CCRC Exam Prep 9 Week Study Plan

Week 1, Part I: Scientific Concepts and Research Design

Difficulty: Heavy

What it covers:

• The foundational scientific architecture of every clinical trial: how a research question becomes a testable hypothesis, how trials are phased, and how design choices either protect or destroy internal validity

• PICOT question framing and FINER quality checks, plus translation into null and alternative hypotheses

• Phase 1 through Phase 4 trial purpose, sample size, and regulatory significance

• Trial endpoints (primary, secondary, exploratory) and why a study is only statistically powered for its primary endpoint

• Randomized controlled trial methodology, including crossover, parallel, and factorial designs

• Adaptive and master protocol architectures (basket, umbrella, platform) and the pre-specification rules that separate valid adaptation from data dredging

• Blinding (single, double, triple, open) and allocation concealment as mechanically distinct safeguards

• Bias and confounding threats, alpha/beta/power/effect size/sample size relationships, and inclusion/exclusion criteria as the balance between generalizability and scientific precision

• Print: 1 Mind Map, 3 Comparison Charts, 2 Cornell Notes pages

Study Tasks

☐ Read the Study Guide first. Complete the High-Yield Objectives, Key Terms and Definitions, and Concept Overview sections before opening the chapter.

☐ Highlight as you read. Follow the Made Easy Highlighting System

☐ Lock in PICOT and FINER before moving past hypothesis writing. PICOT (Population, Intervention, Comparator, Outcome, Timeframe) gives you the structure. FINER (Feasible, Interesting, Novel, Ethical, Relevant) is the quality check. Every well-formed clinical research question runs through both. Then convert the question to a null hypothesis (no difference) and an alternative hypothesis (a real difference exists). The exam tests this translation directly.

☐ Memorize the four phases of trials cold: Phase 1 (safety, dose-finding, ~20 to 80 healthy volunteers or patients), Phase 2 (efficacy and side effects, ~100 to 300 patients), Phase 3 (confirmatory efficacy and safety, ~300 to 3,000+ patients, the pivotal trial supporting NDA/BLA), Phase 4 (post-marketing surveillance after approval). Be able to match each phase to its regulatory submission and its typical sample size.

☐ Build a clean one-page summary of bias types and their countermeasures. Selection bias is controlled by randomization and allocation concealment. Performance and detection bias are controlled by blinding. Attrition bias is controlled by intention-to-treat analysis. Reporting bias is controlled by pre-specification and registration. The exam pairs a bias with a wrong countermeasure as the distractor. You need the right pairing automatic.

☐ Understand the four-way relationship among alpha, beta, power, and sample size. Alpha is the false-positive rate (typically 0.05). Beta is the false-negative rate (typically 0.20). Power equals 1 minus beta (typically 0.80). Sample size rises as effect size shrinks, variance grows, alpha tightens, or power demands climb. Be able to predict the direction of change to sample size when any of these inputs moves.

☐ Complete the Practice Questions for Part I in your quiz bank. Review every rationale, correct and incorrect.

How to Use Your Templates

☐ Mind Map: Central node = Scientific Concepts and Research Design. Main branches: Research Question (PICOT, FINER) → Hypothesis Framing (null, alternative) → Trial Phases 1 to 4 → RCT Designs (parallel, crossover, factorial) → Adaptive & Master Protocols (basket, umbrella, platform) → Blinding & Allocation Concealment → Bias & Confounding → Endpoints (primary, secondary, exploratory) → Statistical Power (alpha, beta, effect size, sample size) → Inclusion/Exclusion Criteria.

Comparison Charts:

☐ Chart 1, Phase 1 vs. Phase 2 vs. Phase 3 vs. Phase 4: Primary objective, typical sample size, population type (healthy volunteers vs. patients), duration, regulatory submission supported, and pre- vs. post-approval status.

☐ Chart 2, Parallel vs. Crossover vs. Factorial Design: How subjects are assigned to interventions, what each design controls for, washout requirements, carryover risk, statistical efficiency, and a representative clinical example.

