1. Using EDC-Rave to Conduct Clinical Trials at Genentech Susanne Prokscha Principal CDM PTM Process Analyst February 2012

2. Objectives 2 At Genentech, we use an electronic data capture (EDC) system called Rave for all clinical trials. Background to EDC  What exactly is EDC?  Activities for clinical data management (CDM) for EDC  The regulatory environment for EDC Case study for large Phase III Trials  Study startup  Study conduct  Study closeout Summary and Rave Demo

3. Background to EDC

4. What is Electronic Data Capture? In order to have data that can be analyzed to draw a conclusion, values have to be collected the same way across all investigator (research) sites. In clinical trials, we use structured forms known as Case Report Forms (CRFs) to collect data. These can be paper forms or electronic forms. EDC refers to collection of clinical trial data on electronic CRFs (eCRFs). The primary function of EDC systems is to support data collection from the sites but they will also support data management activities/tasks. 4

5. CDM Activities for EDC CDM ActivitiesComments Specify and build eCRFsCDM is the lead in designing the data collection forms. Protocol team contributes and approves. When approved, data managers or clinical programmers (CPs) build the forms. Specify and build edit checksCDM specifies the rules that check data for validity (“edit checks”). When an edit check triggers, it automatically creates a query to the site for data clarification. CDM or CP programs them. Oversee study validation testing CDM oversees and conducts testing of the study (per 21 CFR Part 11) prior to production use. Monitor data entryEven though the site enters, often the CDM is responsible for reporting to the protocol team on status of eCRF data 5

6. CDM Activities (continued) CDM ActivitiesComments Collect AE and SAE dataAdverse Event and Serious Adverse Event data typically have special collection and management activities. Code reported termsAEs, medications, and other broader terms are typically coded or matched against a dictionary/thesaurus to allow for appropriate counting of those events or terms. Manage non-CRF dataNearly all studies have data that does not come in on eCRFs but rather arrives electronically from vendors or suppliers. This includes: labs, EKG readings, microbiology, special assays, pharmacokinetic results, and so forth. Generate manual queriesAutomatic edit checks have limitations so protocol teams perform manual reviews and analyses of the data. This typically will result in queries that have to be manually entered into the system. 6

7. CDM Activities (continued) CDM ActivitiesComments Monitor query resolutionFor both automatic and manual queries, the sites are expected to resolve them all and within a reasonable period of time. CDM and clinical staff monitor query resolution. Perform lab data admin tasksLaboratory data from the eCRF or directly from the lab has administrative tasks associated with it including linking normal ranges to reported values. Oversee study lock activitiesAs the study nears close, final cleaning and review activities take place. CDM is responsible for many of the final tasks. After lock, the data can be analyzed. 7

8. EDC Regulatory Environment Any system used to collect data that may be included as part of an NDA to the FDA must be compliant with 21 CFR Part 11 – the rule on electronic records and signatures. The rule includes system requirements such as:  Time-stamped, automatic audit trail  Secure account management and access controls The rule also includes procedural elements:  System and study level validation  Standard operating procedures 8

9. EDC Regulatory Environment A regulatory concern that is not in the rule but is showing up in FDA and EMEA guidance documents has an important implication for EDC systems. Regulatory agencies are clear: the sponsor cannot have “full control” over the site data.  If the sponsor has the system on its own servers, it has access to changing the site data.  Most companies currently have the EDC system “hosted” by service providers who manage site accounts, access to the application, and access to the underlying database. 9

10. Rave at Genentech

11. Rave, a product from Medidata Solutions, is used for all new studies for both Genentech and Roche worldwide. Medidata  Hosts a Roche-Genentech URL on restricted servers  Grants site access and manages site accounts Clinical Data Management  Study Data Managers: define the system, approve and test the build, run the study…  Clinical programmers: b uild the study and create custom functions and reports Informatics Rave Support, System Support Services 11

12. Study Startup – Prep for “First Patient In” Study startup activities begin when the protocol summary is firm and rely on the final protocol to move forward until it is ready for subject data. Specify and build the eCRF  There will be 50-75 unique eCRFs for a Phase III study Specify and build the edit checks  There can be from 600 to 2000 individual edit checks  Estimate 1000 edit checks for a Phase III study Test the study application and release for production (“go live”) 12

13. Study Conduct – Collect and Clean Data Monitor site entry of data and responses to queries Perform Data Reviews  Some checks are more easily done by a humans via listings or reports  Medical review is performed by clinical science Create Manual queries  Example: MS Phase III trial with 105 sites and 450 subjects had 5000 manual monitor and data review queries  Example: Phase II trial with 32 sites and 120 subjects had about 800 manual queries 13

14. Study Conduct – Other Activities Collect non-CRF data (labs, etc.) Code adverse events and medications Collect and reconcile serious adverse events against the safety database An important event during study conduct that occurs in most Phase II and III trials is a database change or “amendment”. This is a time and resource consuming event. 14

15. Study Closeout – Prepare for Lock Ensure data is complete (both eCRF and non-eCRF) Perform final data reviews  Final Data listing review  Review all coding assignments  Check that all SAEs are accounted for Obtain resolution for or close all open queries Obtain Principal Investigator Signature Prepare archival versions of eCRF for the sites and the sponsor files 15

16. Data Management Impact Even though data management is only 12% of the cost of a large trial (20% if biostatistics and statistical programming are included), it is an essential component. If the data is not complete or accurate enough to be analyzed and sustain a conclusion then the entire cost of the trial is wasted. 16

17. References For electronic records in clinical trials in general:  (FDA) 21 CRF Part 11; Electronic Records; Electronic signatures  (FDA) Guidance for Industry: Computerized Systems used in Clinical Investigations  (EMEA) Reflection Paper on Expectations for Electronic Source Documents used in Clinical Trials Using EDC vendors or hosts:  FDA presentation: “Guidance on the Use of Electronic Records and Electronic Signatures;” P. M. Beers Block, 12/2009  (FDA) DRAFT Guidance for Industry: Electronic Source Documentation in Clinical Trials 17