Data Quality and Integrity: From Clinical Monitoring to Marketing Approval Nancy Detich, Ph.D., C.C.R.P. Senior Scientist, Clinical Strategy 18 November 2010 1
Objectives Identify the importance of accuracy, completeness and validity of data collected during a clinical development program Plan for a clinical study report used for marketing approval Discuss the importance of monitors and investigational site personnel in increasing the quality of data required for marketing approval 2
Outline Overview Marketing application Data collection and monitoring Clinical study report (CSR) 3
Start at the end! Keep it simple! Maintain consistency! 4
Start at the end The primary goal in product development is to bring new compounds to market that can either treat previously untreatable diseases or offer improved benefits to patients, when compared to existing drugs 5
Start Line Hypothesis/ Study design and planned analysis Monitor s Pit Stop Investigator 1 Investigator 2 Investigator 3 Finish Line Clinical study report / Marketing Application Investigator 4 Monitor s Pit Stop 6
What is needed to obtain a marketing approval? Regulatory authorities thoroughly review a marketing submission to evaluate the data submitted for a product. The product has to demonstrate efficacy with acceptable safety Results and conclusions of studies -CSRs This relies on data quality and integrity Exploratory analyses on raw data Regulatory Authority audits at sites 7
What should be done to meet the requirements of data quality? Actions must be taken in the earliest clinical stages Sponsors are responsible for developing appropriate study designs and planned analyses 8
What should be done to meet the requirements of data quality? (2) Investigators, site personnel and monitors are the frontline players who ensure protocol compliance and provide clean clinical data which, in turn, will provide quality efficacy and safety analyses in CSRs that ultimately supports marketing approval 9
How should these actions be done? There is no universal way, since each clinical development program is unique There are universal guidelines Applicable laws Directives Guidelines ICH E6 Good Clinical Practices (GCPs) ICH E3 Structure and content of CSRs Standard operating procedures 10
Definition of GCPs «An international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.» 11
GCPs why do we need them? To protect the rights, integrity and confidentiality of subjects To ensure that all data collected and reported during the trial are credible and accurate 12
Principles of GCPs Data collection (1) 1. Clinical trials should be scientifically sound, and described in a clear, detailed protocol 2. Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s) 3. All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification.
Principles of GCPs Data collection (2) 4. Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol 5. Systems with procedures that assure the quality of every aspect of the trial should be implemented.
Marketing application 15
Marketing application Nonclinical data Chemistry, manufacturing and controls (CMC) data Clinical data Overview and summaries of integrated efficacy and safety data - all clinical studies conducted with the product during the clinical development program CSRs 16
Marketing application (2) Labeling Defines appropriate patient population for treatment Provides adequate information to enable safe and effective use 17
Regulatory marketing application CTD Quality Overall Summary (2.3) 1 Regional Administrative Forms LABELING Module 2 CTD Table of Contents (2.1) CTD Introduction (2.2) Nonclinical Overview (2.4) Nonclinical Written and Tabulated Summary (2.6) Clinical Overview (2.5) Clinical Written Summary (2.7) Module 3 Module 4 Module 5 Labeling Overall Summary Detailed Summaries Tabulated Summaries Quality Nonclinical Study Reports Clinical Study Reports Reports/Data Q S E Q = Quality/Chemistry,CMC S = Safety/Nonclinical E = Efficacy/Clinical 18
Marketing application Clinical review (1) The role of the product in the existing treatment standard of care for the indication Efficacy data Study design Choice of endpoints, study population Choice of control, adequacy of blinding Appropriateness of statistical analyses Contribution of sponsors is crucial 19
Marketing application Clinical review (2) Study design Per GCPs Section 6.4: «The scientific integrity of the trial and the credibility of the data from the trial depend substantially on the trial design» The protocol design and planned analyses and ultimately case report forms (CRFs) design have important influences on data quality. Prospectively identify the critical data Simplify data collection Contribution of sponsors is crucial 20
