CRA (OPS) cheat sheet

Nuremberg Code (1947) established that voluntary consent of the human subject is absolutely essential and that subjects may withdraw from research without penalty.

Belmont Report (1979) sets three principles - respect for persons, beneficence, justice - operationalized as informed consent, risk/benefit assessment, and fair subject selection.

21 CFR Part 50 governs informed consent and IRB review of human subjects; Part 56 governs IRB organization and operations; Part 312 governs INDs; Part 812 governs IDEs.

ICH E6(R2) IRB/IEC: at least five members, at least one non-scientific member, at least one member independent of the institution, and diversity of sex; if a sex is not represented, the reason must be documented.

Protocol amendments require IRB/IEC approval before implementation, except when the change is necessary to eliminate an immediate hazard to subjects.

Informed consent may not contain exculpatory language through which the subject waives any legal rights or appears to waive them (21 CFR 50.25).

Vulnerable populations (children, prisoners, pregnant women, cognitively impaired, economically disadvantaged) require additional safeguards under 45 CFR 46 Subparts B–D.

21 CFR 312.32: the sponsor must report unexpected suspected serious adverse reactions within 15 calendar days; fatal or life-threatening ones within 7 calendar days.

Feasibility assesses patient population size, competing trials, expected recruitment rate, staff qualifications, facilities, equipment, and predicted time to first patient in.

The pre-study (qualification) visit confirms site capabilities, GCP familiarity, adequate IP storage, and whether all protocol-required procedures can be performed on site.

Form FDA 1572 (Statement of Investigator) must be signed by the PI before the site conducts the trial; it commits the PI to the protocol and to GCP.

Financial disclosure under 21 CFR Part 54 uses Form FDA 3454 (certification of no disclosable interests) or Form FDA 3455 (disclosure of interests) for investigators and sub-investigators.

ICH E6(R2) Section 8.2 lists essential documents required before trial initiation, including protocol signature page, IB, IRB approval, 1572, CVs, licenses, and lab certifications.

Equipment used for study endpoints must be calibrated or qualified with valid certificates; the site must supply normal laboratory reference ranges and applicable lab certifications.

A confidentiality or disclosure agreement is executed with the site before the protocol or other sponsor-confidential information is shared.

IP storage must be secure, access-restricted, and temperature-controlled with continuous monitoring and alarm capability.

The site initiation visit occurs after IRB and regulatory approval and before any subject is screened; sites must not enrol before initiation is complete.

The SIV confirms PI understanding of protocol obligations, IP handling, AE/SAE reporting, source documentation, and the informed consent process.

The Delegation of Authority log lists each staff member and the tasks delegated to them; the PI signs and dates it before those tasks are performed.

A signature and training log must document protocol-, GCP-, and IP-specific training for every staff member before they perform study tasks.

The monitor verifies that the informed consent form version at the site matches the IRB-approved version and that consent precedes any study-specific procedure.

IP receipt, condition, quantity, and storage conditions are verified at initiation before the first dispensing.

The initiation visit report, action items, and follow-up letter are written and filed in the sponsor and site files within SOP-defined timelines.

Emergency contact lists, the protocol deviation plan, and current laboratory normal ranges must be present in the site file at start-up.

Monitoring types include pre-study, site initiation, routine interim, remote, triggered/for-cause, and close-out visits.

SDV compares CRF entries with source documents; ALCOA+ criteria are Attributable, Legible, Contemporaneous, Original, Accurate, plus Complete, Consistent, Enduring, Available.

The monitor verifies eligibility, informed consent, IP accountability, AE/SAE reporting, protocol deviations, and accuracy of transcribed data.

ICH E6(R2) permits risk-based monitoring and reduced on-site SDV when the sponsor documents the rationale and oversight approach.

A monitoring report is written after each visit within the sponsor's defined timeline (commonly 5–10 business days) and filed in the TMF.

Findings are graded by severity and escalated per SOP; major or critical findings require documented corrective and preventive action (CAPA) follow-up.

Source data include medical records, laboratory reports, ECGs, diaries, and progress notes; certified copies may substitute for originals.

The monitor never alters source data; corrections are made by site staff using a single line, initials, date, and reason.

An adverse event is any untoward medical occurrence in a subject administered a study product; it need not have a causal relationship with the product.

