Documents and procedures

For a trial to be of a high scientific and ethical standard, it is necessary to record it and report it with precision and clarity. Good documentation practice streamlines the conduct of a trial and ensures that the study results are credible and valid. The objective of documentation should be that a person not involved in the trial can audit the trial and reconstruct the course of events just by going through its documents. This objective protects both the study investigators and the participants.

Key attributes for good documentation were first described by the United States Federal Drug Administration agency in the form of ‘ALCOA standard’ – an acronym for Attributable, Legible, Contemporaneous, Original and Accurate. ALCOA was further expanded to ALCOA plus with the addition of Complete, Consistent, Enduring and Available.

Study documentation should be:
Attributable: It is clear who provided the information. The identify of anyone who creates or modifies a record should be documented.
Legible: It is essential that each word able to be read.
Contemporaneous: Study data must be entered at the same time when the activity is being performed. In addition, the date and time of documentation must also be documented.
Original: Paper source documents need to be preserved and kept in their original form.
Accurate: The most important aspect of data integrity is accuracy. The source must be accurate and free of errors.

Standard document terminology
Document names can be confusing, so using a standard set of terms is recommended. A key set of document names is provided in Good Clinical Practice (GCP) guidelines. The International Council for Harmonisation (ICH), in its GCP guidelines E6 R2, defines these terms as follows.

All records, in any form (including, but not limited to, written, electronic, magnetic, and optical records, and scans, x-rays and electrocardiograms) that describe or record the methods, conduct, and/or results of a trial, the factors affecting a trial and the action taken. (ICH-GCP, E6 R2, 1.22)

Documents that individually and collectively permit evaluation of the conduct of a study and the quality of data produced. (ICH-GCP, E6 R2, 1.23)

All information in the original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents, original records or certified copies. (ICH-GCP, E6 R2, 1.51)

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, the laboratories and medico-technical departments involved in the clinical trial. (ICH GCP E6 R2, 1.52)

Detailed written instructions to achieve uniformity of the performance of a specific function. (ICH-GCP, E6 R2, 1.55).

An SOP guides the researcher about what to do, how to do it and what is expected of them. It provides direct instruction to the researcher and maintains consistency between different researchers involved with the conduct and reporting of the clinical trial. SOPs should be written in a simple and sequential format so that the researcher works in an orderly fashion. The SOPs should have an inbuilt system for periodic review, approval and control of their circulation. The SOP must be reviewed and tested before implementation.

A printed, optical, or electronic document designed to record all of the information to be reported to the sponsor on each trial subject. (ICH-GCP, E6 R2, 1.11)

Paper based CRFs have been the traditional way of data collection and may still work well when studies are small. However, when studies are large, multicentre and global, electronic CRF (eCRF) is preferable. Electronic Data Capture (EDC) systems are now being used commonly for clinical trials. EDC systems provide a graphical user interface for data entry, hence decreasing the time and chances of errors in data collection. A validation component of EDC checks the user data and the majority of data cleaning activities (deleting or correcting corrupt or inaccurate data) take place during the completion of the eCRFs, thus reducing the time and effort required by data management personnel. There is also a reporting tool for analysis of the collected data in the EDC. With eCRF clean data is obtained quickly, resulting in timely database lock, faster regulatory submission, and quick approval.

TRIAL MASTER FILE is a collection of Essential Documents that GCP requires must be present before, during and after the trial. It should be designed as a stand-alone document that would not require any additional explanation and would be sufficient to reconstruct the trial. It should have all the protocols, source data, key decisions, and necessary approvals for the trial. There is usually a separate sponsor and an investigator TMF, kept by the sponsor and at the investigation site. The documents in these files may vary. The electronic version of TMF is referred to as eTMF. Essential documents are grouped in TMF in three sections according to the stage of the trial during which they are applied:

  1. Before the commencement of the clinical phase of the trial.
  2. During the clinical trial.
  3. After the completion or termination of the trial.

ICH-GCP E6 R2 Section 8, gives a comprehensive list of essential documents which should be present in a Trial Master File, the main purpose of each documents and its location in investigator/institutional file and/or sponsor file is also indicated.

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