-TMF FINDINGS - Different sponsor companies around 2014

● Inspection suspended due to complexity/time taken to access

different components of the TMF

● Inspection re-scheduled - an opportunity given to provide complete

‘inspectable’ TMF

● E.g. – TMF re-provided in electronic form – TMF re-provided as paper

– TMF re –mapped/ indexed and provided as e-TMF

● Observations given due to inability to provide complete TMFs

within requested timeframe

● Graded as “critical” (only “major” prior to revised criticality definition by

MHRA)



MHRA Updated definition of a critical GCP inspection finding

Following numerous issues with inspector access to TMFs and

incomplete TMFs, the GCP Inspectorate has updated their definition of

critical to include:

‘where provision of the Trial Master File (TMF) does not comply with

Regulation 31A 1-3, as the TMF is not readily available or accessible,

or the TMF is incomplete to such an extent that it cannot form the

basis of inspection and therefore impedes or obstructs inspectors

carrying out their duties in verifying compliance with the regulations.’

MHRA website - 25 April 2014 http://www.mhra.gov.uk/Howweregulate/Medicines/Inspectionandstandards/GoodClinicalPractice/News/CON

408249


EMA - 01 Feb 2013 - EMA/INS/GCP/636736/2012 (DRAFT): Reflection paper on GCP compliance in relation to trial master files (paper and/or electronic) for management, audit and inspection of clinical trials

5.5. Contemporariness of TMF

The TMF should be up to date, with documents placed in the TMF in

a timely manner with the aim to maintain the TMF “inspection ready”.

GCP inspectors would raise concerns if the TMF appeared out of date

such that the ability to manage and oversee the trial conduct was

questionable.

In trials that have more complex TMF arrangements with multiple

parties involved it may be useful to define the timescales for

submission and filing of documents to the TMF in procedural

documents or TMF plans.



http://www.mhra.gov.uk/Howweregulate/Medicines/Inspectionandstandards/GoodClinicalPractice/News/CON408249

http://www.mhra.gov.uk/Howweregulate/Medicines/Inspectionandstandards/GoodClinicalPractice/News/CON408249

EMA Draft Reflection Paper (1 Feb 2013) – Section 6:

Provision of TMF for inspection

The inspectors must have direct access to the entire TMF which means

reviewing the TMF as used by the staff conducting the trial.

A copy or artificial construction is unlikely to be accepted for trials

currently in the live phase and puts an additional QC requirement on the

sponsor. A copy may be acceptable for archived TMFs.

Direct access includes all the systems that comprise the TMF as defined

by the sponsor.

GCP inspectors may not wish to be supervised during review of the TMF.

GCP inspectors inspecting in their own countries may have rights to seize

trial documentation.

Remote access to e-TMF without visiting the site may assist in planning

inspections and could potentially form part of the inspections.


FDA GCP SPONSOR INSPECTION

● For numerous pivotal studies managed with hybrid TMF using paper

and electronic systems for some documents (MVR, correspondence,

IP reconciliation documentation, IB, SUSARs, e-CRF…):

● FDA performed GCP PAI sponsor monitor inspections (including one

in the EU / France)

● FDA insisted to see original documents, this was the reason for

coming to EU – however:

“I am not supposed to look or to search myself in the sponsor's system"

“Show me in the system” online location of e-CTD documents & e-CRF

data by sponsor personnel

“Bring me” for paper documents



MHRA GCP SPONSOR INSPECTION

● 4 inspectors / 10 working days / 40 mandays

● 4 studies in scope - 2 paper TMF, 2 e-TMF (1 sponsor / 1 vendor)

● Access to e-TMF given to inspectors after a training performed on first

inspection day (by sponsor or by vendor)

● Specific inspector view Direct access to e-TMF documents in final

status including financial contracts

● Additionally, direct access to CTMS provided to the inspectors for

navigating through the monitoring visit reports

● Over the shoulder navigation in PV database requested to review

specific SAEs (navigation done by parmacovigilance staff)

● Request to have all sponsor quality documents related to clinical trials

available on a USB key

| 17 AGAH Workshop – Bonn – 3 / 4 November 2016

SELECTED E-TMF FINDINGS & REMARKS

● No possibility during inspection to extract complete system audit trail

● Audit trail by document available in e-TMF was judged not sufficient)

● Audit trail completeness and easy accessibility requested

● Missing documents

● Insufficient evidence of vendor oversight; validation/test files of CRFs,

database, IVRSs and statistical data sets considered part of TMF

● Draft documents (e.g., interim protocol versions) requested to be kept !!!

● Expectation to see all documents in TMF that track the “life of the study”

● Poor quality of some scanned documents (process?)

● Navigation in scanned version of paper TMF criticized

● On-going trial with paper files kept by a vendor in US: emergency

scanning of the TMF (50,000 documents scanned in 10 days); all global

TMF documents requested (even thoug kept at global R&D locations)

● Access to unblinded treatment information not properly restricted

| 18 AGAH Workshop – Bonn – 3 / 4 November 2016


SOME LEARNINGS & RECOMMENDATIONS

● Use the industry-wide TMF Reference Model (DIA SAIC) as the

index (filing structure)

● Use meaningful obvious naming conventions

● Inspectors want bookmarking ability so that they can ask questions

about e-TMF contents (they do not want to have to record folder

paths and structures)

● Multiple associated e-systems (e.g., Data Management / Statistics/

e-CRF design / IMP management / IVRS / PV) usually maintained

separately until the end of the study – expectation: to be updated

in “real time” without delay for immediate access

● TMF indices could include electronic links to the TMFs / TMF

documents in other systems (refer to it or functioning interface ?)


CONSTRAINTS & CHALLENGES - NAVIGATION -

● Fast access to documents and easy navigation

● Indexing of documents

MHRA inspector expectations:

GCP Symposium 11 February 2014 – MHRA presentation on TMF by Andy Fisher



CONSTRAINTS & CHALLENGES - TECHNICAL CONFIGURATION -

● Audit trail: readable and easy to use?

● Generic or personal access?

● Remote access (versus providing documents prior to inspection)?

● If yes, how long before and after inspection is access provided?

● How to track what was accessed and copied or printed?

● How to manage extension of scope in the last minute (e.g., non

announced studies)?

Is there room for negotiation? Contact and clarify upfront?

Mixed approach between full e-access, guided access and print out?


CONCLUDING REMARK

● Both topics, i.e., requirements for e-CRF and e-TMF

in line with the current EU guidances, are also taken

up, at least partly, in both:

● Addendum to ICH GCP - ICH GCP E6(R2)

● Clinical Trials Regulation (EU) N° 536/2014



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Inspection experience and interpretation of guidances · PDF fileInspection experience and interpretation of guidances ... Quality Management in Early Phase Clinical ... GCP inspectors