Agenda. 16:00 16:10 Velkommen 16:10 16:15 Inspektion, hvad er det?

Transcription

1 Agenda 16:00 16:10 Velkommen 16:10 16:15 Inspektion, hvad er det? 16:15 17:15 Electronic systems for handling of: Source data Data collection tools 17:15 17:45 Pause og networking 17:45 18:30 Trial Master File

2 Electronic systems in Clinical Trials Lisbeth Bregnhøj og Philip Lange Møller Lægemiddelstyrelsen June 21, 2016

3 Agenda 16:00 16:10 Velkommen 16:10 16:15 Inspektion, hvad er det? 16:15 17:15 Electronic systems for handling of: Source data Data collection tools 17:15 17:45 Pause og networking 17:45 18:30 Trial Master File

4 EMA inspection request Compliance with GCP and applicable regulations should be verified, in particular where it has impact on the validity of the data or the ethical conduct of the study. The inspection shall focus in the verification of selected efficacy and safety data reported in the Marketing Authorisation Application for a sample of patients to be determined by the inspectors. Verify the existence of the patients. Verification of the method used to assess the primary efficacy measurement Verification of the administration of study medication administration and accountability

5 Documents available We are asked to verify the ethical subject recruitment trial conduct. We are asked to verify that the application is based on solid data collected within a robust quality system. We are not asked to find a needle in a haystack.

6 Verification synonyms in Word Verification = Confirmation Verification = Proof Verification = Certification Verify = Confirm Verify = Prove Verify = Authenticate Verify = Validate Verify = Substantiate Data verification: comparing data to the source. Select a few sites and trust that procedures guarantees the same quality (validity) of data for all other sites in the trial.

7 The fundamental aspect of inspection Investigator generate data and keep the initial data collection. Investigator transfer data to the sponsor. Sponsor include data in the database. Sponsor create the Report and the data listings Inspection Sponsor data = Investigator data Sponsor and Investigator data must be independent

8 Agenda 16:00 16:10 Velkommen 16:10 16:15 Inspektion, hvad er det? 16:15 17:15 Electronic systems for handling of: Source data Data collection tools 17:15 17:45 Pause og networking 17:45 18:30 Trial Master File

9 Legal requirements and guidance regarding electronic systems in clinical trials EU legislation DIRECTIVE 2001/20/EC (Clinical Trial directive) DIRECTIVE 2005/28/EC (GCP directive) News: REGULATION (EU) No 536/2014 (Clinical Trial regulation), planned implementation 2018 The Danish Medicines Act ( Lov om lægemidler ) Executive Order no 695 (12/06/2013) ( GCP-bekendtgørelsen ) ICH GCP (currently under revision) Reflection paper on expectations for electronic source data and data transcribed to electronic data collection tools in clinical trials (to be upgraded to guidance soon) 21. juni

10 EU legislation (new regulation) (51) The information generated in a clinical trial should be recorded, handled and stored adequately for the purpose of ensuring subject rights and safety, the robustness and reliability of the data generated in the clinical trial, accurate reporting and interpretation, effective monitoring by the sponsor and effective inspection by Member States. Article 47, The sponsor of a clinical trial and the investigator shall ensure that the clinical trial is conducted in accordance with the protocol and with the principles of good clinical practice. Without prejudice to any other provision of Union law or Commission guidelines, the sponsor and the investigator, when drawing up the protocol and when applying this Regulation and the protocol, shall also take appropriate account of the quality standards and the ICH guidelines on good clinical practice. The Commission shall make publicly available the detailed ICH guidelines on good clinical practice referred to in the second paragraph. 21. juni

11 DK legislation GCP-bekendtgørelsen: God klinisk praksis: En internationalt anerkendt etisk og videnskabelig kvalitetsstandard, som skal overholdes ved planlægning, gennemførelse, registrering og rapportering af kliniske forsøg, som indebærer deltagelse af forsøgspersoner. Overholdelse af standarden skal sikre, at forsøgspersoners rettigheder, sikkerhed og velfærd beskyttes, og at data fra de kliniske forsøg er troværdige. 21. juni

12 ICH GCP ICH GCP Definitions of documentation (1.22), essential documents (1.23), source data (1.51) and source documents (1.52) Sponsors responsibility when using electronic trial handling and/or remote electronic data systems (5.5.3) (back-up, security, SOPs, audit trail ) ICH GCP is currently under revision and will include more details regarding electronic systems 21. juni

