Data Handling: A Quality Assurance Perspective Prepared by Dr Piera Lukes For ACDM Electronic Data Capture SIG Meeting – London; 05-Dec-02
Agenda • Review the data handling process • Expectations and requirements • Data Audits – Common findings • Continuous improvement
IP Clinical Report Subjects Input Output Protocol Study Conduct Clinical Trial Data Process GCP GCP? Data Capture Data Management Statistics Reporting ICH?
GCP Requirements for Data • Accurate • Reproducible • Verifiable • Attributable ICH = GCP = Good Common Practice!
Risk of non-compliance • Incorrect results in the report • Misleading for sponsors • Economic implications • Misleading for regulatory authorities • Wrong product on the market • Safety and Ethical issues VERY HIGH RISK! Need to minimise the RISK?
IP Clinical Report Subjects Input Output Protocol Study Conduct Clinical Trial Data Process ICH Data Capture Data Management Statistics Reporting QA Audits ?
Auditing • Observe/audit at specific points • CROs • Vendors (e.g. EDC systems) • Sites • Data Handling (data management, statistics, reports) • Assess Compliance • Report observations • Recommend corrective actions
Audit Findings at Sites (1) • Connection problems, investigators writing on paper for subsequent entry..no CRF!! (ICH 8.3.13) • Site staff complain that system is not user friendly • Investigator agreement to CRF not available/documented (ICH 8.2.2) • Source data not available at site
Audit Findings at Sites (2) • Capture more data than required by protocol • Changes to the e-CRFs are not visible at site (ICH 4.9.3) • Incorrect date stamp in audit trail (ICH 4.9.3) • No space for investigator’s notes • AEs and conditions entered through a list of pre-defined events or conditions (ICH 2.10)
Audit Findings at Sites (3) • Staff not appropriately trained on the use of the system(ICH 2.8) • System not appropriately validated (ICH 5.5.3) • Changes not controlled (ICH 5.5.3) • E-signatures not adequate (ICH 8.3.14) • Logical security (passwords)(ICH 5.5.3)
Conclusions • Clinical Research is Regulated by GCP • Risk of non compliance is high • Auditing detect non compliance Auditing is needed to assure GCP, reduce the risk for the sponsors and for the public
Thank You! • Contact details (tel, e-mail, web) • In the handouts • list of relevant ICH requirements • list of events leading to GCP
Events leading to GCP (1) 1938 (US): Food Drug and Cosmetic Act 1947(WW): Nuremberg code: 1956-61(WW): Thalidomide disaster 1962(US): IND application 1963(UK): DoH scrutiny of drug safety (voluntary) 1964 (WW): Declaration of Helsinki 1965(EU): 65/65/EEC (marketing authorisations) 1968(UK): Medicine Act
Events leading to GCP(2) 1980(US): 21 CFR part 50 (protection of human subjects) 1987 (EU): Bonnes Practiques Clinique, 1987 1988 (UK): ABPI, GCP guideline 1989(EU) GCP Nordic Guidelines 1990 (EU): GCP Guidance for trials on Medicinal Products in the EU 1991 (WW): First ICH meeting 1993 (EU): 93/39/EEC
Events leading to GCP(3) 1993 (UK) GCP legal requirement in the UK (SI/29/11/93) 1993 (WW) WHO GCP guideline • ICH E2 (Clinical Safety Data Management) 1995 (WW) ICH E3 Structure and Content of Clinical Study Reports 1995-97(UK) Fraud (Mr Pearce and Mr Anderton) struck off the medical register for fraud.
