Goal of site data management 12/2/2009. Ultimate goal: reliable and valid clinical trial to improve health

Transcription

1 RC-4 Overview of Clinical Site Operations and Management Unit 4: Overview of Data Quality and Monitoring Principal Investigators Lynda Wilson, PhD, RN Marti Rice, PhD, RN Program Manager TBA Course Instructors: Carolynn Thomas Jones, MSPH, RN Cynthia Joiner, MPH, RN Jennifer LaBorde, MN, RN Unit 4 Overview of Data Quality and Monitoring OBJECTIVES As a result of this module, learners will be able to: Define data management terminology Describe site and sponsor data collection processes and methods to assure data quality Discuss endpoint and safety data management Illustrate how to prepare for a site monitor visit Describe HPTN multi-tier monitoring and the role of data safety and monitoring boards Goal of site data management generate high-quality data Ultimate goal: reliable and valid clinical trial to improve health 1

2 Flowchart of participants throughout the conduct of a clinical trial Total Population Considered Prescreened Consented Screened Randomized Eligible for Study Registered on Study Randomized Assigned Treatment Ineligible? Refused Study? Not Randomized? Other Treatment? Completed Trial Withdrawn? Lost to Follow-up? Fully Evaluable! Partially Evaluable? Partially Evaluable? What are the primary elements of data quality? Attributable Legible Contemporaneous Original Accurate Goal of data management at the site: generate high-quality data How to achieve this? Data managers (defining roles/trial) Trained, experienced, dedicated staff Professionalize this work Set and maintain high standards Don t permit bending of the rules Quantitative evaluation of performance Frequent staff meetings to troubleshoot data issues Understanding source document requirements Understanding CFR conventions and processing 2

3 WHAT DATA? Population Hypotheses Pi Primary Objective Secondary Objectives Primary Endpoint Secondary Endpoints Population What is the general population pool? Who specifically qualifies for the study? Inclusion Criteria Exclusion Criteria i Demographics Consent documentation Visit and study adherence Administrative issues Endpoints Key data item Provides the most clinically relevant and convincing evidence directly related to a specific objective of a trial Examples: Occurrence of infection or death Negative cultures Time until CD4+ is less than 200 Time to HIV infection 3

4 Efficacy : A product's ability to produce beneficial effects on the duration or course of a disease. Efficacy is measured by evaluating the clinical and statistical results of subjective and objective assessments (e.g., symptoms, clinical tests). ICH E6, 1.2 Adverse Event (AE): Any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have a causal relationship with the treatment. An AE can be therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not related to the medicinal (investigational) product. Examples of endpoints 4

5 Examples of endpoints Sample Protocol AMB vs Fluconazole For Cryptococcal Meningitis in Persons Infected With HIV Cryptococcal Meningitis Study - Mortality as a 1 Endpoint Death at 6 and 12 months post-completion Some primary endpoints involve a single parameter Example: Cryptococcal Meningitis Mortality as a 1 Endpoint Data required to address this endpoint: Death Yes No Date of Death Time of Death Actual date and Time point in the study 24 hr clock (method) Cause of Death Data surrounding cause, confirmations, labs, hospital reports, other AEs and concomitant medications SAE reporting Generation of SAE report, reporting to IRB/EC and sponsor Death Certificates (if required) Competed study Tx? Yes No (If no, how much?) 5

6 Cryptococcal Meningitis Study Cryptoccocal Infection at 6 and 12 months as a 1 Endpoint How does the study DEFINE cryptococcal meningitis fungal infection? (e.g., SIGNS, SYMPTOMS, and + CULTURE) Headache, Fever, Altered Mental Status + CSF india ink + CSF fungal (C. neoformans) cultures + cryptococcal antigen assays Some primary endpoints involve composite data (varied combinations of all signs/symptoms, labs). Cryptococcal Meningitis Study Fungal Infection as a 1 Endpoint Data required to address this endpoint: Physical Exam Date, time, Hx and PE data, visit # Headache Y or N, Intensity, Date of Onset Lumbar Puncture ** Date, Time, AEs Neurologic Exam CSF Assays CSF India Ink CSF Culture Temperature Completed Study Therapy Tool: Mini Mental Status Exam, others? CBC, Antigen testing results India Ink results Culture results (may take 30 days) C or F, time, method, concomitant meds or illnesses that may effect temp Yes, No (if no, how much tx) ** What if no lumbar puncture was done at the protocol specified time? Two main steps to assure data management. Step 1: Look to the Protocol Understand the hypotheses and objectives Understand the endpoints Understand specific definitions of how to document endpoints. What, How, When, Where and Who Understand sponsor source document requirements and CRF conventions Prepare checklists, visit tools in advance of participant involvement. Run mock participants (using case studies) to assure adequate data collection measures. 6