☐ Chart 3, Bias Types and Countermeasures: Selection bias, performance bias, detection bias, attrition bias, reporting bias. For each: where it enters the trial, what it distorts, and the specific design feature that controls it (randomization, blinding, allocation concealment, ITT analysis, pre-specification).

Cornell Notes:

☐ Page 1, Cue questions: What are the five elements of PICOT, and how does FINER refine a PICOT question before it becomes a protocol? What is the difference between a null hypothesis and an alternative hypothesis, and which one does the statistical test actually reject?

☐ Page 2, Cue questions: How are blinding and allocation concealment mechanically different, and which bias does each control? What happens to required sample size when effect size shrinks, when alpha tightens to 0.01, and when power rises from 0.80 to 0.90?

Week 2, Part II: Ethical Principles, IRB Oversight, and Human Subjects Protection

Difficulty: Heavy

What it covers:

• The historical and regulatory framework that defines who research participants are and how they must be protected

• The ethics lineage from the Nuremberg Code (1947) through the Declaration of Helsinki (1964) to the Belmont Report (1979), and what each document added

• The three Belmont principles (Respect for Persons, Beneficence, Justice) applied to protocol, recruitment, and consent decisions

• Landmark case failures (Tuskegee, Willowbrook, and others) and the regulations each produced

• Vulnerable populations under 45 CFR 46 Subparts B (pregnant women, fetuses, neonates), C (prisoners), and D (children), and the additional protections each requires

• Conflict of interest (financial, intellectual, personal): identification, disclosure, management, mitigation

• IRB composition, quorum, and authority to approve, modify, suspend, or terminate research

• Exempt, expedited, and full board review pathways, and the seven criteria for IRB approval under 45 CFR 46.111

• Continuing review timelines, reportable events, single IRB review models, and international ethics committee equivalents in multinational trials

Print: 1 Mind Map, 3 Comparison Charts, 2 Cornell Notes pages

Study Tasks

☐ Read the Study Guide first. Complete the High-Yield Objectives, Key Terms and Definitions, and Concept Overview sections before opening the chapter.

☐ Highlight as you read using the Made Easy Highlighting System (Red, Purple, Blue, Orange, Green, Yellow as defined in Week 1).

☐ Lock down the ethics lineage in chronological order before anything else. Nuremberg Code (1947): first formal statement that voluntary consent is absolutely essential, written in response to Nazi medical experiments. Declaration of Helsinki (1964, periodically revised): physician-led, broader scope, addresses risk-benefit, vulnerability, and trial registration. Belmont Report (1979): distills ethics into three principles (Respect for Persons, Beneficence, Justice) and directly underpins 45 CFR 46. Every exam question on research ethics history wants you to know which document said what and when.

☐ Memorize the three Belmont principles and their practical applications. Respect for Persons drives informed consent and the additional protections for vulnerable populations. Beneficence drives risk-benefit analysis and the obligation to maximize benefit and minimize harm. Justice drives equitable subject selection: the people who bear research risks should also benefit from research advances. Scenario questions almost always pit two principles against each other and ask which guides the response.

☐ Map the landmark cases to their regulatory consequences. Tuskegee (1932 to 1972, untreated syphilis in Black men): drove the National Research Act of 1974, the National Commission, and the Belmont Report. Willowbrook (hepatitis studies in institutionalized children): drove Subpart D protections for children. Nuremberg trials: drove the Nuremberg Code. Henrietta Lacks (HeLa cells): drove modern tissue-use consent practices. Tearoom Trade and other behavioral studies: drove expansion of IRB review to social and behavioral research. Each pairing is high-yield.

☐ Master 45 CFR 46 Subparts B, C, and D. Subpart B (pregnant women, fetuses, neonates) requires that risks be minimized, that the pregnant woman consent, and that for greater-than-minimal-risk research the father generally must also consent unless specific exceptions apply. Subpart C (prisoners) requires a prisoner representative on the IRB and limits permissible research categories. Subpart D (children) defines minimal risk, minor increase over minimal risk, and the four research categories under §46.404 to §46.407 with their parental permission and child assent requirements.