Events leading to GCP(4) 1997 (WW) ICH – E9: guideline on Statistical Principles for Clinical Trials 1998 (EU) First draft of the EU Directive on Clinical Trials 2000(EU) GCP Directive Aug-02(US) FDA Guidance on the establishment of Data Monitoring Committees (draft)
Events leading to GCP(5) 1997 (WW) ICH – E9: guideline on Statistical Principles for Clinical Trials 1997 (US) 21 CFR Part 11 (e-records and e-signatures) 1999 (EU) EU directive on e-signatures 1999/93/EC 1999(US) FDA guidance on Computerised Systems in Clinical Trials 2000(EU) GCP Directive Aug–01(US) FDA Guidance on 21 CFR part 11-glossary of terms (draft)
Events leading to GCP(6) Sep–01(US) FDA Guidance on 21 CFR part 11-Validation (draft) Aug-02(US) FDA Guidance on the establishment of Data Monitoring Committees (draft) Feb-02(US) FDA guidance on 21 CFR part 11 - Time Stamps (draft) Clinical Trial Data Process
ICH Principle (2.10) • All Clinical Trial information should be recorded, handled and stored in a way that allows its accurate reporting, interpretation and verification.
ICH Principle (2.8) • Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his/her respective task(s)
ICH 4.1.5 • The investigator should maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties.
ICH 4.9.1 • The investigator should ensure the accuracy, completeness and timeliness of the data reported to the sponsor in the CRF and in all required reports.
ICH 4.9.2 • Data reported on the CRF, that are derived from source documents, should be consistent with the source documents or the discrepancies explained.
ICH 4.9.3 • Any change or correction to a CRF, should be dated, initialled, and explained (if necessary) and should not obscure the original entry (i.e. an audit trail should be maintained); this applies to both written and electronic changes or corrections (see 5.18.4 (n)).
ICH 4.9.3 Cont • Sponsors should provide guidance to investigators and/or the investigators’ designated representative on making such corrections.
ICH 4.9.3 Cont • Sponsors should have written procedures to assure that changes or corrections in the CRFs made by sponsor’s designated representatives are documented, are necessary and are endorsed by the investigator. The investigator should retain records of the changes and corrections .
ICH 5.4.1 • The sponsor should utilize qualified individuals (e.g. biostatisticians, clinical pharmacologists and physicians) as appropriate, throughout all stages of the trial process from designing the protocol and CRFs and planning the analyses to analysing and preparing interim and final clinical trial reports.
ICH 5.1.3 • Quality Control should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly.
ICH 5.5.1 • The sponsor should utilize appropriately qualified individuals to supervise the overall conduct of the trial, to handle the data, to verify the data, to conduct the statistical analyses, and to prepare the trial reports.
ICH 5.5.3 When using electronic trial data handling and/or remote electronic trial data systems, the sponsor should: • Ensure and document that the electronic data processing system(s) conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistent performance (i.e. Validation). b) Maintains SOPs for using for using these systems
ICH 5.5.3 cont. When using electronic trial data handling and/or remote electronic trial data systems, the sponsor should: c) Ensure that the systems are designed to permit data changes in such a way that the data changes are documented and there is no deletion of entered data (i.e. maintain an audit trail, data trail, edit trail). d) Maintain a security system that prevents unauthorised access to the data.
ICH 5.5.3 cont. When using electronic trial data handling and/or remote electronic trial data systems, the sponsor should: e) Maintain a list of the individuals who are authorised to make data changes (see 4.1.5 and 4.9.3). f) Maintain adequate backup of the data.
ICH 5.5.3 cont. When using electronic trial data handling and/or remote electronic trial data systems, the sponsor should: g) Safeguard the blinding, if any (e.g. maintain the blinding during data entry and processing).
ICH 5.5.4 • If data are transformed during processing it should always be possible to compare the original data and observations with the processed data.
ICH 5.19.1 • The purpose of a sponsor audit, which is independent of and separate from routine monitoring or quality control functions, should be to evaluate trial conduct and compliance with the protocol, SOPs, GCP, and the applicable regulatory requirements
ICH 8.2.2 (Before the clinical phase of the trial commence) Signed protocol and amendment, if any, and sample Case Report Form (CRF). To document investigator and sponsor agreement to the Protocol/amendment(s) and CRF (in the TMF at site and at sponsor )
ICH 8.3.13 (During the clinical conduct of the trial) Source Documents To document the existence of the subjects and substantiate integrity of the data collected. To include original documents related to the trial, to medical treatment, and history of subjects.
ICH 8.3.14 (During the clinical conduct of the trial) Signed, Dated and completed Case Report Forms To document that the investigator or authorised member of the investigator’s staff confirms the observations recorded.