26.1 Source Records and Foundational ALCOA Principles

Source Records and Foundational ALCOA Principles

Clinical trials are conducted to generate scientifically robust, ethically unassailable evidence of therapeutic safety and efficacy. When regulatory agencies such as the US Food and Drug Administration (FDA), European Medicines Agency (EMA), or Pharmaceuticals and Medical Devices Agency (PMDA) evaluate a Marketing Authorization Application (MAA) or New Drug Application (NDA), their inspectors do not inspect the final marketing claims in isolation.

Instead, inspectors reconstruct the entire clinical trial from primary source records. If primary source documents are fragmented, fabricated, illegible, or unverified, the reliability of the conclusions is threatened, regardless of how promising the treatment appears.

Source Data vs. Source Documents (ICH E6(R3))

A foundational source-record distinction is the operational and regulatory definition separating Source Data from Source Documents under ICH E6:

The Relationship Between Source Records and Case Report Forms (CRFs)

Under ICH E6(R3), the Case Report Form (CRF) is defined 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.

Crucially, a CRF can be a source record when data are first captured there. The CRF is a reporting instrument intended to capture transcribed summaries of primary clinical events. However, where the source/data-capture arrangement defines direct capture onto a dedicated paper worksheet or electronic form without prior independent medical charting (e.g., a visual analog pain scale completed directly on an electronic tablet), that specific form is designated as direct data entry or eSource.

Where direct data entry is permitted, the protocol and trial monitoring plan must explicitly document that the CRF page serves as its own primary source document.

Common Examples of Primary Source Documents

In hospital, outpatient, and academic research settings, source documents encompass diverse media:

• Electronic Health Record (EHR) Progress Notes: Attending physician notes, sub-investigator progress narratives, consultation reports, and discharge summaries.
• Nursing Flowsheets & Vital Sign Records: Bedside observation logs, infusion administration records, triage sheets, and timed post-dose monitoring logs.
• Diagnostic Instrument Outputs: 12-lead Electrocardiogram (ECG) rhythm strips, Spirometry pulmonary function curves, Polysomnography traces, and Holter monitor digital recordings.
• Clinical Diagnostic Laboratory Reports: Automated hematology, clinical chemistry, coagulation printouts, and pathology/histology biopsy reports.
• Investigational Pharmacy Records: Master Drug Accountability Logs (DAL), individual Subject Dispensing Logs, temperature monitoring tapes, and compounding records.
• Participant-Generated Records: Paper symptom diaries, electronic patient-reported outcome (ePRO) logs, and quality-of-life survey forms.
• Medical Imaging Files: Digital Imaging and Communications in Medicine (DICOM) optical discs or Picture Archiving and Communication System (PACS) servers for CT scans, MRIs, and PET scans.

The Evolution of ALCOA and ALCOA+ Principles

ALCOA+ is a useful data-integrity mnemonic: attributable, legible, contemporaneous, original and accurate, extended to complete, consistent, enduring and available. Terminology varies; the ECO uses ALCOA+. Do not memorise an invented claim that one universally defined nine-item ALCOA+ regulation exists. Apply the attributes to the data's full lifecycle.

Deep-Dive Analysis of ALCOA+ Elements

Attributable (A)

Every observation, measurement, clinical assessment, and record modification must be traceable to the specific individual who performed the assessment and authored the entry. In paper documentation, attribution requires an identifiable handwritten signature or registered initials accompanied by the calendar date and, where applicable, time where relevant. In electronic systems, attribution is established through unique, non-shared user credentials linked to immutable, time-stamped system logs.

• DOA Log Verification: Verify appropriate authorisation, qualifications and training for the activity; use proportionate delegation documentation rather than assuming every routine-care activity must appear on one log.
• Prohibition of Proxy Documentation: Coordinators or nurses may never sign for a physician, nor may staff enter data using another colleague's login credentials.

Legible (L)

Clinical records must remain decipherable, readable, and comprehensible for decades following trial completion. Illegible handwriting, blurred thermal paper, low-resolution scans, or compressed digital files violate this principle.

• Compliant Error Correction Standards: When an error occurs on a paper source document, the correction must follow strict Good Documentation Practice (GDP):
  1. Draw a single strike-through line through the erroneous text (e.g., 128/80).
  2. Ensure the original erroneous entry remains completely visible and readable.
  3. Enter the correct value adjacent to the strike-through (e.g., 138/80).
  4. Initial and date the correction contemporaneously.
  5. Document a brief reason for the change if the reason is not self-evident (e.g., "transcription error" or "wrong subject chart").
• Strictly Prohibited Practices: Using opaque correction fluid ("white-out"), correction tape, heavy scribbling, obliterating markers, erasable pens, erasers, or overwriting numbers (such as converting a '3' into an '8') is considered potential evidence of fraudulent alteration.

Official sources

Checked October 18, 2026: ICH E6(R3), Principles and Annex 1, ICH E9(R1).