GCP Inspection findings Tiina Holmberg GCP Inspector Fimea
Content of the presentation EU Clinical Trials Regulation 526/2014 (GCP point of view) ICH E6 addendum Common inspection findings Vuosi-kk-pv Tapahtuma Esiintyjä 2
EU Clinical Trials Regulation 536/2014 In force since April 2014 Slides include the most relevant parts from GCP point of view NOT exhaustive Vuosi-kk-pv Tapahtuma Esiintyjä 3
Clinical Trials Regulation 536/2014 Chapter VIII Article 47 Compliance with protocol and good clinical practice 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 shall take appropriate account of the quality standards and the ICH guidelines on good clinical practice Vuosi-kk-pv Tapahtuma Esiintyjä 4
Clinical Trials Regulation 536/2014 Chapter VIII Article 49 Suitability of individuals involved in conducting the clinical trial Documented professional qualification, experience, training (GCP, protocol) Article 51 Traceability, storage, return and destruction of investigational medicinal products Appropriate and proportionate (authorized IMP? Low-intervention?) Article 56 Recording, processing, handling and storage of information GCP! Personal data protection Technical and organisational methods Vuosi-kk-pv Tapahtuma Esiintyjä 5
Clinical Trials Regulation 536/2014 Chapter VIII Article 57 Trial master File Shall at all times contain the essential documents relating to trial which allow verification of the conduct of a trial and the quality of the data generated Readily available and directly accessible Article 58 Archiving The sponsor and the investigator shall archive the TMF for at least 25 years after the end of the clinical trial. (Medical files of subjects in accordance with national law.) Content shall remain legible Vuosi-kk-pv Tapahtuma Esiintyjä 6
Clinical Trials Regulation 536/2014 Chapter VIII Article 48 Monitoring The sponsor shall adequately monitor the conduct of a clinical trial, in order to verify that The rights, safety and well-being of subhjects are protected The reported data are reliable and robust The conduct of the clinical trial is in compliance with the requirements of the regulation The extent and nature of the monitoring shall be determined by the sponsor on the basis of an assessment that takes into consideration all characteristics ot the trial (incl. Whether low interventional, objective and methodology, deviation from normal clinical practice) Vuosi-kk-pv Tapahtuma Esiintyjä 7
ICH E6 GUIDELINE FOR GOOD CLINICAL PRACTICE INTEGRATED ADDENDUM (Step 2 version dated 11 June 2015) NOT FINAL Since the development of the ICH GCP Guideline, the scale, complexity, and cost of clinical trials have increased. Evolutions in technology and risk management processes offer new opportunities to increase efficiency and focus on relevant activities. This guideline has been amended to encourage implementation of improved and more efficient approaches to clinical trial design, conduct, oversight, recording and reporting while continuing to ensure human subjects protection and data integrity. Standards regarding electronic records and essential documents intended to increase clinical trial quality and efficiency have also been updated. Vuosi-kk-pv Tapahtuma Esiintyjä 8
Investigator oversight ICH GCP 4.1-4.2 4.1 Qualifications and agreements Documentation of training, written delegation 4.2 Adequate resources Qualified staff, adequately informed about their trial related duties and functions Sufficient time ADDENDUM 4.2.5 The investigator is responsible for supervising any individual or party to whom the investigator delegates study tasks conducted at the trial site. 4.2.6 If the investigator/institution retains the services of any party to perform study tasks they should ensure this party is qualified to perform those study tasks and should implement procedures to ensure the integrity of the study tasks performed and any data generated. Vuosi-kk-pv Tapahtuma Esiintyjä 9
Common findings Investigator oversight Documented delegation of duties did not reflect the actual conduct of the trial / not all members of staff were included on the delegation log Late documentation of trial related duties (Design of delegation log) (Contracts) Study specific training missing or not completed before delegation of trial related duties Lack of study specific training of staff in other departments besides the clinic Oversight of the PI lacking (in Finland also the investigator responsible for clinical trial = TVH) Training and adequate informing about the trial Medical decisions (SAE assessment, eligibility criteria) (ICH GCP 4.3.1) Vuosi-kk-pv Tapahtuma Esiintyjä 10
Records and reports ICH GCP 4.9 Reported data consistent with source data. Accuracy, completeness, legibility and timeliness of reported data. Documentation of changes to data ADDENDUM The investigator 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) Vuosi-kk-pv Tapahtuma Esiintyjä 11