13 EMA and FDA guidance on electronic systems EMA Reflection paper on expectations for electronic source data and data transcribed to electronic data collection tools in clinical trials (link) FDA Electronic source data in clinical investigations (link) Computerized systems used in clinical investigations (link)

14 Inspection project on electronic systems A project primarily (but not exclusively) directed at investigator initiated trials was initiated in 2015 and is currently ongoing. Part I: to cover some of the primary parties operating in this field, i.e. delivering services in connection with investigator initiated trials. Part II: to cover investigator initiated trials, where the sponsorinvestigator has done the data handling her-/himself. Deviations from this project will be used in this presentation as examples of deviations to each section of the reflection paper.

15 EMA reflection paper on electronic systems Reflection paper on expectations for electronic source data and data transcribed to electronic data collection tools in clinical trials Effective date 01/ This paper outlines the current expectations of GCP inspectors and deviations needs justification. The reflection paper will be updated to reflect the CT regulation and the revised ICH GCP and presumably upgraded to guidance

16 Electronic systems in clinical trials 21. juni

17 The scope of the paper The scope of the reflection paper is electronic systems, (including instruments, software and services) used in clinical trials in the creation/capture of electronic clinical data, such as: Electronic Case Report Forms (e-crfs) Electronic patient data capture devices used to collect Patient Reported Outcome (PRO)

18 Scope (cont.) Instruments supplied to investigators for recording clinical data either by data entry or by automated capture of events such as biometric measures (e.g. blood pressure, respiratory measures, ECG monitoring etc.). Instrumentation or electronic systems to capture, generate, manipulate or store data in an environment where analysis, tests, scans, imaging, evaluations, etc. are performed in support of clinical trials. Electronic Health Records

19 General principles Accurate Legible Contemporaneous Original Attributable Complete Consistent Enduring Available when needed

20 Reflections based on: CDISC publication CDISC 12 requirements, independent of media/technology support requirements for source data ICH GCP

21 Topics Topic 1: Creation and modification of systems Topic 2: Creation, modification and transfer of data Topic 3: Control Topic 4: Copying Topic 5: Storage

22 Topic 1: Creation and modification of systems An instrument used to capture source data should ensure that the data are captured as specified within the protocol. (Requirement 1, ICH GCP 2.6 and 6.4.9)

23 Examples of deviations related to systems The process for communikation between sponsor and vendor regarding production of the CRF and the randomization system could not be re-contructed as relevant documents had not been retained (GCP-bekendtgørelsen 17 og 18 og ICH GCP og 8. (critical)) Validation status of the CRF and changes to the CRF could not be confirmed as the documentation was not retained (GCPbekendtgørelsen 17, stk. 1 og 18, stk.1 samt ICH GCP (a) og (c). (critical)) The CRF has not been designed to capture interim sign-off in spite of interim data being used for MA filing (GCP-bekendtgørelsen 3 and ICH GCP pkt and a. (major))

24 Examples of deviations related to systems The CRF has been released for production in spite of lacking validation checks and no risk evaluation of the lacking validation was documented (GCP-bekendtgørelsen 3 samt ICH GCP pkt a. (major)) There is no traceability of user access rights to the CRF. It is not documented which users had access to the systems and with which roles for a given periode (GCP-bekendtgørelsen 3 og ICH GCP 2.13 og (major)) Recovery from back-up was not performed or the documentation was not available (GCP-bekendtgørelsen 3 samt ICH GCP (minor))

25 Examples of deviations related to systems Contemporaneous records of the testing were not available. The testing was documented in an Excel spreadsheet and no screen shots or other records were available. In addition, the test instance of the database was not retained as it was overwritten when new versions were to be tested (GCP-bekendtgørelsen 3, and ICH GCP pkt a, and 8. (major))

26 Topic 2: Creation, modification and transfer of data Source data should be Accurate, Legible, Contemporaneous, Original, Attributable, Complete and Consistent. (Requirement 2, ICH GCP 1.51, 1.52, and 6.4.9) An audit trail should be maintained as part of the source documents for the original creation and subsequent modification of all source data. (Requirement 3, ICH GCP and 5.5.4) The location of source documents and the associated source data should be clearly identified at all points within the capture process. (Requirement 11, ICH GCP 6.4.9)

