Clinical Data Management Process Overview_Katalyst HLS

Introduction to Clinical Data Management Process Overview in Pharmaceuticals, Bio-Pharmaceuticals, Medical Devices, Cosmeceuticals and Foods.

1. Clinical Data Management (CDM) Process Overview 2/21/2017 Katalyst Healthcares & Life Sciences 1

2. Icons Used Questions Demonstration Hands on Exercise Coding Standards A Welcome Break Tools 2 Reference Test Your Understanding Contacts Icons Used 2/21/2017 Katalyst Healthcares & Life Sciences

3. Clinical data management includes the entry, verification, validation and quality control of data gathered during the conduct of a clinical trial. Clinical Data Management is involved in all aspects of processing the clinical data. It involves working with a range of computer applications, database systems to support collection, cleaning and management of clinical trial data. Review and approval of new drugs by Regulatory agencies is dependent upon the integrity of clinical trial data which is the core purpose of CDM. Overview 3 Overview 2/21/2017 Katalyst Healthcares & Life Sciences

4. After this chapter you will be able to understand: Overview of Clinical Data Management Process flow of data management activities Activities performed during the course of a trial Analysis and reporting process overview Roles and responsibilities of all personals involved in CDM Objectives 4 2/21/2017 Katalyst Healthcares & Life Sciences

5. The average number of discrepancies created during the course of a Phase 3 study ranges from 3,000 to 30,000 The turn around time to action a discrepancy from the time of generation is 2-3 days A single open discrepancy or a Database update can lead to Database unlock Do You Know 5 2/21/2017 Katalyst Healthcares & Life Sciences

6. Abbreviations 6 CRF Case Report Form DB Database QC Quality Control DMP Data Management Plan CSR Clinical Study Report UAT User Acceptance Testing 2/21/2017 Katalyst Healthcares & Life Sciences

7. Definition of Clinical Trial It is a systematic study of new drug(s) in human subject(s) to generate data for discovering and/or verifying the clinical, pharmacological (pharmacokinetic and Pharmacodynamics), and/or adverse effects with the objective of determining safety and /or efficacy of the a new drug. 7 2/21/2017 Katalyst Healthcares & Life Sciences

8. Clinical Trial Phases Phase I Trials —Involve a small group (20 to 100) of healthy volunteers to discover if the drug is safe in humans Phase II Trials —Involve 100 to 500 patients who actually have the disease. Clinical studies are conducted to evaluate the effectiveness of the drug and to determine the common short-term side effects and risks associated with the drug Phase III Trials —Involves thousands of patients to generate statistically significant data about safety, efficacy, and an overall benefit/risk profile Phase IV Trials —Certain post marketing studies to find out additional information about the drug's risks, benefits, and its optimal use. 8 2/21/2017 Katalyst Healthcares & Life Sciences

9. Why Clinical Trials? Species difference Some effects seen only in humans Correlation of effects in animals and human –not always possible To assess if the treatment is safe and effective in humans Man is final experimental animal to be tested 9 2/21/2017 Katalyst Healthcares & Life Sciences

10. Multidisciplinary Roles in Clinical trial Clinical Investigator Site coordinator Pharmacologist Trialist/Methodologist Biostatistician Lab Coordinator Reference lab Project manager Clinical Research Manager/Associate Monitor 10 Regulatory affairs Clinical Data Management* Clinical Safety Surveillance Associate (SSA) IT IT/IS personnel Trial pharmacist Clinical supply Auditor/Compliance Study Physician 2/21/2017 Katalyst Healthcares & Life Sciences

11. Clinical Data Management - Overview 11 Investigator Monitor Central Laboratory Data Manager Statistician Clinician Regulatory Authority Subject CRF DCF CRF DCF Sample Lab Results Clinical Data NDA DCF 2/21/2017 Katalyst Healthcares & Life Sciences

12. Definition of Data Data with reference to CDM means the Patient Information which is collected during Clinical trial. Data is collected to establish whether the objective of the Clinical Trial is met 12 2/21/2017 Katalyst Healthcares & Life Sciences