Common findings Documentation practices and source data Paper worksheets: Not possible to verify by whom and when data was recorded (signatures, dates) Use of pencils or preprinted stickers Corrections not explained or not completely legible Recording of source data not systematic -> what is source? Worksheets contents not in line with protocol (updates) Worksheets design does not support good documentation practice Recorded data not traceable to a trial subject (missing subject nrs, loose pages) Vuosi-kk-pv Tapahtuma Esiintyjä 12
Common findings Documentation practices and source data Electronic data capture: Late recording of (source) data No documentation of SAE assessment by investigator Changes poorly traceable from the ecrf system (audit trail) Missing source data -> Source data location! No documentation that each inclusion/exclusion criteria have been reviewed (ecrf) Vuosi-kk-pv Tapahtuma Esiintyjä 13
Monitoring ICH GCP 5.18.3. Adequate monitoring In general there is need for on-site monitoring, before, during, and after the trial; however in exeptional circumstances the sponsor may determine that central monitoring in conjunction with procedures suh as investigators training and meetings, and extensive written guidane can assure appropriate conduct of the trial in accordance with GCP Statistically controlled sampling may be an acceptale method for selecting the data to be verified Vuosi-kk-pv Tapahtuma Esiintyjä 14
Monitoring ICH GCP 5.18.3 ADDENDUM The sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials. The flexibility in the extent and nature of monitoring described in this section is intended to permit varied approaches that improve the effectiveness and efficiency of monitoring. A combination of on-site and centralized monitoring activities may be appropriate. The sponsor should document the rationale for the chosen monitoring strategy (e.g., in the monitoring plan). On-site monitoring is performed at the sites at which the clinical trial is being conducted. Vuosi-kk-pv Tapahtuma Esiintyjä 15
Centralized monitoring Centralized monitoring is a remote evaluation of ongoing and/or cumulative data collected from trial sites, in a timely manner. Centralized monitoring processes provide additional monitoring capabilities that can complement and reduce the extent and/or frequency of on-site monitoring by such methods as: (a) Routine review of submitted data. (b) Identification of missing data, inconsistent data, data outliers or unexpected lack of variability and protocol deviations that may be indicative of systematic or significant errors in data collection and reporting at a site or across sites, or may be indicative of potential data manipulation or data integrity problems. (c) Using statistical analyses to identify data trends such as the range and consistency of data within and across sites. (d) Analyzing site characteristics and performance metrics. (e) Selection of sites and/or processes for targeted on-site monitoring. Vuosi-kk-pv Tapahtuma Esiintyjä 16
Monitoring reports ADDENDUM Monitoring results should be provided to the sponsor (incl. Appropriate management and staff responsible for trial and site overight) in a timely manner for review and follow up as indicated. Results of monitoring activities should be documented in sufficient detail to allow verification of compliance with the monitoring plan. (15.8.6. e) Outcomes of any centralized monitoring should also be reported (1.39) Vuosi-kk-pv Tapahtuma Esiintyjä 17
Common findings related to monitoring Insufficient monitoring at the site Discrepancies between source data and reports to sponsor SDV not done from the actual source data Source data location! Verification of adhering to the delegation by PI and timeliness of recording data not monitored (electronic systems, audit trail) Monitor s limited access to medical files (EHR) No escalation of findings of monitor Delayed / lack of action by the sponsor to findings by monitor No re-evaluation of adequacy of monitoring Personal data protection compromised by sending patient data to sponsor Vuosi-kk-pv Tapahtuma Esiintyjä 18
Centralized monitoring Is not meant to replace on-site monitoring Should not involve source data verification Centralized monitoring can give timely information of data quality and help target the on-site monitoring efficiently and complement it Vuosi-kk-pv Tapahtuma Esiintyjä 19
Other common observations Essential documents (ICH GCP chapter 8 + addendum): Filing essential documents at the investigator/institution site in a timely manner can greatly assist in a successful management of a trial by investigator and monitor The sponsor should ensure that the investigator has control of and continuous access to the CRF data reported to the sponsor. Vuosi-kk-pv Tapahtuma Esiintyjä 20
Monitoring ICH GCP 5.18 The purposes of monitoring are to verify that The rights and well-being of human subjects are protected The reported trial data are accurate, complete, and verifiable from source documents The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s). Vuosi-kk-pv Tapahtuma Esiintyjä 21
THANK YOU! KIITOS! TACK! QUESTIONS?