27 Examples of deviations related to creation, modification and transfer of data There was no clear definition of source data (GCP-bekendtgørelsen 3 + bilag 1 og ICH GCP pkt (minor)) + Q&A There was no documentation for test of transfer of lab data (GCPbekendtgørelsen 3 og ICH GCP pkt (minor)) The transfer has not been performed in accordance with own transfer specification (company data transfer specification, samt GCPbekendtgørelsen 3 og ICH GCP pkt (minor)) The sponsor did not receive all of the metadata associated with the database, and the audit trail could not be restored as a dataset which was needed for a regulatory inspection. GCP-bekendtgørelsen 3 og ICH GCP pkt og (part of a major deviation))

28 Topic 3: Control The investigator should maintain the original source document or a certified copy. (Requirement 5, ICH GCP 2.11, ) Source data should only be modified with the knowledge or approval of the investigator. (Requirement 6, ICH GCP 4.9.3, and chapter 8) The sponsor should not have exclusive control of a source document. (Requirement 10, ICH GCP ) Source documents should be protected against unauthorized access. (Requirement 9, ICH GCP 2.11, )

29 Examples of deviations related to control There is no procedure for revoking investigators access to the CRF at the end of the trial and it has not been ensured that the investigator has access to an independent copy of the data (GCP-bekendtgørelsen 3 og bilag 2 (2.13 og 2.14) samt ICH GCP (major)) Sponsor has access to enter, change or delete investigator s data (GCP-bekendtgørelsen 3 og ICH GCP 2.13 og (major)) The investigator s independent copies of the CRFs were created as PDF files on CDs. The CDs were however, sent to the sponsor to forward to the investigators (GCP-bekendtgørelsen bilag 2, nr og 2.14 and ICH GCP (part of a major deviation))

30 Topic 4: Copying The source document should allow for accurate copies to be made. (Requirement 8, ICH GCP 1.51) When source data are copied, the process used should ensure that the copy is an exact copy preserving all of the data and metadata of the original. (Requirement 12)

31 Examples of deviations related to copying There was insufficient information on the procedure for document scanning and quality controls to ensure certified copies that were accurate with respect to their content and meaning. In addition incomplete scans were seen GCP-bekendtgørelsen 3 og ICH GCP pkt og 2.13 (part of a major deviation on TMFs))

32 Topic 5: Storage The storage of source documents should provide for their ready retrieval. (Requirement 4, ICH GCP 2.11, ) Source documents and data should be protected from destruction. (Requirement 7, ICH GCP 4.9.3, and chapter 8)

33 Examples of deviations related to storage Server breakdown had resulted in data loss, including metadata and restore had not been possible, jf. GCP-bekendtgørelsen 3 and ICH GCP The data loss has not been reported to the Danish Medicines Agency as a serious breach, jf. GCP-bekendtgørelsen 5, stk.1 nr. 8. (joint critical deviation) Not all relevant documents had been archived in the Trial Master File and the contracts were unclear on the distribution of tasks (GCPbekendtgørelsen 17, stk. 1 og 18, stk. 2 samt ICH GCP 8.1. and (major)) System documentation (system validation, SOP s, audit documentation ) Trial specific documentation

34 Examples of deviations related to storage Not all relevant documents belonging in sponsor s TMF had been delivered from the CRO to the sponsor. At the CRO site not all essential documents are archived consistently ( s, system documentation (SOPs, codings, validation documentation etc.)). There was no formal process for QC or QA checks of the TMF to be delivered to the sponsor. Deviations regarding archiving and the TMF are usually referencing GCPbekendtgørelsen 17, stk. 1 and 18, stk. 2 plus ICH GCP The classification will depend on number of documents impacted.