SAE criteria: death, life-threatening event, inpatient hospitalization or prolongation, persistent or significant disability, congenital anomaly, or important medical event.

Seriousness (regulatory outcome criteria) is distinct from severity (mild, moderate, severe); a severe headache is not automatically a serious adverse event.

The investigator reports SAEs to the sponsor within 24 hours of becoming aware, per ICH GCP and most protocol requirements.

SUSAR = Serious + Unexpected (not listed in the reference safety information) + Suspected Adverse Reaction (reasonable possibility of causal relationship).

21 CFR 312.32: fatal or life-threatening unexpected suspected adverse reactions are reported to FDA within 7 calendar days; other IND safety reports within 15 calendar days.

Expectedness is judged against the Reference Safety Information (IB or approved labeling), not against an individual investigator's judgment.

Pregnancy in a subject or partner is reported and followed to outcome; it is not itself an adverse event but requires documentation and follow-up.

Accountability records must allow reconciliation of quantities received, dispensed, returned, and destroyed, with lot/batch numbers and expiry dates.

IP is stored per protocol and IB under monitored temperature with restricted access; excursions are documented, assessed, and reported to the sponsor.

Only staff listed on the Delegation of Authority log may dispense IP, and only to subjects who meet all eligibility criteria.

Dispensing records capture date, subject identifier, kit or container number, quantity dispensed, and the initials of the dispensing staff member.

Emergency unblinding follows the protocol-defined procedure, is documented with the reason, and the sponsor is notified promptly.

Used, expired, or recalled IP is quarantined and returned or destroyed only after written sponsor authorization and per local regulations.

The monitor verifies that kit allocations match the randomization schedule and that no unauthorized unblinding has occurred.

A query is raised when data are missing, inconsistent, or out of range; it must be answered with source-supported information and closed with documented resolution.

Query lifecycle is open, answered by the site, reviewed by data management, and closed; each step carries user identity, date/time, and reason in the audit trail.

21 CFR Part 11 requires validated systems, secure access controls, audit trails, electronic signatures, and record retention capability for eCRFs.

Corrections use a single line through the error, the correct entry, initials, date, and where required a reason; entries are never obliterated.

MedDRA is used to code adverse events and medical history; WHO Drug (or equivalent) is used to code concomitant medications.

Database lock occurs after all queries are resolved and data are cleaned; post-lock changes require documented authorization and an audit trail entry.

Source data review evaluates source documentation quality and completeness, whereas source data verification compares source to CRF.

The close-out visit is conducted after the last subject completes, data are cleaned, and outstanding queries are resolved.

The monitor verifies final IP accountability, return or destruction documentation, and reconciliation of all used and unused kits.

Confirm all SAEs and AEs are reported and followed to resolution or stabilization, and that the site has notified the IRB/IEC of study completion.

Essential documents are collected for the investigator and sponsor files, and eCRF access is deactivated at database lock.

The close-out report and letter document outstanding issues, final drug accountability, and archiving arrangements.

21 CFR 312.62(c) requires records to be retained 2 years after the marketing application is approved or 2 years after the investigation is discontinued.

ICH E6(R2) requires retention for at least 2 years after the last marketing approval in an ICH region or 2 years after formal discontinuation.

Financial reconciliation and final payment follow the executed contract, and equipment is returned or its disposition documented.

Essential documents are records that individually and collectively permit evaluation of trial conduct and the quality of the data produced (ICH E6 Section 8).

The sponsor maintains the Trial Master File and the site maintains the Investigator Site File; both must be contemporaneous and complete.

ICH E6(R2) requires records be retained for at least 2 years after the last approval of a marketing application or 2 years after formal discontinuation of the trial.

21 CFR 312.62(c) requires 2 years after IND withdrawal or marketing approval; device records follow 21 CFR 812.140, and local or institutional rules may be longer.

Records must be retrievable and available for inspection by regulatory authorities, IRBs, and monitors throughout the full retention period.

Electronic records must comply with 21 CFR Part 11: validated systems, audit trails, access control, and backup and restore capability.

If the PI leaves the site, custody of records transfers to another responsible party with documented notification to the sponsor.

Records may not be destroyed without documented sponsor authorization and compliance with institutional and local regulatory requirements.