☐ Memorize the three IRB review pathways and the seven criteria for IRB approval under 45 CFR 46.111: risks minimized, risks reasonable in relation to benefits, equitable subject selection, informed consent sought and documented, adequate data monitoring, privacy and confidentiality protected, and additional safeguards for vulnerable populations. Exempt review applies to specific categories under §46.104 (most often education research, anonymous surveys, certain secondary research). Expedited review applies to minimal-risk research in defined categories. Full board review covers everything else.

☐ Complete the Practice Questions for Part II in your quiz bank. Review every rationale, correct and incorrect.

How to Use Your Templates

☐ Mind Map: Central node = Ethical Principles, IRB Oversight, and Human Subjects Protection. Main branches: Ethics History (Nuremberg, Helsinki, Belmont) → Belmont Principles (Respect for Persons, Beneficence, Justice) → Landmark Cases & Resulting Protections → Common Rule (45 CFR 46) → Subparts B, C, D & Vulnerable Populations → Conflict of Interest (financial, intellectual, personal) → IRB Composition, Quorum & Authority → Review Pathways (exempt, expedited, full board) → Seven Criteria for IRB Approval (§46.111) → Continuing Review & Reportable Events → Single IRB Models & International Equivalents.

Comparison Charts:

☐ Chart 1, Nuremberg Code vs. Declaration of Helsinki vs. Belmont Report: Year, issuing body, central contribution, scope (research only vs. broader), how each addresses consent and vulnerability, and what regulation each ultimately produced.

☐ Chart 2, Exempt vs. Expedited vs. Full Board Review: Risk level required, type of research permitted, who reviews (chair/designee vs. convened IRB), continuing review requirement, and a representative protocol example for each.

☐ Chart 3, Subpart B vs. Subpart C vs. Subpart D: Population protected, definition of permissible research, additional consent or assent requirements, special IRB membership requirements (if any), and one classic example of a study that triggers each Subpart.

Cornell Notes:

☐ Page 1, Cue questions: What did the Nuremberg Code, the Declaration of Helsinki, and the Belmont Report each contribute that the prior document did not? How do the three Belmont principles (Respect for Persons, Beneficence, Justice) map to specific protocol decisions in recruitment, consent, and risk-benefit analysis?

☐ Page 2, Cue questions: What are the seven criteria for IRB approval under 45 CFR 46.111, and which criterion is most commonly cited when an IRB requires modification? What are the additional protections required under Subparts B, C, and D, and what scenario triggers each?

Week 3, Part III: Informed Consent and Participant Safety

Difficulty: Heavy, High Yield

What it covers:

• The single most-tested domain on the CCRC: the informed consent process and the safety reporting workflow that protects enrolled subjects

• Basic and additional elements of informed consent under 45 CFR 46.116 and ICH GCP, and which elements must appear in every consent document

• The Subject's Bill of Rights as a separate document and the coordinator's role in facilitating (not replacing) the consent discussion with the investigator

• Decision-making capacity assessment and the surrogate consent hierarchy when capacity is impaired

• Pediatric assent by age, cognitive development, and risk category, paired with parental permission under Subpart D

• Short-form consent and IRB-approved translated consent for non-English speakers, including the impartial witness requirement

• Re-consent triggers, the re-consent process, and version tracking

• Adverse event (AE) and serious adverse event (SAE) classification, the SAE reporting workflow to sponsor and IRB, and timelines

• Unanticipated Problems Involving Risks (UPIRSO), pregnancy reporting, voluntary and investigator-initiated withdrawals, and communication of new safety information to enrolled participants

Print: 1 Mind Map, 4 Comparison Charts, 3 Cornell Notes pages

Study Tasks

☐ Read the Study Guide first. Complete the High-Yield Objectives, Key Terms and Definitions, and Concept Overview sections before opening the chapter.

☐ Highlight as you read using the Made Easy Highlighting System (Red, Purple, Blue, Orange, Green, Yellow as defined in Week 1).