13. Objectives of CDM 13 Data Collection Data integration System / Data Validation Paper, Electronic and Remote data capture Integration of data received from all sources in a single DB. Ensures consistency and correctness System validation done via UAT, QC and Programming Data Validation via Edit check programs and manual review 2/21/2017 Katalyst Healthcares & Life Sciences

14. Scope of CDM Main scope of CDM is to Collect, Validate and Analyze the clinical data Design and development of data collection instrument such as Paper CRF, Electronic CRF, Clinical database etc Design and development of tools for Validation such as Edit Checks, User Acceptance Testing etc Design and development of tools for Analyzing data such as DDR/DDS (Derived Dataset Requirement/Specification) etc. 14 2/21/2017 Katalyst Healthcares & Life Sciences

15. Importance of CDM CDM is a vital vehicle in Clinical Trials to ensure integrity & quality of data being transferred from trial subjects to a database system. It helps : To provide consistent, accurate & valid clinical data To support accuracy of final conclusions & report Clinical Data Management ensures: That collected data is complete & accurate so that results are correct That trial database is complete, accurate & a true representation of what took place in trial That trial database is sufficiently clean, to support statistical analysis, its subsequent presentation & interpretation 15 2/21/2017 Katalyst Healthcares & Life Sciences

16. 16 Inter-dependent groups in CDM Clinical Data Management 2/21/2017 Katalyst Healthcares & Life Sciences

17. DM role in Clinical Research CDM has evolved from a mere data entry process to a much diverse process today The data management function provides all data collection and data validation for a clinical trial program Data management is essential to the overall clinical research function, as its key deliverable is the data to support the submission Assuring the overall accuracy and integrity of the clinical trial data is the core business of the data management function It provides data and database in a usable format in a timely manner It ensures clean data and a ‘ready to lock’ database 17 2/21/2017 Katalyst Healthcares & Life Sciences

18. DM role in Clinical Research At the study level, data management ends when the database is locked and the Clinical Study Report is final At the compound level (of the drug), data management ends when the submission package is assembled and complete 18 2/21/2017 Katalyst Healthcares & Life Sciences

19. 19 Data Acquisition Site / Investigator Programmers Coders Safety Study Team/Client Monitor / CRA DM Communication & Interfaces

20. 20 CDM Activities –Phase-wise 2/21/2017 Katalyst Healthcares & Life Sciences

21. 21 Study Start-up Process Protocol CRF Design Database Design Validation/ Derivation Procedures Activated database ready to accept production data 2/21/2017 Katalyst Healthcares & Life Sciences

22. Study Set-up –Roles and Responsibilities CRF Designers - Design CRF as per protocol DB designers -Design DB as per protocol OR CRF OR CRF Specs and activate the same Programmers -Program Validation and Derivation procedures, and activate the same Data Managers -Review the CRF prior to activation, test the database prior to activation, write the validation and derivation procedures/checks and test the same prior to activation 22 2/21/2017 Katalyst Healthcares & Life Sciences

23. 23 Study Conduct Process Activated DB Data Entry / Loading (CRF & external data) Discrepancy Management Query Generation Safety Data Recon. Coding terms Resolution & update of DB Manual Check/ QC 2/21/2017 Katalyst Healthcares & Life Sciences

24. 24 Study Conduct –Roles and Responsibilities Data Entry/Data Loaders- Manually enter the data (in case of paper studies), load data in case of electronic studies) and external data (Example: lab, ECG, subject diaries etc.) Data Managers - Identify and resolve discrepancies, issue queries to site & resolve them, carry out manual checks, lab review and CRF tracking Safety Data Managers - Perform the safety reconciliation by comparing the clinical database with the safety database Dictionary Coders - Code medical terms collected during clinical trial. Example: Medications and Adverse events

25. Data Capture Regardless of whether you’re running a small, single Phase I trial or many, complex Phase III trials you look for ways to ensure that your organization is collecting and managing clinical data reliably, efficiently and in compliance with industry and government regulations. 25 Electronic Data Capture Paper Data Capture Remote Data Capture Data Capture 2/21/2017 Katalyst Healthcares & Life Sciences

