ACRP-CP cheat sheet

Phase I trials typically enroll 20–80 participants to characterize safety, tolerability, and pharmacokinetics; Phase II enrolls roughly 100–300 to explore efficacy and dose; Phase III enrolls about 300–3,000 for confirmatory evidence; Phase IV occurs after approval.

Type I error (alpha) is the probability of rejecting a true null hypothesis; Type II error (beta) is failing to reject a false null hypothesis; power equals 1 minus beta and is conventionally set at 80–90%.

Sample size grows with larger variance, smaller treatment effect, higher power, and lower alpha; the required evaluable N is divided by (1 minus the expected dropout rate) to get the number to enroll.

Superiority designs test whether a difference exists; non-inferiority designs test whether the new treatment is no worse than control by a pre-specified margin, and regulators usually require both intention-to-treat and per-protocol analyses.

Randomization approaches include simple, permuted block, stratified, and covariate-adaptive (minimization); allocation concealment prevents site staff from predicting the next assignment.

Blinding levels run from open-label (no masking) to single-blind (participant or assessor), double-blind (participant, investigator, and often sponsor), and triple-blind (analysts added).

Intention-to-treat analyzes all randomized participants as assigned and preserves randomization but may dilute effect; per-protocol analyzes only compliant participants and is more susceptible to attrition bias.

Major bias categories are selection (allocation), performance, detection (assessment), attrition, and reporting; each is countered by concealment, blinding, intention-to-treat, and pre-registration of the analysis plan.

Interim analyses use alpha-spending functions: O'Brien-Fleming is conservative early and preserves alpha for the final analysis, while Pocock spends alpha more evenly across looks; an independent data monitoring committee reviews unblinded results.

The Nuremberg Code (1947) established voluntary consent as fundamental; the Declaration of Helsinki (1964, World Medical Association) governs physician-conducted research; the Belmont Report (1979) set out respect for persons, beneficence, and justice.

The US Common Rule (45 CFR 46) requires IRB review, informed consent, and additional protections for pregnant women, prisoners, children, and persons with impaired decision-making capacity.

IRB composition requirements: at least five members, at least one whose primary concerns are non-scientific, at least one not affiliated with the institution, and diversity of race, gender, and cultural background.

Expedited review applies only to research posing no more than minimal risk within published federal categories; anything greater than minimal risk requires a convened full-board review.

Serious adverse event criteria: death, life-threatening event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability, congenital anomaly, or an important medical event requiring intervention to prevent one of these outcomes.

ICH E2A timelines: unexpected suspected serious adverse reactions that are fatal or life-threatening are reported to regulators within 7 calendar days; other SUSARs within 15 calendar days.

Children generally provide written assent from about age 7 using age-appropriate language, while a parent or legally authorized representative provides permission; assent is not legally binding consent.

An unanticipated problem involving risks to subjects or others (UPIRSO) is not necessarily a serious adverse event; it is unexpected, related or possibly related to participation, and suggests increased risk, and it is reported to the IRB on institutional timelines.

Therapeutic misconception is a participant's belief that research is individually tailored treatment; the consent discussion must distinguish research aims from personal clinical care.

In the US an IND must be filed before human testing and takes effect 30 days after FDA receipt unless FDA imposes a clinical hold; the EU uses a Clinical Trial Application under Regulation 536/2014 submitted through CTIS.

US marketing applications: 505(b)(1) contains full nonclinical and clinical data; 505(b)(2) relies partly on published literature or prior FDA findings; ANDA 505(j) is the abbreviated generic bioequivalence pathway.

FDA expedited programs: Fast Track for serious conditions with unmet need; Breakthrough Therapy for preliminary clinical evidence of substantial improvement; Priority Review shortens the goal to 6 months versus 10; Accelerated Approval uses a surrogate endpoint.

Orphan Drug Act designation covers US diseases affecting fewer than 200,000 patients and grants 7 years of marketing exclusivity plus tax credits and fee waivers; EU orphan exclusivity runs 10 years.

The first-in-human starting dose (maximum recommended starting dose) is derived from the animal no-observed-adverse-effect level converted to human equivalent dose and divided by a default safety factor of 10.

ICH mapping: E6 = GCP; E2A = clinical safety reporting; E8 = general trial considerations; E9 = statistical principles; E10 = control group selection; M4 = Common Technical Document (Modules 1–5).

US exclusivity periods: 5 years for a new chemical entity, 3 years for new clinical investigations, 12 years for reference biologics; patent term runs 20 years from filing.

Post-approval obligations include Phase IV commitments, REMS for serious safety risks, periodic safety reports (PSUR/PBRER), and pharmacovigilance signal detection.

The Pediatric Research Equity Act requires pediatric assessments for drugs with potential pediatric use; the EU equivalent is the Paediatric Investigation Plan agreed with EMA's pediatric committee.

ICH E6(R2) added quality management, risk-based monitoring, and explicit sponsor oversight of computerized systems and contracted CROs to the original 1996 GCP framework.

Investigator qualifications rest on education, training, and experience, documented by a current CV, GCP training record, professional license, and delegation log.

Essential documents listed in ICH E6 Section 8 are generated before, during, and after the trial to demonstrate compliance and data quality, and are retained for the applicable regulatory period.

ALCOA-C: attributable, legible, contemporaneous, original, accurate, complete; corrections are made with a single line, dated and initialed, with the original entry still readable and an explanation added.

A protocol deviation is any unintended departure from the protocol; an important deviation (violation) affects participant safety, rights, or data integrity and requires prompt reporting to sponsor and IRB.

