Regulatory authorities want to trust results of clinical trials
Site investigators will provide unbiased data because they have no vested interest in the efficacy or safety of the therapy being tested.
The FDA has mandated [Ref 5, 21CFR312.62 (b)] that an investigator is required to “prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation…”
“ When source data are transmitted from one system to another (e.g. from a personal data assistant to a sponsor’s server), …a copy of the data should be maintained at another location, typically at the clinical site but possibly at some other designated site.” [CSUICI]
Compare to: “Source Documents – Purpose: to document the existence of the subject and substantiate the integrity of the trial data collected –Located in Files of Investigator/ Institution” [ICH E6 Essential Documents 8.3.13, May 1997]
“Where data is stored on a remote (often central) server without retention of a contemporary local copy, the method by which an investigator or other party retains control of data they have generated should be clearly established, and this control should be demonstrable.” [REFLECTION PAPER ON EXPECTATIONS FOR ELECTRONIC SOURCE DOCUMENTS USED IN CLINICAL TRIALS, EMEA Draft, Oct 2007.]
In the EU, there has been some regulatory encouragement for use of eDiaries to increase data integrity.
Guidance on endpoints in asthma: “If home recording equipment is used, reproducibility is particularly important and an electronic diary record should be considered to validate the timing of measurements.”
Guidance on efficacy for steroid contraceptive: “The separate calculation of the Pearl Index for method failure requires reliable methods for recording of compliance (e.g. electronic patient diaries) not to include non-compliers in the denominator.”
Subjects are more willing to reveal sensitive personal data (e.g. ratings of sexual performance by a partner) when an eDiary is used
that will not allow an outsider (e.g. husband) to see the ratings.
The Data Protection Directive 95/46/EC dated 24 October 1995; Ref 7, The HIPAA Security and Privacy Rule, 2000; Ref 4, The Clinical Trials Directive 2001/20/EC, dated 4 April 2001, Ref 9, Act on the Protection of Personal Information, Japan, dated May 2003).
Experience suggests the privacy controls on eDiaries have been effective.
Prepare: Sponsors using eDiaries interpret the provision to mean that the Investigators “prepare” the eDiary records by instructing subjects about how to enter diaries and by answering any questions concerning the eDiary data.
Direct, unsupervised entry of data by the subjects is OK
Maintain: The investigators “maintain” the eDiary records in files “of the institution” by reviewing (and clarifying as necessary) the electronic records, and by monitoring compliance with completion schedules
usually via a web application supplied by the eDiary provider to provide access at will to authorized users at the sites
Files “of” the institution (not “at” the institution) also OK
Typical eDiary System To support reconstruction of the trial for auditing the trustworthiness of the results
“ The FDA considers the investigator to have met his or her responsibility when the investigator retains the ability to control and provide access to the records that serve as the electronic source documentation for the purpose of an FDA inspection. The FDA recommends that the study protocol, or a separate document, clearly specify how the electronic PRO source data will be maintained.” PRO Draft Guidance May 2006
Source: 1. The specific permanent record(s) upon which a user will rely for the reconstruction and evaluation of a clinical investigation. 2. Sometimes used as shorthand for source documents and/or source data . NOTE: accuracy, suitability, and trustworthiness are not defining attributes of “source”. The term identifies records planned (designated by the protocol) or referenced as the ones that provide the information underlying the analyses and findings of a clinical investigation See also original data, certified copy [CDISC Glossary V. 7]
eSource Document. The electronic record used to aggregate a particular instance of eSource data items for capture, transmission, storage, and/or display, and serving as a source document for a clinical investigation.
Note:…documents are recorded in electronic systems according to conventions (such as those for PDF documents) that ensure that all the fields of eSource data and associated contextual information (e.g. time of capture, time zone, authorship, signatures, revisions) are linked to each other in a particular structure… same role as the physical properties of paper (binding items together)…
Example of Designating Source EHR record at institution. First record of “original data” items eRecord containing the original data items extracted And “certified” to have the same values and metadata by validated process or a manual check This is the source document, and it is under the (Part 11) controls of a clinical trial system This is an original document that is NOT the source for the Report and is under the controls of the EHR system Source Data Final report containing analysis, findings based on original data CRF or eCRF with original data items Clinical Database
“ There is a need to define what an accurate copy is in an electronic sense. Accurate copies should include the meaning of the data (for example date formats), as well as the full audit trail.” [EMEA Reflection Paper…]
“ A copy of original information that has been verified as indicated by a dated signature, as an exact copy having all the attributes and information as the original.” [CSUICI, FDA]
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