7 Two main steps to assure data management. Step 2: Look to the MOP and CRF Manuals of Procedure further elucidate data collection and procedure guidelines Be thoroughly familiar with the CRF Determine how lab data will be obtained: locally or through a central lab Determine how lab data will be recorded: centrally or by the site ICH E6, 1.11 Case Report Forms (CRF) - a printed, optical or electronic document designed to record all of the protocol-required information to be reported to the sponsor on each trial subject. DESIGNED TO: Case Report Forms Identify & describe the consented population under study Collect data to evaluate endpoints Collect data to evaluate safety Collect data to describe exposure to study material (drug, device, interventions) Collect behavioral information (e.g., adherence, QOL, diaries, preventions) Collect data to define exposures while in the study (e.g., procedures, concomitant medications, behavioral modifications) Data Collection & CRF Flow Within the Site Study Visits & Clinic Sources Participant Source Documents Clinic notes Checklists Lab reports Interviews Hospital records Signed forms Computer verifications CRF Site Complete s 7

8 Source Documentation ICH E Source Data- All information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies) Source Documents- original documents, data, records (e.g., hospital records, clinical i l and office charts, laboratory notes, memoranda, subjects diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies of transcriptions certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial. Potential Source Document Sources Example of HPTN Study 046 Suggested Source Documents for specific data collection elements: HPTN 046 Required Case History Element HPTN 046 Source Documents [EXAMPLE TEXT] Basic mother and infant participant identifiers. (e.g., name, date of birth) Documentation that the mother provided written informed consent to participate in the study prior to initiation of study procedures. If she chooses, documentation that the mother provided written informed consent to storage and future use of samples. Locator form; screening and enrollment logs; Medical records; Signed and dated Informed Consent Form; signed and dated Informed Consent Coversheet. Signed and dated Specimen Storage Consent Form; signed and dated Informed Consent Coversheet. Documentation that the mother met the study selection (eligibility) criteria: Age HIV status Current or serious complications of this pregnancy Free of active serious infection other than HIV or other serious illnesses Intend to Breastfeed If not already delivered: Intend to Delivery at facility where study is based Mother s Medical Record Laboratory Records Mother s Medical Record Mother s Medical Record Chart Note Chart Note or Mother s Medical Record Have sponsors specify in advance of study start-up what they require for source documents. Worksheets as Source Documents Should represent data collection for visits, be signed, dated and credentialed Are only as good as their design Facilitate data capture during visits Establishes a layer of source documents Developed by: site coordinators coordinating centers sponsors CROs WORKSHEETS- May require sponsor approval May not substitute for other source documents 8

9 CRF Flow- Transmission to Sponsor TYPES OF PAPER CASE REPORT FORMS: NCR (No Carbon Required) OCR (Optical Character Recognition) CRF CRF Site Complete s Site Complete s SITE FAX Monitor collects Mail Air Courier Fax Sponsor QA & Data Entry Sponsor Database Sponsor QA & Data Entry or Directly to database CRF Flow- Transmission to Sponsor Remote Data Capture Systems - Data is entered onto worksheets by the site and then entered into a computer CRF and transmitted to the sponsor database through the internet. Site Complete s Data entry at site By CRC By monitor Site PC Internet transmission From site to sponsor CRF Worksheets Sponsor Database DATA MANAGEMENT CHALLENGES: TRACKING CRFs/SOURCE DOCS Identify CRF supply inventory and needs assessment Identify how the CRFs will flow within a visit Identify who will complete forms Have a documentation system to track: location of blank CRF pages location of activated CRF pages (in process or completed) status of forms (completed, not completed, partially completed) status of form approval (internal QC, PI signatures) status of forms monitored by sponsor/sponsor agents date of faxing to sponsor (DataFax CRFs) receipt of CRF by sponsor (sponsor notifications of receipt) Hmmm, where did I put that form? 9

10 Study (Shadow) Charts Multiple Methods 6-Part File Folder Method (Shadow Chart): 1. Informed Consent and Demographics 2. Visit flowsheet, log, visit checklists, progress notes and other source documents 3. Lab: requisitions iti and results 4. Drug/Device accountability record 5. Concomitant medications 6. Adverse events/serious Adverse Events CRF- filed separately or in a distinct section. 10