University of Pittsburgh Guideline: Study Documentation for FDA Regulated Research
Data integrity is vital in the conduct of clinical research because data is necessary for the evaluation, reconstruction, and validation of clinical findings, observations and other study activities. Record-keeping requirements for research records are outlined in the federal regulations and guidance documents. Specifically, 21 CFR 312.62 provides that investigators are 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 used as a control in the investigation. The record-keeping requirements for investigators conducting research involving investigational devices are outlined in 21 CFR 812.140. The International Conference on Harmonization (ICH), E6 Good Clinical Practice (GCP) Guideline defines the essential documents that must be maintained before, during and after the conduct of the study.
In considering the FDA regulations and the ICH GCP Guideline for record keeping, the University of Pittsburgh Education and Compliance Office for Human Subject Research (ECO-HSR) has established the following record-keeping requirements for FDA regulated research.
1. Informed Consent
Informed consent is the primary ethical requirement underpinning research involving humans; it reflects the basic principle of respect for persons. Informed consent is an ongoing process, not a single event.
According to the University of Pittsburgh Institutional Review Board (IRB) policies, a licensed physician investigator must obtain consent for studies involving a drug, device or surgical procedure and must sign the investigator’s certification statement at the time of this involvement. With permission from the IRB, the consent process may be conducted by an individual who is a listed sub-investigator and licensed healthcare professional. This individual must have the appropriate expertise and credentials to perform this duty.
Signatures on the consent form must be personally dated by each person signing the form. If the consent form will be uploaded into the UPMC medical record system, each person signing the consent document must personally record the time of signing on the consent form.
A narrative note of the process for obtaining informed consent must be documented in the research record in addition to obtaining a signed consent form. The narrative note should document that informed consent was obtained prior to participation in the study, unless the IRB granted an exception for the evaluation of an emergency procedure, and it may include the following additional information:
· A list of the persons present during the informed consent discussion,
· A statement that risks were presented,
· A notation, if applicable, that significant issues of concern to the subject were addressed,
· A statement that all questions were answered to the satisfaction of the subject, and
· A notation that a copy of the consent form was provided to the subject.
If re-consenting is required, a narrative note of this process should also be documented in the research record.
All signed consent forms with original signatures, not photocopies, and the narrative notes of the consent process must be maintained. Signed consent forms can be kept in a file separate from the subject research records, provided this process is consistently implemented for all subjects and any signed revised or addendum consent forms are maintained in the same manner.
2. Case Report Forms
The ICH GCP Guideline defines a case report form (CRF) as, “A printed, optical, or electronic document designed to record all of the protocol required information [e.g., study data] to be reported to the sponsor on each trial subject.” There must be source documentation to substantiate all data recorded on the CRFs.
3. Source Documentation
Source documents are the original recording of any observations made or data generated about a subject during his/her participation in a clinical trial. These documents serve to substantiate the integrity of the study data, confirm the recorded observations and confirm the existence of the subjects. The ICH GCP Guideline defines source documents as:
Original documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical trial).
a. Case Report Forms Used as Source Documentation
Case report forms may be used as source documents if they represent data collected for the study and are where the data were initially recorded. An example of data initially recorded on the CRF may include verbal responses from the subject.
If data are transcribed from another source onto the CRF, the CRF is not considered to be the original source document and it cannot be used as source documentation. Examples of data that are routinely transcribed from other sources include: laboratory results, radiology reports, histories documented in referral letters, etc.
As a source document, the original CRF must be signed/initialed and dated by the individual recording the data on the CRF. If data are obtained at a later date, i.e., after the study visit and are recorded on the CRF as source documentation, it must be signed/initialed and dated at the time of entry.
A list of the CRFs that are considered source documentation should be maintained to ensure consistency throughout the study and to clearly indicate for potential reviewers (e.g., monitors, auditors and regulatory authorities) which CRFs are being used as source documentation.
b. Computer Records Used as Source Documentation
When data is entered directly into a computer system that is 21 CFR Part 11 compliant, the electronic data in the computer system is the original source document. A paper record, e.g., a printout or print screen of the electronic data is considered to be a copy.
An example of direct data entry is the collection of vital signs during a study visit and the immediate entry of this information into a computer system, without recording the vital signs on paper. If the vital signs were initially recorded on paper and then entered into the computer system, the data recorded on paper would be considered the original source and not the data in the computer system.
For questions regarding compliance with Title 21 Part 11 for systems stored on a server maintained by the University of Pittsburgh, contact The University of Pittsburgh Computer Services and Systems Development.
For questions regarding compliance with Title 21 Part 11 for systems stored on a server maintained by the University of Pittsburgh Medical Center, contact a representative of UPMC information technology management executive leadership. Of note, information contained within UPMC legacy computer systems (e.g., e-record systems developed prior to August 1997) is presumed to be noncompliant with Title 21 Part 11 unless verified prospectively by UPMC information technology management executive leadership.
4. Documentation Standards
The ECO-HSR has adopted the following documentation standards as best practices for study documentation. Utilizing these standards will ensure data quality by creating audit trails and enabling verification that data are present, complete and accurate.
To achieve data quality the ALCOA principle should be applied to source documentation, which is as follows:
Attributable Is it obvious who wrote/did it and when?
Legible Can it be read?
Contemporaneous Is the information current and in the correct time frame?
