QUALITY TIPS FOR CLINICAL SITES. Athena Thomas-Visel. Clinical Quality Consultant QUALITY TIPS FOR CLINICAL SITES

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1 QUALITY TIPS FOR CLINICAL SITES Athena Thomas-Visel Clinical Quality Consultant QUALITY TIPS FOR CLINICAL SITES Purpose of presentation: Share best practices seen from 150+ sites visited Spark conversation Share best practices between attendees 1

2 QUALITY TIPS FOR CLINICAL SITES Updates to regulations globally move towards systembased regulatory inspections Quality systems are no longer a nice-to-have for sites, they are expected. Sites are expected to have SOPs and systems in place The concept of quality in clinical trials has received a lot of attention in recent years with the publication of final FDA Guidance on Risk Based Monitoring and the EMA reflection paper on risk based quality management in clinical trials -SCRS RSM White Paper The Quest for Site Quality and Sustainability UPDATES TO GCP ICH E6 (R2) Addendum Updates to ICH E6 have been added as an Integrated Addendum 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 subject protection and data integrity. Standards regarding electronic records and essential documents intended to increase clinical trial quality and efficiency have also been updated. 2

3 UPDATES TO GCP ICH E6 Even before the update, quality requirements were outlined Quality Assurance (QA) All those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented (recorded), and reported in compliance with Good Clinical Practice (GCP) and the applicable regulatory requirement(s) Quality Control (QC) The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled Systems with procedures that assure the quality of every aspect of the trial should be implemented. RISK MANAGEMENT The emphasis in conducting clinical trials is riskmanagement. Focus resources on the highest risk areas Subject safety Data Integrity The final CTTI official recommendations define quality as the absence of errors that matter (i.e., errors that have a meaningful impact on patient safety or interpretation of results). -SCRS RSM White Paper The Quest for Site Quality and Sustainability 3

4 OPPORTUNITIES FOR IMPROVEMENT Top 5 1. Informed Consent Process 2. Study data documentation / data reporting 3. Safety monitoring and oversight 4. Protocol compliance 5. PI oversight INFORMED CONSENT PROCESS 4

5 INFORMED CONSENT PROCESS Most common issues seen: Used expired ICF Process is not documented Process is documented using a checklist, which is inaccurate or incomplete Missing signatures/dates (and checks/initials) INFORMED CONSENT PROCESS Preventive Measures Check the IRB portal prior to each consent Have an SOP with an overview of the process Document the process. A few sentences are adequate. Time taken, any questions, PI/sub-I availability Have an independent person QC the form 5

6 INFORMED CONSENT PROCESS FDA s Informed Consent Information Sheet states: The Consent Process Informed consent is more than just a signature on a form, it is a process of information exchange that may include, in addition to reading and signing the informed consent document, subject recruitment materials, verbal instructions, question/answer sessions and measures of subject understanding. Thus, rather than an endpoint, the consent document should be the basis for a meaningful exchange between the investigator and the subject. STUDY DATA DOCUMENTATION AND REPORTING 6

7 STUDY DATA DOCUMENTATION Most common issues seen: Lack of attributability Who did this? Compliance with protocol requirements Was the subject laying down for 5 minutes before this procedure was conducted? Study worksheets errors Typo in inclusion / exclusion criteria No documentation of subject status (including when there are AEs) Positive documentation Transcription errors Copying data from EMR Changes made without explanation Will I remember why I changed this a year from now? STUDY DATA DOCUMENTATION Preventive Measures Quality control review of the study worksheets Independent review of record to see if it makes sense Documentation of each study visit / positive documentation Subject compliance, No AEs / Con-meds Ensure AEs are documented by a delegated medical professional Do not transcribe Place certified copy of original source into study chart 7