Visit types: pre-study qualification visit, site initiation visit, routine monitoring visit, triggered or for-cause visit, and close-out visit; source data verification compares source records with the CRF.

Sponsor responsibilities include quality assurance and quality control, investigational product supply, ongoing safety evaluation and reporting, monitoring, and audit; the investigator cannot delegate overall responsibility.

An audit is an independent systematic examination by the sponsor or its designee; an inspection is a review by a regulatory authority and may be routine or for-cause.

Informed consent must be obtained before any study-specific procedure and documented with the signature and date of the participant or legally authorized representative and of the person conducting the discussion.

Typical startup sequence: feasibility questionnaire, confidentiality agreement, site evaluation visit, budget and contract negotiation, IRB or ethics submission, site initiation visit, then first participant enrolled.

A study budget separates per-participant payments, procedure pass-through costs, startup fees, institutional overhead, and invoice timing; payment terms are fixed in the clinical trial agreement.

Screen failure rate equals screen failures divided by total participants screened; enrollment targets are grossed up for both screen failure and post-enrollment dropout.

The delegation log names each person authorized to perform specific trial tasks, with start and end dates and the signatures of the investigator and each delegate.

Investigational product handling requires documented receipt, continuous temperature monitoring, restricted access storage, dispensing records per participant, and reconciliation, return, or destruction at close-out.

The investigator site file mirrors the sponsor trial master file index; the sponsor maintains the TMF, increasingly as an audit-trailed eTMF with documented filing and completeness checks.

Records retention under 21 CFR 312.62: at least 2 years after a marketing application is approved, or 2 years after the IND is withdrawn if the drug is not approved.

Recruitment draws on chart review, institutional databases, IRB-approved advertising, and referral networks; retention uses visit reminders, flexible scheduling, and reimbursement of out-of-pocket costs.

Close-out includes the final monitoring visit, drug reconciliation, resolution of outstanding queries, record archiving, notification of the IRB, and return or destruction of supplies.

CDISC standards: CDASH governs data acquisition at the CRF level, SDTM structures tabulation datasets for submission, ADaM provides analysis-ready datasets with traceability, and Define-XML carries the metadata.

Common SDTM domains include DM (demographics), AE (adverse events), LB (laboratory), VS (vital signs), EX (exposure), CM (concomitant medications), and MH (medical history).

21 CFR Part 11 requires validated systems, secure and role-based access, computer-generated audit trails, and electronic signatures composed of two distinct components tied to the signer.

Database lock follows query resolution, SAE reconciliation, medical coding, and final data review; any change after hard lock requires a documented unlock and relock procedure.

Edit checks are programmed validation rules for range, consistency, cross-form logic, and missing values; they generate queries, and query metrics track cleaning progress before lock.

Medical coding uses MedDRA for adverse events and medical history and WHODrug for concomitant medications; the dictionary version is fixed per study and documented.

SAE reconciliation compares the pharmacovigilance safety database with the clinical database to resolve differences in event term, dates, severity, and causality before analysis.

Data privacy relies on HIPAA authorization or an approved waiver in the US and a lawful basis under GDPR in the EU; de-identification may use Safe Harbor removal of 18 identifiers or expert determination.

Audit trails must record who changed what, when, and why, and must not be editable or deletable by any user, including administrators.

Research misconduct is defined as fabrication, falsification, or plagiarism in proposing, performing, or reviewing research; honest error and differences of scientific opinion are excluded and require institutional investigation procedures.

Financial disclosure under 21 CFR Part 54 covers payments, equity interests, and intellectual property; significant interests are managed, reduced, or eliminated by the institution or FDA.

The principal investigator retains ultimate responsibility for site conduct, participant safety, and data integrity, including work performed by delegated staff and sub-investigators.

Quality improvement tools include root cause analysis, the five whys, the fishbone (Ishikawa) diagram, and plan-do-study-act cycles applied to recurring site or data problems.

Leadership styles relevant to trials: transactional leadership emphasizes compliance and milestones, transformational leadership builds vision and development, and situational leadership adapts to team readiness.

Ethical leadership requires transparent reporting, escalation of suspected misconduct, and protection of whistleblowers from retaliation under institutional and federal policy.

Mentoring develops competency through structured feedback and role modeling; effective delegation matches task complexity to the delegate's documented training and experience.

Key trial roles: sponsor, CRO, principal investigator, sub-investigator, clinical research coordinator, monitor/CRA, data manager, biostatistician, medical monitor, and regulatory affairs specialist.

SBAR (Situation, Background, Assessment, Recommendation) structures escalations, and a written follow-up within 24 hours of a verbal safety communication preserves a contemporaneous record.

Consent communication uses plain language at roughly a 6th–8th grade reading level, teach-back verification of understanding, and certified translation with back-translation for non-English speakers.

Escalation pathways state who is contacted, through which channel, and within what timeframe for safety events, protocol questions, and data queries.

Investigator meetings align sites on protocol procedures, safety reporting, data entry rules, and monitoring expectations; attendance and training completion are documented.

Cross-cultural communication accounts for health literacy, language proficiency, cultural norms, and family authority structures that shape participant decisions.

Conflict modes are avoidance, accommodation, competition, compromise, and collaboration; collaboration is generally preferred for cross-functional trial decisions because it preserves long-term working relationships.

Communication records include call logs, meeting agendas and minutes, and confirmatory emails; undocumented verbal agreements cannot be substantiated during an audit or inspection.

Effective feedback is specific, timely, behavior-focused, and actionable; performance reviews are linked to documented competency, training records, and observed deliverables.

Multidisciplinary meetings such as safety review and blinded data review require a defined agenda, quorum, and minutes distributed to attendees and archived in the TMF.