clinical data management process overview_katalyst hls

CDM Process Overview

Clinical Data Management (CDM) Process Overview

2/21/2017Katalyst Healthcares & Life Sciences1

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Icons Used2/21/2017Katalyst Healthcares & Life Sciences

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.Overview3Overview2/21/2017Katalyst Healthcares & Life Sciences

CDM is consistently being recognized as a primary part of clinical development team & in some instances leads this team. CDM has evolved from a data entry process into a diverse process:to provide clean data in a useable format in a timely mannerprovide a database fit for useensuring data is clean & database is ready to lockNow CDM manages entry of CRF datamerging of non-CRF datasystems & processes designed to identify bad datagenerate & track CRFs & queriesdetermine protocol violatorsinteract with site personnel to resolve data issues

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After this chapter you will be able to understand:Overview of Clinical Data ManagementProcess flow of data management activitiesActivities performed during the course of a trialAnalysis and reporting process overviewRoles and responsibilities of all personals involved in CDM

Objectives42/21/2017Katalyst Healthcares & Life Sciences

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 Know52/21/2017Katalyst Healthcares & Life Sciences

Abbreviations6CRFCase Report FormDBDatabaseQCQuality ControlDMPData Management PlanCSRClinical Study ReportUATUser Acceptance Testing

2/21/2017Katalyst Healthcares & Life Sciences

Definition of Clinical TrialIt 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.

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Clinical Trial PhasesPhase I Trials Involve a small group (20 to 100) of healthy volunteers to discover if the drug is safe in humansPhase 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 drugPhase III Trials Involves thousands of patients to generate statistically significant data about safety, efficacy, and an overall benefit/risk profilePhase IV Trials Certain post marketing studies to find out additional information about the drug's risks, benefits, and its optimal use.

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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

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Multidisciplinary Roles in Clinical trialClinical InvestigatorSite coordinatorPharmacologistTrialist/MethodologistBiostatisticianLab CoordinatorReference labProject managerClinical Research Manager/AssociateMonitor

10Regulatory affairsClinical Data Management*Clinical Safety Surveillance Associate (SSA)ITIT/IS personnelTrial pharmacistClinical supplyAuditor/ComplianceStudy Physician


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Clinical Data Management - Overview11

Investigator

Monitor

CentralLaboratory

Data ManagerStatistician

Clinician

RegulatoryAuthority

Subject

CRFDCFCRFDCFSampleLabResultsClinicalDataNDA

DCF


Clinical trials often involve patients with specific health conditions who then benefit from receiving otherwise unavailable treatments. In planning a clinical trial, the sponsor or investigator first identifies the medication or device to be tested. In coordination with a panel of expert investigators, the sponsor decides what to compare the new agent with, and what kind of patients might benefit from the medication or device. During the clinical trial, the investigators: recruit patients with the predetermined characteristics, administer the treatment(s), and collect data on the patients' health for a defined time period. These data include measurements like vital signs, concentration of the study drug in the blood, and whether the patient's health improves or not. The data collected is recorded on the CRFs and the lab samples are sent to the laboratory for assessment. The data recorded on the CRF by the investigator is verified by the site monitor against the source documents. Both data from the CRF and laboratory are then sent to the data manager who runs validation checks on the data and performs data cleaning activities. As a result of data cleaning activities, DCFs(data clarification form) are generated which are sent to the investigator for clarification. The database is updated based upon the resolutions received. The clean data is then sent to the statistician who then analyzes the pooled data using statistical tests. Clinical study reports are created by medical writer based upon the statistical analysis results which is submitted to the regulatory agencies for approval.

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Definition of DataData 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 met12


Objectives of CDM13

Data Collection

Data integration

System / Data Validation

Paper, Electronic and Remote data captureIntegration of data received from all sources in a single DB. Ensures consistency and correctnessSystem validation done via UAT, QC and ProgrammingData Validation via Edit check programs and manual review2/21/2017Katalyst Healthcares & Life Sciences

Data in a clinical trial may be collected through various modes. The most common include Paper CRF, remote and electronic data capture. In addition to these methods some data may also be collected through IxRS (Interactive Voice and Web Response System). The data coming in through the above modes is required to be integrated into one centralized system or the clinical database. Integration of clinical data means to ensure that the data incorporated in the clinical data management systems are correct, consistent and an exact replica of the data received on the paper forms. No data manipulation is expected during the data transfer between one or more modes. The next step in the data management process is the validation of data entered into the system for correctness. All the systems being used and the incoming data should be validated before release. The systems are validated through User Acceptance testing methods (UAT), while the clinical data is validated through electronic programs written by the programmer and manually as well.

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Scope of CDMMain 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.