26. Difference between Data Capture Tools 26 The difference between Paper, Electronic and Remote data capture is : Paper Data is entered on Paper Case Report Form Data Entry associate will enter the data in to the Clinical Data base No real time access to the data Electronic Data is captured in electronic Case Report Form Investigator enters the data into the database Real time access to the data Remote data entry/ capture Data is captured in electronic Case Report Form RDE systems allow research staff to enter data directly at the medical setting, useful when a multicenter study is being conducted with many institutions participating Not web based thus no real time access to the data 2/21/2017 Katalyst Healthcares & Life Sciences

27. CRF –DEMO Snap shot 27 2/21/2017 Katalyst Healthcares & Life Sciences

28. CRF Tracking Receipt and Tracking of CRF The tracking process encompass verification of the arrival date & its acknowledgement & its progress through the process Checking of quality and completeness of the documents Tracking missing documents 28 2/21/2017 Katalyst Healthcares & Life Sciences

29. Data Entry & Verification Data Entry Processes is of two types as follows: 1.Single Pass Data Entry → Single entry with a manual review → Single entry without manual review 2.Double Pass Data Entry → Double data entry with blind verification, where two people enter the data independently and any discrepancies between first and second entry are resolved by the third person based on the verification report on records that failed data entry verification → Double entry with interactive verification where the second entry operator resolves discrepancies between 1st & 2nd entry and is aware of the first entered values 29 2/21/2017 Katalyst Healthcares & Life Sciences

30. Data Review Why Data Review? To ensure complex medical data are reviewed and assessed to detect any discrepancy in the data. Discrepancy Examples: Empty fields Incorrect Range One value greater/less than/equal to another Dates not in logical sequence Inconsistent header information Any missing visits or pages Visits not in compliance with protocol Inclusion/exclusion criteria not met 30 2/21/2017 Katalyst Healthcares & Life Sciences

31. Data Review –Edit Checks Consist of computer checks on the data to assure the validity and accuracy of the data Validate data manually against predetermined specifications Primarily used to check the efficacy data unique to the current study 31 2/21/2017 Katalyst Healthcares & Life Sciences

32. Edit Checks Types Range checks To identify inaccurate or invalid data & statistical outliers To ensure that data outside of permitted range are to be clarified and verified E.g. Systolic blood pressure (***) is outside the Critical Range (***). Consistency checks To highlight area where the data in the database are inconsistent E.g. Adverse Event stop date is always after AE start date Presence checks To ensure completeness of data E.g. SEX is missing 32 2/21/2017 Katalyst Healthcares & Life Sciences

33. Data Query A query is an official communication to the investigative site to question on a discrepant data on the case report form. Subsequent changes in the data must be supported by signed Data Clarification Form (DCF). EDC Query Data Clarification Form (DCF) 33 2/21/2017 Katalyst Healthcares & Life Sciences

34. Medical Coding It is a process which involves grouping or classifying new and amended terms like medications, adverse events, medical history medical procedures, diagnoses, disease conditions with reference to known standard terms as mentioned in medical dictionary Importance of coding : The use of medical coding dictionaries for medical term data such as adverse event, medical history, medications & treatments/procedures are valuable from the standpoint of minimizing variability in the way data are reported and analyzed. To provide control & consistency, a variety of medical coding dictionaries may be used to process, analyze and report collected data. 34 2/21/2017 Katalyst Healthcares & Life Sciences

35. Medical Coding Dictionaries Coding Dictionaries: MedDRA Medical Dictionary for Regulatory Activities, is a standardized dictionary of medical terminology WHO: WHOART, drugs World Health Organization Adverse Reaction Terminology ICD International Classification of Diseases FDA-COSTART Coding Symbols for a Thesaurus of Adverse Reaction Terms 35 2/21/2017 Katalyst Healthcares & Life Sciences

36. Safety Data Reconciliation What is AE : Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. What is a Serious Adverse Event: Any adverse event that leads to: Results in death Is life-threatening Requires inpatient hospitalization or Prolongation of existing hospitalization Results in persistent or significant disability / incapacity Is a congenital anomaly / birth defect 36 2/21/2017 Katalyst Healthcares & Life Sciences