35 Electronic Health records and other electronic systems at the investigator site The sponsor must assess the systems in use by investigators to determine how well they meet the requirements of GCP including those detailed in the reflection paper If the systems do not meet the GCP requirements then mitigating actions should be taken as necessary prior to trial site initiation

36 Other typical/important deviations Poor or missing contracts (tasks, standard, TMF responsibility, serious breaches, possibility of audit/inspections, sub-contracting ) EudraCT application form incomplete (regarding CROs) No back-up plan in case the electronic system fails Changes in paper worksheets not reflected in the electronic CRF

37 Other typical/important deviations Data entry at site with insufficient quality control Printouts from electronic medical records not complete or not checked by monitor IVRS/IWRS does not ensure that IMP is available for the patient

38 Other typical/important deviations Some electronic data are not reported to the investigator Obvious Data Modifications are not always obvious and there is no agreement with the investigator Modifications are not presented to the investigator in an easily understandable format

39 Conclusions on e-source As a sponsor or sponsor-investigator you have overall responsibility for the trial Ensure the EudraCT application form is complete Ensure contractual obligations are described and that contracted parties have a quality system and GCP-understanding) Ensure electronic systems are compliant (in place in a timely manner, validated, trained, documented ) If in doubt, you are welcome to contact: gcp-krav@dkma.dk

40 Agenda 16:00 16:10 Velkommen 16:10 16:15 Inspektion, hvad er det? 16:15 17:15 Electronic systems for handling of: Source data Data collection tools 17:15 17:45 Pause og networking 17:45 18:30 Trial Master File

41 Definition of inspection [Regulation 536/2014, article 2, 2 (31)] Inspection means the act by a competent authority of conducting an official review of documents, facilities, records, quality assurance arrangements, and any other resources that are deemed by the competent authority to be related to the clinical trial and that may be located at the clinical trial site, at the sponsor's and/or contract research organisation's facilities, or at other establishments which the competent authority sees fit to inspect.

42 TMF: basis for control [GCP Directive 2005/28/EC: Chapter 4 Article 16] The trial master file shall provide the basis for the audit by the sponsor s independent auditor and for the inspection by the competent authority.

43 The Regulation regarding Trial Master File [Regulation No 536/2014 preamble (52)] In order to be able to demonstrate compliance with the protocol and with this Regulation, a clinical trial master file, containing relevant documentation to allow effective supervision (monitoring by the sponsor and inspection by Member States), should be kept by the sponsor and by the investigator. The clinical trial master file should be archived appropriately to allow for supervision after the clinical trial has ended. [Regulation (EU) No 536/2014 Article 57] The sponsor and the investigator shall keep a clinical trial master file. The clinical trial master file shall at all times contain the essential documents relating to that clinical trial which allow verification of the conduct of a clinical trial and the quality of the data generated, taking into account all characteristics of the clinical trial, including in particular whether the clinical trial is a low-intervention clinical trial. It shall be readily available, and directly accessible upon request, to the Member States.

44 Old archiving of TMF [Directive 2005/28 Articles 17 20] The sponsor and the investigator shall retain the essential documents relating to a clinical trial for at least five years after its completion. They shall retain the documents for a longer period, where so required by other applicable requirements or by an agreement between the sponsor and the investigator. Essential documents shall be archived in a way that ensures that they are readily available, upon request, to the competent authorities. Any transfer of ownership of the data or of documents shall be documented. The new owner shall assume responsibility for data retention and archiving in accordance with Article 17. The sponsor shall appoint individuals within its organization who are responsible for archives. Access to archives shall be restricted to the named individuals responsible for the archives. The media used to store essential documents shall be such that those documents remain complete and legible throughout the required period of retention and can be made available to the competent authorities upon request. Any alteration to records shall be traceable.

45 Old long term archiving [Directive 2003/63 Annex 1, section 5.2 (c)] Marketing authorisation holders must arrange for essential clinical trial documents (including case report forms) other than subject s medical files, to be kept by the owners of the data: for at least 15 years after completion or discontinuation of the trial, or for at least two years after the granting of the last marketing authorisation in the European Community and when there are no pending or contemplated marketing applications in the European Community, or for at least two years after formal discontinuation of clinical development of the investigational product.

46 Future archiving of the TMF [Regulation 536/2014, Article 58] Unless other Union law requires archiving for a longer period, the sponsor and the investigator shall archive the content of the clinical trial master file for at least 25 years after the end of the clinical trial. However, the medical files of subjects shall be archived in accordance with national law. The content of the clinical trial master file shall be archived in a way that ensures that it is readily available and accessible, upon request, to the competent authorities. Any transfer of ownership of the content of the clinical trial master file shall be documented. The new owner shall assume the responsibilities set out in this Article. The sponsor shall appoint individuals within its organisation to be responsible for archives. Access to archives shall be restricted to those individuals. The media used to archive the content of the clinical trial master file shall be such that the content remains complete and legible throughout the period referred to in the first paragraph. Any alteration to the content of the clinical trial master file shall be traceable.