Importance of CDMCDM 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 dataTo support accuracy of final conclusions & report

Clinical Data Management ensures:That collected data is complete & accurate so that results are correctThat trial database is complete, accurate & a true representation of what took place in trialThat trial database is sufficiently clean, to support statistical analysis, its subsequent presentation & interpretation


16 Inter-dependent groups in CDMClinical Data Management2/21/2017Katalyst Healthcares & Life Sciences

Data Management activity begins with the receipt of the final approval protocol. All Data management activities are performed closely in conjunction with the programming and biostatistics team. The programming team helps to program the validation and derivation checks required to identify discrepancies in the data received. When these validation checks are executed on the received data discrepancies are generated in the clinical data management system. The discrepancies are resolved either internally using study conventions or through queries answered by the investigator. The clean data is provided to the biostatistics team at the end of the study. The biostatisticians perform data analysis using different methods. The results of data analysis are used for generation of a clinical study report.

A Separate SAS Programming team works on the SAS checks (more complex checks / checks that involve comparison of multiple data points / or involve comparison of study data with external data). This team is a part of the Setup team handling validation procedures.

Also, there exists a SAS Programming team which is part of Biostatistics. This team works with Biostatisticians to create Tables, Listings and figures for analysis.

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DM role in Clinical ResearchCDM has evolved from a mere data entry process to a much diverse process todayThe data management function provides all data collection and data validation for a clinical trial programData management is essential to the overall clinical research function, as its key deliverable is the data to support the submissionAssuring the overall accuracy and integrity of the clinical trial data is the core business of the data management functionIt provides data and database in a usable format in a timely manner It ensures clean data and a ready to lock database172/21/2017Katalyst Healthcares & Life Sciences

CDM is a vital vehicle in Clinical Trials to ensure integrity & quality of data being transferred from trial subjects to a database system.To provide consistent, accurate, & valid clinical dataTo support accuracy of final conclusions & report

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DM role in Clinical ResearchAt the study level, data management ends when the database is locked and the Clinical Study Report is finalAt the compound level (of the drug), data management ends when the submission package is assembled and complete


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Data AcquisitionSite / InvestigatorProgrammersCodersSafety Study Team/ClientMonitor / CRADM Communication & Interfaces

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20CDM Activities Phase-wise


The study start up activities include the build-up activities like CRF development, database designing. Data collection instruments like CRF, DB, are to be designed and the validation tools should be ready during this phase. Different documents created by data manager during study start up includes CRF completion guideline, Data Management plan, edit check specification. The very first activity performed by data mangers during study set up is creation of CRF based on the approved protocol. The start up activities form the base of a clinical trial at the data management end. The roles involved during the study start up phase from the DM team are the CRF designers, DB designers, Programmers, and Data Managers.Completion of the start up activities are a trigger for the start of conduct activities. Data cleaning is the core objective during the conduct of the study. Data entry is the first step that is performed after which all the data coming in from the CRF, through electronic transfers (lab, ECG) are validated through the programming checks. Medical terminologies are coded to maintain consistency and also as a reporting requirement. Personnel involved during the conduct of a study are:Data entry associate entre the clinical data into CDMS, Data Managers validate the data, Coders are responsible to coding the medication and adverse events reported in the clinical trial and Safety data managers.Once the data cleaning activities are complete, all the electronic and manual checks are performed on the data and the data is error-free, it is ready to be frozen & locked. It is essential to confirm that there are no outstanding queries or resolutions that need update to be made in the database. Data manager is responsible for freezing & locking the study.

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21Study Start-up ProcessProtocolCRF DesignDatabase DesignValidation/ Derivation ProceduresActivated database ready to accept production data 2/21/2017Katalyst Healthcares & Life Sciences

Study Set-up Roles and ResponsibilitiesCRF Designers -Design CRF as per protocolDB designers -Design DB as per protocol OR CRF OR CRF Specs and activate the sameProgrammers -Program Validation and Derivation procedures, and activate the sameData 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

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23Study Conduct ProcessActivated DBData Entry / Loading (CRF & external data)Discrepancy ManagementQuery GenerationSafety Data Recon.Coding termsResolution & update of DBManual Check/ QC2/21/2017Katalyst Healthcares & Life Sciences

24Study Conduct Roles and ResponsibilitiesData 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

Data managers can also execute / perform Safety Data Manager's responsibility depending on the project requirement.24

Data CaptureRegardless of whether youre 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.

25Electronic Data CapturePaper Data CaptureRemote Data CaptureData Capture2/21/2017Katalyst Healthcares & Life Sciences

Difference between Data Capture Tools 26The difference between Paper, Electronic and Remote data capture is :PaperData 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

ElectronicData is captured in electronic Case Report Form

Investigator enters the data into the database

Real time access to the data

Remote data entry/ captureData 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 participatingNot web based thus no real time access to the data


CRF DEMO Snap shot27


CRF TrackingReceipt 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

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Data Entry & VerificationData 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

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Data ReviewWhy Data Review?