Marketing application Clinical review (3) Aspects of the conduct of the study which are deemed critical to conclusions Protocol compliance Eligibility, blinding, randomization, treatment, assessments, concomitant medications Contribution of monitors and investigational site personnel is crucial 21
Marketing application Clinical review (4) Safety data Extent of safety testing, size of the safety database Duration of exposure Common adverse events Deaths, other serious adverse events and adverse events that led to discontinuation Narratives, listings, CRFs Contribution of sponsors, monitors and investigational site personnel is crucial 22
Marketing application Clinical review (5) Listings Tables Data Consistency Labeling Summaries 23
Marketing application Lessons learned (1) Complete case report forms are submitted for: Deaths Other serious adverse events Other significant adverse events (e.g., adverse events leading to discontinuation) Adequate completion and monitoring are important since authorities require the case report forms to be part of the submission! 24
Marketing application Lessons learned (2) Data uniformity Laboratory testing units For same tests, various units could be used in different countries/sites 25
Marketing application Lessons learned (2) Adverse events causality definitely, probably, possibly, suspected, likely etc. Be consistent and keep it simple! 26
Data collection and monitoring 27
Clinical data flow - data collection and monitoring 28
Purpose of monitoring Assures the integrity of data generated Assures appropriate study conduct in accordance with GCP To ensure the validity and accuracy of the data, sponsors periodically send monitors to study sites to verify that subjects are treated according to the study protocol and that the information is reported accurately. 29
Protocol compliance and data validity Appropriately trained investigators and site personnel are critical to ensure the protocol is followed correctly and that CRFs are properly completed Study monitors check on the progress and quality of performance of the study by reviewing CRFs and other study records to ensure that the documentation is complete 30
What can the sponsor do to help obtain clean data? Ensure all study documents (protocol, lab manual, CRF, etc..) are clear and contain enough detail Will minimize ambiguity on the site s end and make the execution of the study easier CRF completion guidelines Will reduce the number of queries Ensure the monitors are appropriately trained
What can a monitor do to obtain cleaner data? (1) Training does not end at the site initiation visit; it is done throughout the study New site personnel and every time errors/omissions are noted in the CRF Understand what needs to be captured Review tools available (e.g., CRF completion guideline, Q&A log and meeting minutes) Keep track of individual CRF entry decisions 32
What can a monitor do to obtain cleaner data? (2) Ensure consistency: between sites with respect to CRF entry and DCR resolution between SAE reports and AE CRF pages between the same data collected on more than one CRF page Provide instruction to site if new DCRs should be expected on-site after the site termination visit Maintain a good rapport with the study coordinator! 33
Data collection is conducted according to GCPs Consequences of noncompliance Suspension or cancellation of trial and seizure of investigational product Market approval of investigational product declined Prosecution under penalties defined in each country law 34
Data collection and monitoring Lessons learned (1) Documentation is the key for auditors to be able to reconstruct the study. Document everything! If it isn t documented it wasn t done! 35
Data collection and monitoring Lessons learned (2) Safety assessments AE Causality It is often the study coordinator that is entering the AE causality in the CRF and it is rarely documented in the source documents A good monitor will ensure that the investigator has been the one to do the final determination It is important to remember that it is the investigator s responsibility to assign each AE causality, not the study coordinator nor the sponsor. 36
Data collection and monitoring Lessons learned (3) When discussed with monitors, they all say that they became better monitors when they helped reviewing data listings and assisted authoring CSRs Look at things from a different perspective! 37
Clinical study report 38
Clinical data flow Clinical study report 39
Clinical study report Guidelines ICH Harmonised Tripartite Guideline E3, Structure and Content of Clinical Study Reports : Single core clinical study report acceptable to all regulatory authorities of the ICH regions Additional modules/appendices meet regional regulatory requirements http://www.ich.org/lob/media/media479.pdf 40