47 Actual content of the TMF GCP Directive 2005/28: Chapter 4, Article 16 The documentation referred to Article 15(5) of Directive 2001/20/EC as the trial master file shall consist of essential documents, which enable both the conduct of a clinical trial and the quality of the data produced to be evaluated. Those documents shall show whether the investigator and the sponsor have complied with the principles and guidelines of good clinical practice and with the applicable requirements and, in particular, with Annex I to Directive 2001/83/EC.

48 Future content of the TMF [Regulation 536/2014 Article 57] The clinical trial master file shall at all times contain the essential documents relating to that clinical trial which allow verification of the conduct of a clinical trial and the quality of the data generated

49 Organisation of the Trial Master File

50 New guidelines EudraLex Volume 10, Chapter V: Recommendation on the content of the trial master file and archiving July 2006 EMA/INS/GCP/636736/2012: Reflection paper on GCP compliance in relation to trial master files (paper and/or electronic) for management, audit and inspection of clinical trials EU GCP Inspectors Working Group - Subgroup NEW GUIDANCE 2016

51 Guideline on GCP compliance in relation to trial master file (paper and/or electronic) Initially planned to be a Reflection paper published at the EMA s web site under documents from Inspectors Working Group. However, following the new regulation 536/2014 it will be a commission document published under EudraLex volume 10.

52 Trial Master File (TMF) = masterfil A TMF is the collection of essential documentation that facilitates the conduct and management of the clinical trial and allows that the integrity of the trial data and the compliance of the trial with GCP can be evaluated. The Regulation does not differentiate between paper and electronic TMFs therefore all the requirements are the same for both formats. The TMF is used by sponsors and investigators for the management of the trial. The TMF is used by auditors, monitors and inspectors to assess whether the sponsor and the investigator(s) have complied with the Regulation, the principles and guidelines of GCP and with any other applicable regulatory requirements.

53 TMF content and index The sponsor and the investigator should identify and make a record of the location(s) of all of the potential documentation that is considered to form the TMF, even if several locations, departments, country organisations and systems are involved, so that it is effectively organised. The investigator/institution is responsible for and should therefore have control of all essential documents and records generated by the investigator/institution before, during and after the trial. Some documents may be pertinent to more than one clinical trial; such as the Investigator Brochure or documents that are stored in a centralised system, for example central training records, SOPs and delegation logs, documentation demonstrating the validation of computer systems that are not trial-specific.

54 Use of a portal Where a portal is used to provide documents to the investigator, if this is not part of the investigator TMF there needs to be a mechanism to ensure such documentation is filed in the official investigator TMF. Also, consideration should be given to provision of an audit trail to demonstrate investigator access to documents in the portal at the appropriate time.

55 Timeliness of the TMF update The TMF shall be up to date, with documents placed in the TMF in a timely manner as this greatly assists the successful management of a trial by the investigator and sponsor (or party to whom the sponsor has delegated its duties). In trials that have more complex TMF arrangements with multiple parties involved, the timescales for submission and filing of documents to the TMF in procedural documents or TMF plans should be defined.

56 Essential documents The index of the TMF in chapter 8 of the CPMP/ICH/135/95 (ICH GCP) defines the minimum number and types of documents that usually is considered essential for any given trial. This can not always be considered exhaustive list.

57 Essential Documents Documents required to reconstruct the trial conduct to allow its evaluation ICH/volume 10 essential documents Documents not applicable or not required for the trial ICH - International Conference for Harmonisation

58 Electronic TMF (etmf) User accounts (created and deleted within a formal approval process); Secure passwords for users; A system in place locking/protecting individual documents or the entire etmf (e.g. at time of archiving) to prevent changes to documents; An audit trail in place to identify date/time/user details for creation, uploading, approval and deletion of and changes to a document; Role based permissions for activities being undertaken and for files/documents with restricted access (e.g. randomization codes, unblinded AE-data).

