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

Overview At Genentech, we use an electronic data capture (EDC) system called Rave® for all clinical trials. Background to EDC What exactly is EDC? Activities of clinical data management for EDC The regulatory environment for EDC Case study for large Phase III Trials at Genentech Study startup Study conduct Study closeout Summary and Rave Specifics Rave is a product offered by Medidata Solutions Worldwide: http://mdsol.com/

Background to EDC

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 these systems will also support data management activities/tasks. Collecting data the same way: The same variables/data at equivalent time-points The same data type (i.e., numeric, categorical) With sufficient context to identify the data (subject id, date)

What is Clinical Data Management? Clinical Data Management (CDM) is the management of clinical data from its collection through to its extraction for analysis. Clinical Data Managers are responsible for ensuring the data is complete and of a quality to reliably support a conclusion. The slides that follow list the activities of clinical data manager typical for biopharmaceutical and medical device companies.

CDM Activities for EDC CDM Activities Comments Specify and build eCRFs CDM 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 checks CDM 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 entry Even though the site enters, often CDM is responsible for reporting to the protocol team on status of eCRF data In order to understand the numbers around EDC trials at GNE, we need to quickly go over what the data management tasks typically are for an industry group. I’ve chosen to list 11 of the broadest categories *Query is bold here because it is not the same as a database query. In the industry a “query to the site” is a specific request for clarification of a particular data point

CDM Activities (continued) Comments Collect AE and SAE data Adverse Event and Serious Adverse Event data typically have special collection and management activities. Code reported terms AEs, 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 data Nearly 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 queries Automatic 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. An SAE is defined by the FDA as “any adverse drug experience occurring at any dose that results in any of the following outcomes: Life-threatening Death Hospitalization/prolongation of hospitalization Congenital anomaly Persistent or significant disability/incapacity Required intervention to prevent permanent impairment/damage”

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

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 Because of 21 CFR Part 11, most companies will buy rather than build EDC systems “after the first” There are also guidance documents from the FDA and agencies outside the US that impact CDM (see references)

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. Guidance and opinion documents from FDA and EMEA support this

Large Phase III Trials at Genentech Case Study Large Phase III Trials at Genentech

Rave at Genentech Supporting Rave at Genentech involves several groups: Medidata Solutions 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: build the study and create custom functions and reports Informatics Rave Support, System Support Services Provide systems support, liaison to Medidata, and internal accounts Now that we have the background on CDM tasks and regulatory environment, we can address the specifics at Genentech. It is common for companies to set up EDC as an integrated effort between multiple groups to support the independent hosting. For the estimates and examples of effort and cost, we will see only at the budget for CDM, the numbers that follow do not include Medidata costs, or internal Rave Support costs.

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”) The cost of effort for study startup is closely related to the complexity of a study. For a Phase III study, we can make some rough estimates.

Study Conduct – Collect and Clean Data Study conduct runs from first patient in to lock. Monitor site entry of data and responses to queries Perform Data Reviews Some checks are more easily done by 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

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”. Most studies have multiple amendments. Amendments can be related to a change to the protocol (protocol amendment). Often this involves a change to the clinical procedures and/or visit structure. Sometimes, amendments happen because errors in the database design are found or because experience with the data leads to changes in the edit checks. Because the database holds active patient data so changes have to be evaluated and tested before they impact the data.

Study Closeout – Prepare for Lock Preparation for lock of a study often begins prior to last patient “out” and must be complete before 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 CIU = chronic idiopathic urticaria, anti-IgE for asthma

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