☐ Memorize the basic and additional elements of informed consent under 45 CFR 46.116 cold. The eight basic elements include: a statement that the study involves research, description of procedures, foreseeable risks, expected benefits, alternatives, confidentiality protections, compensation for injury, and contact information. The six additional elements (required only when applicable) include: unforeseeable risks, circumstances of withdrawal, new findings, costs to subject, consequences of early withdrawal, and approximate number of subjects. The exam will give you a consent excerpt and ask which element is missing. You have to know the list.

☐ Master the distinction between informed consent as a process and the consent document. The process is a conversation with the investigator (the coordinator facilitates but does not replace it), conducted in a private, unrushed setting, in language the subject understands, with time for questions. The document is the artifact of that conversation. The Subject's Bill of Rights (required in California and by many IRBs) is a separate document that summarizes participant rights in plain language and accompanies, but does not replace, the consent form.

☐ Lock down the surrogate consent hierarchy when a subject lacks capacity. State law varies, but the general order is: court-appointed guardian, durable power of attorney for healthcare, spouse, adult child, parent, adult sibling, then other adult relative. Capacity is decision-specific and assessed in the moment: the subject must understand, appreciate, reason, and communicate a choice. A diagnosis alone (dementia, psychiatric illness) does not equal lack of capacity.

☐ Master pediatric assent under Subpart D. Children old enough to understand (typically age 7 and up, though IRBs set the threshold) must provide assent in addition to parental permission. Both parents must sign for greater-than-minimal-risk research with no prospect of direct benefit (§46.406 and §46.407 categories), unless one parent is deceased, unknown, incompetent, not reasonably available, or does not have legal custody. Know the §46.404 to §46.407 categories: minimal risk, minor increase over minimal risk with direct benefit, minor increase over minimal risk without direct benefit (requires special review), and not otherwise approvable (federal panel review).

☐ Memorize the SAE definition and reporting workflow. An SAE meets at least one of six criteria: death, life-threatening, inpatient hospitalization or prolongation, persistent or significant disability, congenital anomaly, or important medical event requiring intervention to prevent the above. The sponsor must be notified within 24 hours of the site becoming aware. The IRB must be notified per protocol and IRB policy (usually within 10 working days for unanticipated problems). Sponsors must report IND safety reports (21 CFR 312.32): fatal or life-threatening suspected adverse reactions within 7 calendar days, others within 15 calendar days. These numbers are tested directly.

☐ Complete the Practice Questions for Part III in your quiz bank. Review every rationale, correct and incorrect.

How to Use Your Templates

☐ Mind Map: Central node = Informed Consent and Participant Safety. Main branches: Informed Consent Process vs. Documentation → Basic Elements (8) → Additional Elements (6) → Subject's Bill of Rights → Capacity Assessment & Surrogate Hierarchy → Pediatric Assent & Parental Permission (Subpart D §46.404 to §46.407) → Short-Form Consent & Translated Consent (Impartial Witness) → Re-Consent Triggers & Version Tracking → AE vs. SAE Classification → SAE Reporting Workflow & Timelines → UPIRSO → Pregnancy Reporting → Withdrawals (voluntary vs. investigator-initiated).

Comparison Charts:

☐ Chart 1, Basic vs. Additional Elements of Informed Consent: The 8 basic elements always required, the 6 additional elements required when applicable, and one scenario triggering each additional element.

☐ Chart 2, AE vs. SAE vs. UPIRSO: Definition, the six SAE criteria, examples that qualify and don't qualify, reporting recipient (sponsor, IRB, FDA), and reporting timeline for each.

☐ Chart 3, Pediatric Assent Categories under Subpart D (§46.404 to §46.407): Risk level, prospect of direct benefit, parental permission requirement (one vs. two parents), child assent requirement, and IRB review level required for each category.

☐ Chart 4, Long-Form vs. Short-Form Consent: When each is used, who signs (subject, impartial witness, person obtaining consent), translation requirements, IRB approval needed, and what makes a consent process valid for a non-English speaker.

Cornell Notes:

☐ Page 1, Cue questions: What are the eight basic and six additional elements of informed consent under 45 CFR 46.116, and which elements are required only when applicable? What is the difference between the informed consent process, the consent document, and the Subject's Bill of Rights, and what is the coordinator's role in each?