To ensure complex medical data are reviewed and assessed to detect any discrepancy in the data.

Discrepancy Examples:Empty fieldsIncorrect Range One value greater/less than/equal to anotherDates not in logical sequenceInconsistent header information Any missing visits or pagesVisits not in compliance with protocolInclusion/exclusion criteria not met

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Data Review Edit ChecksConsist 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

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Edit Checks TypesRange checks To identify inaccurate or invalid data & statistical outliersTo ensure that data outside of permitted range are to be clarified and verifiedE.g. Systolic blood pressure (***) is outside the Critical Range (***).

Consistency checks To highlight area where the data in the database are inconsistentE.g. Adverse Event stop date is always after AE start date

Presence checks To ensure completeness of dataE.g. SEX is missing

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Data QueryA 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 QueryData Clarification Form (DCF)

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Medical CodingIt 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.


Medical Coding DictionariesCoding Dictionaries:

MedDRAMedical Dictionary for Regulatory Activities, is a standardized dictionary of medical terminology

WHO: WHOART, drugsWorld Health Organization Adverse Reaction Terminology

ICDInternational Classification of Diseases

FDA-COSTARTCoding Symbols for a Thesaurus of Adverse Reaction Terms


Safety Data ReconciliationWhat 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 deathIs life-threateningRequires inpatient hospitalization or Prolongation of existing hospitalizationResults in persistent or significant disability / incapacityIs a congenital anomaly / birth defect

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Safety Data ReconciliationReconciliation: 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 databaseIt 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.


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Study Closeout Process 38Discrepancy ManagementQuery generationResolution and/or update of DBManual check/QC/CRF tracking DB lock and freezeSafety Data Recon.Coding terms2/21/2017Katalyst Healthcares & Life Sciences

Declaring Clean File & Database LockClean 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 appropriatelyThis 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 dataData is consistentData is accurate Data is reliable

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Validated clean data will be transferred to a final databasePrior to locking the study, the following steps are completed:

Checklist for Database Lock40 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 discrepanciesAll lab data, external and internal (e.g. PK, ECG), are loaded and reconciledAll lab normals are present, loaded and complete Adverse event coding is complete and approved by the study MDAll other medical coding is completeThe Statistician confirms that the data meet previously agreed acceptance criteria The Statistician and CDM agree that the database is ready for lockingAll approvals are obtained on the Database Lock/Freeze/Unfreeze Approval form


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Unlock ScenariosCan 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.


Critical Data points are those datapoints which decide the Safety and Efficacy of the Investigational Product. This is mentioned in the Protocol as Primary endpoint.For eg : On SAE form hospitalization has been reported. However, the subject died subsequently but the data was not updated which needs to be updated in the Database.41

Quality ControlQuality 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.


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Quality AssuranceQuality 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 AuditsInspection is by Governmental Agencies, Health Authorities and the Drug Regulatory AuthoritiesAuditing is by pharmaceutical, devices companies, CROs, and others


Audits TypesInternal audit (first party audit):Carried out by service providers 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.


Benefits of Internal AuditAudit 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


Roles & ResponsibilitiesProgrammers 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.

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A & R Tables & Listings snap shot47


Roles & ResponsibilitiesMedical 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

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Slide No. 49 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 21CFR11, OverviewSubstantive rule from 20 August 1997Applies to any e-record in any FDA regulated work including legacy systemsCriteria for e-records and e-signatures:Trustworthy and reliableE-signatures = hand-written signaturesMinimum requirements / fraud prevention2/21/2017Katalyst Healthcares & Life Sciences






















Slide No. 71 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 Systems not ApplicationsAll definitions and clauses in 21 CFR 11 refer to systemsApplication is not mentionedIT 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.

EquipmentCOMPUTER RELATED SYSTEM2/21/2017Katalyst Healthcares & Life Sciences

Slide No. 72 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 21 CFR Part 11, BasicsElectronic records equivalent with paper recordsStorage, retrieval and copying in full retention periodSubmitting to FDAProtection of electronic recordsSecurity (physical and logical)ValidationAudit trail (who did what, when including reason where req.)Permission to use of electronic signatureEquivalent with handwritten signaturesName, date and meaningLinking of signature to recordUnique for an individual


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.?


Questions74


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 Understanding75


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 ResearchSummary762/21/2017Katalyst Healthcares & Life Sciences

Practical Guide to Clinical Data Management; Second Edition: by Susanne ProkschaCOMPUTERIZED SYSTEMS USED IN CLINICAL TRIALS, U.S. Department of Health and Human Services, Food and Drug Administrationhttp://en.wikipedia.org/wiki/Clinical_trial

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Thank You&Questions2/21/201778Contact:Katalyst Healthcares & Life SciencesSouth Plainfield, NJ, USA 07080.E-Mail: [email protected]

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