59 Validation of an etmf The etmf should be validated in accordance with published standards to demonstrate that the functionality is fit for purpose, with formal procedures in place to manage this process. The procedures should describe system installation including functionality testing, system maintenance, system security measures, change control, data backup, recovery, contingency planning, decommissioning and, if applicable, transition to a new system. All members of staff involved in the conduct of the trial and using the system should receive appropriate training.

60 Transferral of documents Where different TMF systems are linked to facilitate the trial conduct, for example the CRO etmf system uploads documents into the sponsor etmf system, then the process for transferring documents should be robust and should be validated to prevent failure of transferring the entire content of the original TMF without loss (i.e. there should be a demonstrable 1:1 mapping between the content of the two systems).

61 Version control og prints from the etmf Version control should be applied to electronic documents in the system. If the document is printed to paper the same version control should be apparent on the printed version.

62 Backup and migration There should be a regular back-up of the etmf with the back-up stored in a separate location and/or media. Any migration of data and documents to new media or a new format should be validated to ensure long-term readability. There should be periodic test retrieval or restores to confirm the ongoing availability of the data.

63 The digitisation process The use of etmfs and electronic archiving generally requires the digitisation of original paper records to generate electronic copies. The digitisation process of transfer should be validated in order to ensure that certified copies are made to ensure that information will not be lost or altered.

64 Certificeret kopi A certified copy is a paper or electronic copy of the original record that has been verified (e.g. by a dated signature) or has been generated through a validated process to produce a copy having the exact content and meaning of the original. The ICH addendum: A paper or electronic copy of the original record that has been verified (e.g., by a dated signature) or has been generated through a validated process to produce an exact copy having all of the same attributes and information as the original

65 The SOP for the digitisation process approval for digitisation; transportation of the records to the location of digitisation; preparation and digitisation of the records; indexing and assignment of metadata; import of the digitised records into the etmf system; quality control; destruction of the records; access to the etmf system; changes to documents and metadata; migration of digitally hosted/archived records; deletion of digitally hosted/archived records.

66 The SOP cont. The organisation should maintain records to demonstrate that the digitisation is effectively validated. As part of the validation a formal process should be in place for regular QC checks of digitised and indexed documents in the etmf. This would usually be undertaken on a sampling basis, including escalation procedures where errors occur beyond a pre-defined Acceptance Quality Limit (AQL). The sponsor is responsible for deciding the AQL. The AQL may vary for different sets of documentation on a risk based approach.

67 The quality control includes accuracy of the metadata attributed to the document; quality of the image (suitable resolution, readability, legibility, reproduction of colour - where the colour has meaning, the quality of wet ink signature or annotations and handwriting in general etc.); whether it is the correct document (as expected); that the document has the correct number of pages; that a page or document was added as new to the digital archive and not marked as a corrected version of an already-existing page or document; the etmf audit trail associated with the document; chain of records transfer documentation; approval process (where applicable);

68 Destruction of digitised copies Taking into account the implications for providing legally recognized evidence and after consultation with its liability insurer, the sponsor as well as the investigator should decide whether documents legally requiring a signature (e.g. written informed consent of trial participants, contracts) should be sorted out and retained in the original form instead of being destroyed.

69 Archiving of investigators TMF The sponsor can arrange long term archiving for the investigator. Investigator must continue to have control over their TMF and data. Retrieval of archived files and documents must never cross the sponsor or be in their hands at any time.

70 Inspection of TMF The inspectors shall have direct read only access, without any restriction (e.g. to final documents), to the entire TMF for inspection during preparation and conduct of the trial, which means that they can review the same TMF as used by the staff conducting the trial. Direct access includes all the systems that comprise the TMF as defined by the sponsor, however, due to the technical nature of some of these systems, for example those containing data rather than documents, these may require the direct access to be assisted by a representative of the sponsor familiar with the system.

71 Access during the inspection Individual access codes and passwords to read only access. Printing of documents must be possible. Audit trail must be available. The etmf should allow review in an efficient manner, analogous to that possible with paper TMFs.

72 Document Uploading (audit trail) 1000 etmf (sponsor site level files) Multicentre Trial Document Upload from Audit Trail N u m b e r o f D o c u m e n t s U p l a o d e d INSPECTION 25-Jun Aug-13 3-Oct Nov Jan-14 2-Mar Apr Jun Jul-14 Date

73 Questions: Phone: Ask for one of the GCP inspectors