EDC, CRFS and PRO Data
The ICH Guidance for Industry: E6 Good Clinical Practice defines the term “case report form” as, “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.” This includes studies using paper CRF, electronic data capture (EDC) and/or patient-reported outcomes (PRO). Certain factors should be taken into account for electronic CRFs that do not apply to paper CRFs, such as thoroughly validation (ie. edit checks and UAT) to ensure they function as intended and comply with regulatory guidelines per FDA Guidance for Industry: Computerized Systems Used in Clinical Trials and Code of Federal Regulations, Title 21, Part 11, Electronic Records; Electronic Signatures. CRF standards first released in 2008 by CDISC to standardize data collection fields as outlined in CDISC CDASH Core and Domain Teams.
Electronic Data Capture
When using an EDC system meet the requirements specified in applicable regulatory guidance documents. This review should ensure that the study documentation address expectations from regulatory agencies. Some of the guidance and specifications for this review include FDA Guidance for Industry: Providing Regulatory Submissions in Electronic Format for NDAs and ICH M2 EWG Electronic Common Technical Document Specification.
The clinical data management system (CDMS) used to conduct a clinical study ”…should be designed to…prevent errors in data creation, modification, maintenance, archiving, retrieval or transmission…”. As required by 21 CFR
Part 11 and the predicate rule(s) applicable to the drug, device, or biologic in development, thorough documentation should exist at all levels of a clinical study’s data collection and management. Given the multifaceted responsibilities of a CDMS, the validation process is necessary, ongoing and often complicated.
Validation versus user acceptance testing (UAT)—In Guidance for Industry: Computerized Systems Used in Clinical Investigations, the Food and Drug Administration (FDA) defined software validation as “Confirmation by examination and provision of objective evidence that software specifications conform to user needs and intended uses and that
the particular requirements implemented through the software can be consistently fulfilled.” UAT is one element of the examination, and documented UAT results serve as one component of “objective evidence” supporting the validation process. UAT is performed by users of the database or CDMS, and should test for both false positive and false
negative results in all fields and functions. UAT does not constitute validation by itself; other elements of validation include, but are not limited to, the validation plan, requirements specifications, a traceability matrix, a UAT summary and a validation summary.
As stated by the FDA, “The computerized system should be designed to…prevent errors in data creation, modification, maintenance, archiving, retrieval or transmission…”.
Those responsible for validation must be mindful of how their validation activities and documentation would be perceived in an audit or inspection by regulatory bodies. Although referring specifically to software, the following statement by the FDA could just as easily apply to study-specific validation. “Software verification and validation are difficult because a developer cannot test forever, and it is hard to know how much evidence is enough. In large measure, software validation is a matter of developing a ‘level of confidence’ that the device meets all requirements and user expectations for the software automated functions and features of the device. Measures such as defects found in specifications documents, estimates of defects remaining, testing coverage, and other techniques are all used to develop an acceptable level of confidence before shipping the product. The level of confidence, and therefore the level of software validation, verification, and testing effort needed, will vary depending upon the safety risk (hazard) posed by the automated functions of the device.”, per FDA General Principles of Software Validation; Final Guidance for Industry and FDA Staff.
Patient Reported Outcomes
Many clinical studies use PRO data to some degree, and for some of these studies PRO data is a primary efficacy parameter. If an investigator cannot observe, quantify or measure a variable, it may instead be reported by the subject. The best way to learn about an individual’s personal experience is to ask the individual to describe it. In some cases, PRO data can also be used for registration or economic evaluation purposes. Although PRO data have been used in clinical studies for many years, the advent of electronic tools may improve the quality of data and ease of data collection. Guidance for Industry Patient Reported Outcome Measures provides guidance for the selection or creation of a PRO questionnaire or test. It should be noted that this draft guidance also states, “If a patient diary or some other form of unsupervised data entry is used, the FDA plans to review the protocol to determine what measures are taken to ensure that patients make entries according to the study design and not, for example, just before a clinic visit when their reports will be collected.”