8 STUDY DATA DOCUMENTATION #2 most common deficiency = Inadequate/inaccurate case histories The most important purpose of a subject s case history: Let s an independent reviewer reconstruct the trial as it happened Provides an audit trail Documents the progress of the subject from consenting until study exit Serves as the complete medical record of the subject as the reference to the treating physician at any point of time. Foundation for the data reported on the ecrf => clinical study report Accurate documentation supports the fundamental principle of protecting subject s rights, safety, and well-being. Good documentation practice in clinical research STUDY DATA DOCUMENTATION ICH E6 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). 8

9 STUDY DATA REPORTING Most common issues seen: Data on the ecrfs do not match the study records Data on the ecrfs cannot be found in the study record Data not reported on ecrf (e.g. exit visit, unscheduled visit) Data not entered in timely manner (e.g. AEs) Queries not resolved STUDY DATA REPORTING Preventative Measures: Quality Control check Review queries in a weekly meeting Ask sponsor for metrics to help track performance Don t rely on your Monitor to catch everything 9

10 SAFETY MONITORING SAFETY MONITORING Most common issues seen: Lab values are trending up, but is not addressed Adverse events are recorded and assessed by a study coordinator Association with IP is determined by the coordinator PI/sub-I only signs off and does not do any assessment of the subject Safety event are not reported to the sponsor in a timely manner (via EDC or directly) 10

11 SAFETY MONITORING Preventative Measures: Review subject from a holistic standpoint, just as if they were a patient A designated medical professional should always be present / available during visits in case of an AE Only designated medical professionals should be completing AE data Safety event are the most important data point, and must be treated as such. PROTOCOL COMPLIANCE 11

12 Common issues PROTOCOL COMPLIANCE Hidden Easter Eggs in protocol cause noncompliance down the line Instructions given by sponsor/monitor are not in, or conflict with protocol Study worksheets contain errors/typos/or don t include all requirements Site relies on Monitor and sponsor training and doesn t read protocol PROTOCOL COMPLIANCE Preventive Measures Highlight study-specific requirements ( Easter Eggs ) subject must be supine for 5 minutes X assessment must be done prior to Y assessment Only do if... Must be done by... Review visit requirements prior to visit Proof-read study worksheets/edc and compare to protocol Your monitor is awesome, but not omniscient (double check their instructions, they work on many trials) Check the IRB Portal regularly 12

13 PI OVERSIGHT PI OVERSIGHT ICH E6 ADDENDUM The investigator is responsible for supervising any individual or party to whom the investigator delegates study tasks conducted at the trial site. 13

14 Commonly seen issues PI OVERSIGHT Reliance on the person and not the process Personnel work in a vacuum Lack of cross-training Inadequate training and continuing education support Turnover without systems in place to support new staff Over delegation (coordinators are really the boss) Preventive Measures Have study staff write out the process they follow. Evolve these into SOPs Invest in training staff. It pays for itself. Carve out regular meetings to discuss studies We have hallway meetings! Always have a backup PI OVERSIGHT Don t delegate to the point you are removed from the study 14

15 QUALITY SYSTEM RECOMMENDED SOPs Informed Consent Process Good Documentation Practices IRB Communication / Reporting Quality Control / Quality Assurance Don t over do it if you create them, you have to maintain them (and follow them) 15

16 Great tool, if used properly CHECKLISTS Use to guide someone through the process Caution against using checklists in place of study documentation. Informed Consent documentation checklists Location of consent? Who performed consent? Any questions? Was PI needed for questions? Approx. time taken NOTES TO FILE Not just a memo Use for systemic issues One-off errors can be explained in the study data (where the error happened) Notes to File should contain the following elements: Statement of issue Correction Corrective Action (what was done to prevent the issue from reoccuring) 16

17 REFERENCES ICH E6 Good Clinical Practices R2 (Addendum) E6_R2 Addendum_Step2.pdf Reflection paper on risk based quality management in clinical trials 1/WC pdf A Guide to Informed Consent - Information Sheet Society of Clinical Research Sites (SCRS) White Papers DISCUSSION 17