Design of Case Report Forms

RDC/RDE (Remote Data Capture, Case Report Form ..CRF Official clinical data-recording document or tool used in a clinical study The Case Report Form is a data-reporting document used in a clinical study. Its purpose is to collect the study data in a specific format that allows for efficient analysis. Data from clinical trials is also collected using computerized Case Report Forms. This is referred to as Remote Site Monitoring (RSM) or Remote Data Entry (RDE). If RSM/RDE is utilized, data is generally entered onto paper workbooks, then input on computer screens which mimic the format of a paper CRF. Data can then be electronically transferred to Pfizer. PAPER RDC/RDE (Remote Data Capture, Remote Data Entry)

Purpose in accordance with the protocol Collects relevant data in a specific format in accordance with the protocol compliance with regulatory requirements Allows for efficient and complete data processing, analysis and reporting Facilitates the exchange of data across projects and organizations esp. through standardization

CRF Relationship to Protocol Protocol determines what data should be collected on the CRF All data must be collected on the CRF if specified in the protocol Data that will not be analyzed should not appear on the CRF

CRF Development Guidelines Collect data with all users in mind Collect data required by the regulatory agencies Collect data outlined in the protocol Be clear and concise with your data questions Avoid duplication Request minimal free text responses

CRF Development Guidelines (con’t) allows for computer summarization Provide units to ensure comparable values Provide instructions to reduce misinterpretations Provide “choices” for each questions allows for computer summarization Use “None” and “Not done”

CRF Development Guidelines (con’t) Collect data in a fashion that: allows for the most efficient computerization similar data to be collected across studies CRF book needs to be finalized and available before an investigator starts enrolling patients into a study Take the time to get it right the first time

Elements of the CRF Three major parts: Header Safety related modules Efficacy related modules Module block of specific questions CRF module(s) make up a single CRF page CRF Book series of CRF pages The term CRF indicates a single CRF page. A series of CRF pages makes up a CRF Book, and one CRF book is completed for each subject enrolled in a study.

Header Information MUST HAVES Key identifying Information Study Number Site/Center Number Subject identification number

Creating Safety Modules Usually come from a standard library Select modules appropriate for your study Keep safety analysis requirements in mind Safety Modules usually include Demographic Adverse Events Vital Signs Medical History/Physical Exam Concomitant Medications Patient Disposition

Efficacy Modules Designed for each therapeutic area based on the protocol Considered to be “unique” modules and can be more difficult to develop Use existing examples from similar protocols where applicable Consider developing a library of efficacy pages Design modules following project standards for data collection

Creating Efficacy Modules Follow general CRF design guidelines Use pages or modules from the therapeutic library Define diagnostics required Include appropriate baseline measurements Repeat same battery of tests Define and identify key efficacy endpoints additional tests for efficacy

Importance of Standard CRFs Prepares the way for data exchange Removes the need for mapping during data exchange Allows for consistent reporting across protocols, across projects Promotes monitoring and investigator staff efficiency Allows merging of data between studies Provides increased efficiency in processing and analysis of of clinical data

CRF Development Process Drafts CRF from protocol CRF Designer CRF Review Meeting Comments back to designer Reviewers CRF Designer The slide shows an overview of the CRF development process. One of the first decision points is to determine which CRA Book format to use. There are two types of formats; one format is designed to retrieve data upon treatment completion (log form), and the other is designed to retrieve data on a visit-by-visit basis. To help with the design, you can access Pfizer’s library of standard CRF pages for collecting safety and demographic data. You can select a template that is appropriate to the needs of the study. Using a template facilitates the assembly of the CRF. With appropriate approval from your group, you may make changes or edits to the safety templates to meet the specific needs of the study. Date requests on the CRF pages which collect efficacy or, for Phase I studies, pharmacokinetic or pharmacodynamic data must parallel the protocol. After drafting any new or unique efficacy or pharmacokinetic/pharmacodynamic pages, it is a good idea to send them to one or two sites that will be conducting the study and ask the site personnel for feedback. Updates CRF to incl. comments Review and Sign off Coordinate printing and distribution Site CRF Book

CRF Development Process Responsibility for CRF design can vary between clinical research organizations (CRA, data manager, specialty role) Include all efficacy and safety parameters specified in the protocol using standards libraries To collect ONLY data required by the protocol Work with protocol grid/visit schedule The CRA is responsible for designing the CRF Book to parallel the efficacy and safety parameters indicated in the protocol.

CRF Development Process Interdisciplinary review is necessary each organization has its own process for review/sign-off Should include relevant members of the project team involved in conduct, analysis and reporting of the trial Begins As soon in the study prep process as possible The CRA is responsible for designing the CRF Book to parallel the efficacy and safety parameters indicated in the protocol.

CRF Development Process Review Team (example) Project Clinician Lead CRA Lead Statistician Lead Programmer Lead Data Manager Others Database Development, Dictionary Coding, Standards CRF development should begin as soon as possible in the study preparation process. However, some CRF pages, such as those relating to efficacy or pharmacokinetics and pharmacodynamics, cannot be finalized until the final protocol has been completed. Draft CRFs are usually reviewed by the clinician, statistician and group leader. There also may be a CRF Review Committee that includes clinical staff as well as Data Management personnel.

CRF Development Process After the CRF book is approved Initiate the process for printing Note: the Protocol must be approved before the CRF book is approved and printed After it is printed Stored according to organizational guidelines Printed and distributed to research sites After the CRF Book has been approved, the process for printing the document is initiated. The completion of this process will vary. After the CRFs have been finalized and printed, a copy of the CRF Book is sent to: Central Files (CRF Librarian), Statistician, Data Coordination Group.

Properly Designed CRF + Components/All of the CRF pages are reusable Saves time Saves money +

Poorly Designed CRF Data not collected Database may require modification Data Entry process impeded Need to edit data Target dates are missed Collected too much data – Wasted resources in collection and processing

The Case Report Form How do we use it? Collect data from the investigational sites Helps project team and study site team Reminder to investigator to perform specific evaluation CRA uses to verify protocol is being followed and compare with source documents Biometrics uses it to build database structures, develop edit checks and programming specs The CRA and Clinician will monitor the data recorded on the CRFs. Although the purpose of the CRF is to collect data, it also helps the study site team and you perform your jobs. The CRF acts as a reminder to the investigator to perform specific evaluations and you can use the CRF to verify that the protocol is being followed (i,e, correct evaluations are being conducted at the appropriate time) and subject safety is being maintained.

The Case Report Form e.g.. APR ...Used for Subject tracking Data analysis and reporting Reports to FDA on subject safety e.g.. APR Promotional materials New Drug Application submissions Support of labeling claims Articles in medical journals CRFs collect all subject data required by the protocol and are used for subject tracking and data analysis. The data that is collected is very important, because it is the basis for making decisions about the drug, its benefits, risks, and potential marketability. Biometricians/Statisticians and Data Management personnel analyze and report the data recorded on the CRFs in the final study reports for the clinical trial. This data is used for reports to the FDA on subject safety (e.g. serious adverse events, annual progress reports, is included in promotional materials and is submitted in NDAs. Additionally, the data from the clinical trial may be used to support labeling claims for the drug or may be published in medical journals. So it is critical that the data be accurate and completes

Electronic CRFs The use of RDC is increasing In general, the concepts for the design of electronic CRFs/RDC screens are the same as covered for paper Electronic CRFs will impact the following: Review of CRF is different (screen review) No need to print and distribute paper