37. Safety Data Reconciliation Reconciliation: It is the comparison of particular data points related to SAEs that appear in both the Safety and Clinical Databases and must be cleaned 100%, with all acceptable discrepancies documented. All SAEs entered into the clinical trial database are also entered into the drug safety database and are reconciled to ensure the consistency between specified data points. Reason for performing Reconciliation : It is necessary because SAE data is considered CRITICAL DATA in both , the safety and clinical databases. Critical data is made up of dosing, demography, adverse event and final subject summary pages, all of which are data points that make up the cases that are reported to the safety database It is essential to understand that these data are submitted to Regulatory Agencies both at end of study and for subsequent aggregate reporting which occurs well after database lock. 37 2/21/2017 Katalyst Healthcares & Life Sciences

38. Study Closeout Process 38 Discrepancy Management Query generation Resolution and/or update of DB Manual check/QC/CRF tracking DB lock and freeze Safety Data Recon. Coding terms 2/21/2017 Katalyst Healthcares & Life Sciences

39. Declaring Clean File & Database Lock Clean File means that the data generated from clinical trial is clean & ready for Database Locking/freezing Clean File can be declared for a study when all required data management activities (as per the Data Management Plan) have been completed and documented appropriately This is a procedure which is done at the end of clinical trial after the last query is resolved & prior to DB locking/Freezing This procedure ensures the following points are met: Data is complete i.e., No missing data Data is consistent Data is accurate Data is reliable 39 2/21/2017 Katalyst Healthcares & Life Sciences

40. Validated clean data will be transferred to a final database Prior to locking the study, the following steps are completed: Checklist for Database Lock 40   All expected CRFs are entered    All CRFs have been Verified by the CRA All data discrepancies are resolved Final validations are executed with no remaining unresolved discrepancies All lab data, external and internal (e.g. PK, ECG), are loaded and reconciled All lab normals are present, loaded and complete Adverse event coding is complete and approved by the study MD All other medical coding is complete The Statistician confirms that the data meet previously agreed acceptance criteria The Statistician and CDM agree that the database is ready for locking All approvals are obtained on the Database Lock/Freeze/Unfreeze Approval form 2/21/2017 Katalyst Healthcares & Life Sciences

41. Unlock Scenarios Can a Database be unlocked? Ans : Yes When can Unlocking be Done? Unlocking of the database is carried out only if corrections to the critical errors (such as Adverse Event, Medication, Lab, etc.) are required. For e.g. -Updates to serious adverse events data may require edits to the data. A request to unlock the study usually requires review of detailed reasons by higher level management before the database administrator removes the locks. Appropriate quality control, review and approval will again be required to unlock the study. 41 2/21/2017 Katalyst Healthcares & Life Sciences

42. Quality Control Quality Control (QC): Periodic operational checks within each functional department to verify that clinical data are generated, collected, handled, analyzed, and reported according to protocol, SOPs, and GCP. Example: QC activities performed during the data management process: Double Data Entry: Accuracy of the initial data entry is verified by an independent entry of the same data and a subsequent comparison of both sets of data for non-agreement. Edit Checks/ Manual Review: The reality of the data is checked with a preprogrammed logic check program and a subsequent manual review Final QC: The database entries are then QC'dversus the CRFs Tables, Listings and Graphs (TLG) inspection : The TLGs that are generated as part of a statistical analysis of the data are also inspected to ensure their accuracy. 42 2/21/2017 Katalyst Healthcares & Life Sciences

43. Quality Assurance Quality Assurance: “ 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). Involves Inspections and Audits Inspection is by Governmental Agencies, Health Authorities and the Drug Regulatory Authorities Auditing is by pharmaceutical, devices companies, CROs, and others 43 2/21/2017 Katalyst Healthcares & Life Sciences

44. Audits Types Internal audit (first party audit): Carried out by service provider’s Audit Department to ensure implementing, maintaining and improvement of the system audited. Customer audit (second party audit): Carried out by client to evaluate the service providers’ performance and compliance for standards. External audit (third party audit): Carried out by regulators or external auditors contracted by sponsor to ensure implementing and documenting according to standards. 44 2/21/2017 Katalyst Healthcares & Life Sciences

45. Benefits of Internal Audit Audit of processes to identify systemic problems Identify the root of a problem and plan for corrective and preventive actions Review of employee training records Compliance with SOPs and regulatory requirements Documented evidence that QC was appropriately conducted on the output of each internal process Achieve better allocation of resources 45 2/21/2017 Katalyst Healthcares & Life Sciences