Clinical study reports Advantages of the standard format Familiarity for all reviewers Consistency for marketing application in multiple ICH regions 41
Clinical study report Structure Fully integrated clinical and statistical report Report body Sections 1.0 to 15.0 Appendices Section 16.0 42
Clinical study report Organization (1) Section 1.0: Title page Section 2.0: Synopsis Section 3.0: Table of contents Section 4.0: List of abbreviations, definitions of terms Section 5.0: Ethics Section 6.0: Investigators and study administrative structure Section 7.0: Introduction Section 8.0: Study objectives 43
Clinical study report Organization (2) Section 9.0: Investigational plan Section 10.0: Study subjects Section 11.0: Efficacy evaluation Section 12.0: Safety evaluation Section 13.0: Discussion and overall conclusions Section 14.0: Tables, figures, and graphs referred to but not included in the text Section 15.0: Reference list Section 16.0: Appendices 44
Clinical study report Content Provide adequate detail to allow regulatory authorities to replicate critical analyses Clear explanation of how critical study design features were chosen Clear explanation of the planned and actual methods, and conduct of the study Adequate individual subject data and details of analytical methods (data listings) 45
Clinical study report High quality document Complete Design, methods, conduct, deviations Summary and individual subject data Efficacy and safety evaluations and conclusions Well organized, free of ambiguity or inconsistencies Accurate representation of the clinical data 46
Clinical study report Tables and figures Essential results for the following should be presented and summarized in text and repeated in Section 14.0: Demographics Efficacy Safety Pharmacokinetics (if applicable) Cross reference to text, and supporting tables, figures, and data listings in Appendices. 47
Clinical study report Typical timelines 2 months is a reasonable period to finalize a CSR but Can be accelerated depending on sponsor needs! 48
Clinical study report Study specific documents (1) Final protocol and amendments Statistical analysis plan and amendments, if available CRF Investigator s Brochure Information on waivers and protocol deviations Study procedures manual, if available Central lab manuals with reference ranges Investigational product information Study s regulatory history 49
Clinical study report Study specific documents (2) Site visit reports Compliance Issues Adverse events Serious adverse event reports SAE reports/medwatch forms Site narratives 50
Clinical study report Study specific documents (3) Site correspondence related to deviations/ exceptions Inclusion / exclusion exception request Deviation request Notes to file Previous example of CSR from sponsor (if available) 51
Clinical study report Lessons learned (1) Do not wait for the study to finish to start the clinical study report Begin authoring as soon as the protocol and statistical analysis plan are finalized! 52
Clinical study report Lessons learned (2) The CSR data presentation should be based on the efficacy and safety summaries required for the marketing application If a sponsor thinks far enough ahead to plan for marketing application from the beginning, they are more likely to successfully cross the finish line! 53
Clinical study report Lessons learned (3) Ensure that the tables and listings have undergone a quality control review and are considered final before beginning to author the efficacy and safety evaluation sections of the CSR Otherwise you may be in for plenty of unwanted surprises and lots of re-writing! 54
Clinical study report Lessons learned (4) Protocol deviations Usually not in the CRF but presented in monitoring reports Determine what information is to be included and how detailed it will be Plan ahead! It is more efficient to build a tool at the planning and initiation stages than try to retrieve the information at the end when time is precious 55
Conclusion Obtaining high-quality data in the most efficient way is a question of team effort! Interaction and contribution Sponsors, investigational sites and regulatory authorities Processes Monitoring Auditing Tools Guidance documents Study documents Quality control plan 56
Start Line Hypothesis/ Study design and planned analysis Monitor s Pit Stop Investigator 1 Investigator 2 Investigator 3 Finish Line Clinical study report / Marketing Application Investigator 4 Monitor s Pit Stop 57
Rational study design and analyses Data standardization / simplification Sponsor Monitor Investigator/site Careful monitoring Protocol compliance Adequate completion of source documents / CRF Adequate safety reporting Well- organized and high quality CSR and marketing application Inspection preparation 58
Start at the end! Keep it simple! Maintain consistency! 59
Questions? 60