Original Is it a copy? Has it been altered?
Accurate Are conflicting data recorded elsewhere?
At a minimum, the following general standards must be followed:
· Keep handwritten notes and signatures legible. If necessary, the individual’s name may be printed underneath the signature.
· Sign and date all entries in real time.
· Make error corrections by: 1) drawing a single line through the incorrect information, 2) initialing, dating, and stating a reason for the change (if necessary), and 3) inserting the correction. If the change is obvious, i.e., a transcription error that can be verified with the original source, then a rationale for the change is not required. If the change is not obvious, i.e., a diagnosis or symptom that was deleted after initial entry, then there should be a rationale for the change.
· Never obliterate entries that require correction.
· Never destroy original documents, even if they require error correction.
· Keep subject records secure yet accessible.
· Do not alter past-dated notes, chart notes/progress notes, e.g., by writing alongside or adding to prior entries.
· Only use dark ink.
· Never use whiteout.
· Never use pencil.
a. Signing/Initialing and Dating Source
If more than one person makes an entry on the same source document, each entry must be signed and dated. However, multiple entries to a source document made by the same person on the same day require only one signature and date on the page if there have been no interim entries made by other individuals. It is incumbent upon the individual signing the source document to ensure that there have been no entries other than his/her own. A single date on a source document with multiple entries is permitted if all entries were made on that same date.
Initials may be used in place of signatures on source documents provided that a signature key is maintained by the research staff. The signature key should include initials, signatures and credentials (if applicable).
b. Subject Identifiers
All source documents must be consistently labeled with at least one unique identifier to enable verification that the documents correspond to a particular subject. The labeling method should be consistent with the method described in the consent document and protocol.
c. Entry Criteria
Eligibility checklists should be developed to capture each criterion outlined in the protocol. Source documentation to address the presence and absence of the protocol’s inclusion and exclusion criteria must be present in the research record.
d. Communications
Verbal and written communications pertinent to research data collection must be documented in the research record in enough detail to support the data collected, such as actual or attempted contacts, emails, letters, etc. The communications must have appropriate identifiers to verify that they correspond to the specified subject.
e. Laboratory Tests
It is acceptable to write a note that broadly indicates that specimens were obtained for the protocol required tests. All laboratory reports must have the appropriate subject identifiers, date of specimen collection and specify where the test was performed.
A qualified investigator or sub-investigator should review laboratory reports and as documentation of this review, sign/initial and date the laboratory report or note the completion of this review in the research record. A clinical assessment should be documented for out-of-range values along with documentation of any action taken with respect to the assessment.
f. Questionnaires
The actual data on a subject completed questionnaire does not need supporting source documentation because the questionnaire is the source document. However, documentation is required to demonstrate that the protocol required questionnaire was given to the subject in accordance with protocol requirements. This can be accomplished by a checklist or with documentation in the research record indicating the questionnaire was given to the subject to complete on a specified date. This is important in cases where the subject refuses or fails to complete the questionnaire.
If a questionnaire is not personally completed by the subject, documentation should be present to indicate who completed it and the reason it was completed by this individual. If questions are completed by research staff, the staff member should sign/initial and date those questions/sections and document in the research record the method for obtaining the information, e.g., personally interviewed subject.
g. Investigational Drug/Agent
Investigational agents should be dispensed only upon the written order of the investigator or upon the order of a licensed practitioner directly responsible to the investigator as stated on the Form FDA 1572. A copy of the order must be maintained in the research record.
By signing the Form FDA 1572, the investigator has certified that the investigational agent will be administered only to subjects under his/her personal supervision or under the supervision of sub-investigators responsible to him/her. Use of the investigational agent by the subject must be recorded in the research record along with any changes in the study intervention. The following are examples of changes in study intervention:
· Any change in investigational agent status must be documented with sufficient detail to support and provide an explanation for the change.
· Entries regarding dose modifications must include the reason for the change and the actual dosage change.
· Notes regarding the holding of the investigational agent must include the reason for the agent being held.
· Notes regarding the reinstitution of the investigational agent must include the reason for reinstitution of the agent and the dosage.
If the services of the UPMC Investigational Drug Service (IDS) are utilized, IDS will ensure that procurement, receipt, storage, accountability, preparation, dispensing and labeling of investigational agents comply with state, federal (FDA) and institutional (JCAHO) standards for handling such agents.
h. Investigational Device
An investigator shall permit an investigational device to be used only with subjects under the investigator’s supervision. An investigator shall not supply an investigational device to any person not authorized under 21 CFR Part 812 to receive it.
The best strategy for reducing the risk that an investigational device could be improperly dispensed, i.e., whether purposely or inadvertently is for the investigator to closely monitor devices. Investigators are required to maintain complete, current and accurate records of the receipt, use, or disposition of investigational devices. Specific recordkeeping requirements are set forth at 21 CFR 812.140(a).
Upon completion or termination of a clinical investigation or the investigator’s part of an investigation, or at the sponsor’s request, an investigator shall return to the sponsor any remaining supply of the device or otherwise dispose of the device as the sponsor directs.
i. Endpoints
For study defined clinical or laboratory-based endpoints, subject research records must document the specifics of the events or test results as required by the protocol. The results of all diagnostic evaluations needed to substantiate a diagnosis must be included in the research record.