46. Roles & Responsibilities Programmers extract data and map the same into specific formats (reports and listings) as specified by the sponsor to aid the statistical analysis. Statisticians use the programmed reports and listings and analyze the data as per a pre approved statistical plan. 46 2/21/2017 Katalyst Healthcares & Life Sciences

47. A & R –Tables & Listings snap shot 47 2/21/2017 Katalyst Healthcares & Life Sciences

48. Roles & Responsibilities Medical Writers – Generate Clinical Study Report, using the statistical analysis and other study documents thus summarizing the overall findings and conclusions of a clinical trial. The CSR is used for submission to the regulatory authorities 48 2/21/2017 Katalyst Healthcares & Life Sciences

49. Slide No. 49 • QS CRS Quality Services / Svend Martin Fransen • 03.Oct.2002 21CFR11, Overview Substantive rule from 20 August 1997 Applies to any e-record in any FDA regulated work including legacy systems Criteria for e-records and e-signatures: Trustworthy and reliable E-signatures = hand-written signatures Minimum requirements / fraud prevention 2/21/2017 Katalyst Healthcares & Life Sciences

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71. Slide No. 71 • QS CRS Quality Services / Svend Martin Fransen • 03.Oct.2002 Systems not Applications All definitions and clauses in 21 CFR 11 refer to systems Application is not mentioned IT part of the GXP environment. Do they know? Working environment Computer based system Computer system Application -software Platform - hardware - system SW Controlled function Instructions, Manuals, etc. Equipment COMPUTER RELATED SYSTEM 2/21/2017 Katalyst Healthcares & Life Sciences

72. Slide No. 72 • QS CRS Quality Services / Svend Martin Fransen • 03.Oct.2002 21 CFR Part 11, Basics Electronic records equivalent with paper records Storage, retrieval and copying in full retention period Submitting to FDA Protection of electronic records Security (physical and logical) Validation Audit trail (who did what, when including reason where req.) Permission to use of electronic signature Equivalent with handwritten signatures Name, date and meaning Linking of signature to record Unique for an individual 2/21/2017 Katalyst Healthcares & Life Sciences

73. Slide No. 73 • QS CRS Quality Services / Svend Martin Fransen • 03.Oct.2002 FDA 21CFR11 inspection questions (source: : 21CFR11 Compliance Report, Vol.2, No. 4). Who is allowed to input data? Who is allowed to change data? How can you tell who entered the data? How do you know which data had been changed? When do you lock down the data input? Can you do the following actions? “Show me some data, show me you can see the history of the data, show me you control the data life cycle.” Is the system validated and are the requirements met? Can you show me the results of the validation activities? Does the validation include: “Pass/fail, signature, date/time stamp”; and “objective evidence - screen prints or page printouts with a link to the direction that generated the output.”? 2/21/2017 Katalyst Healthcares & Life Sciences

74. Questions 74 2/21/2017 Katalyst Healthcares & Life Sciences

75. When do the CDM activities start. What is the first activity performed by CDM in Study Start-up? What are the modes of data collection? What are the different ways of Validating data? What does CSR stand for? Test Your Understanding 75 2/21/2017 Katalyst Healthcares & Life Sciences

76. In this session we have understood the following points: ● What is Clinical Research? ● What is Clinical Data Management? ● Importance of CDM ● CDM work flow ● Roles and Responsibilities across all processes ● Activities performed by Data Managers in Clinical Research Summary 76 2/21/2017 Katalyst Healthcares & Life Sciences

77. Practical Guide to Clinical Data Management; Second Edition: by Susanne Prokscha COMPUTERIZED SYSTEMS USED IN CLINICAL TRIALS, U.S. Department of Health and Human Services, Food and Drug Administration http://en.wikipedia.org/wiki/Clinical_trial Source 77 2/21/2017 Katalyst Healthcares & Life Sciences

78. Thank You & Questions 2/21/2017 78 Contact: Katalyst Healthcare’s & Life Sciences South Plainfield, NJ, USA 07080. E-Mail: [email protected]