☐ Page 2, Cue questions: What are the four components of decision-making capacity, and what is the general surrogate consent hierarchy when capacity is impaired? What are the four pediatric research categories under §46.404 to §46.407, and what parental permission and child assent requirements apply to each?

☐ Page 3, Cue questions: What are the six criteria that define a serious adverse event, and what are the reporting timelines to sponsor, IRB, and FDA (IND safety reports under 21 CFR 312.32)? What is an Unanticipated Problem Involving Risks to Subjects or Others, and how does the reporting requirement differ from a standard SAE?

Week 4, Part IV: Product Development and Regulation

Difficulty: Heavy

What it covers:

• The regulatory landscape that defines what your trial actually is: drug, biologic, device, or combination product, and what review pathway each follows

• The drug development lifecycle from discovery through Phase 4 surveillance, and the regulatory submission required at each transition

• Medical device classification (Class I, II, III) by risk and the corresponding marketing pathway: 510(k), De Novo, PMA, HDE

• Investigational New Drug (IND) application components, the 30-day FDA review window, and the difference between an active IND and a clinical hold

• Investigational Device Exemption (IDE), Significant Risk (SR) vs. Non-Significant Risk (NSR) device studies, and the correct review path for each

• FDA centers and what each regulates: CDER (drugs), CBER (biologics, vaccines, gene/cell therapy), CDRH (devices), CTP (tobacco products)

• Common decision letters: refuse-to-file, complete response, approval, clinical hold

• Key US regulatory citations: 21 CFR Part 50 (consent), Part 56 (IRBs), Part 312 (IND), Part 812 (IDE), and the Common Rule (45 CFR 46)

• ICH GCP E6(R3): the 2025 risk-based, proportionate, technology-neutral revision

• Combination products, the BLA pathway for biologics, and expedited programs (Orphan Drug, Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review, RMAT)

Print: 1 Mind Map, 4 Comparison Charts, 3 Cornell Notes pages

Study Tasks

☐ Read the Study Guide first. Complete the High-Yield Objectives, Key Terms and Definitions, and Concept Overview sections before opening the chapter.

☐ Highlight as you read using the Made Easy Highlighting System (Red, Purple, Blue, Orange, Green, Yellow as defined in Week 1).

☐ Build a one-page reference card for the four key US regulatory citations and what each governs. 21 CFR Part 50: protection of human subjects (informed consent rules for FDA-regulated research). 21 CFR Part 56: Institutional Review Boards (IRB composition, function, recordkeeping for FDA-regulated research). 21 CFR Part 312: Investigational New Drug application. 21 CFR Part 812: Investigational Device Exemption. The Common Rule (45 CFR 46) governs federally funded human subjects research broadly. The exam will give you a research scenario and ask which Part applies. Mix-ups between 21 CFR (FDA-regulated) and 45 CFR 46 (Common Rule) are the most common distractor.

☐ Lock down medical device classification and marketing pathways. Class I (low risk, general controls): most exempt from premarket review, examples include bandages and exam gloves. Class II (moderate risk, special controls): most cleared via 510(k) by demonstrating substantial equivalence to a predicate, examples include infusion pumps. Class III (high risk, life-sustaining or implantable): requires Premarket Approval (PMA), examples include heart valves and implantable defibrillators. The De Novo pathway is for novel low-to-moderate risk devices without a predicate. The Humanitarian Device Exemption (HDE) is for devices treating conditions affecting fewer than 8,000 US patients annually.

☐ Memorize the IND timeline. After IND submission, the FDA has 30 calendar days to review. If the FDA does not respond, the IND becomes effective on day 30 (a "safe harbor" effective date). If the FDA places the IND on clinical hold, clinical studies cannot proceed until the hold is resolved. An IND is required before administering an investigational drug to humans in the US, with limited exceptions (some Phase 1 academic studies, expanded access).

☐ Master the SR vs. NSR distinction for devices. A Significant Risk device study (implants, devices that support life, devices substantially important in diagnosis or treatment) requires a full IDE application to the FDA plus IRB approval. A Non-Significant Risk device study requires IRB approval only (the IRB determines SR/NSR, and the FDA may override). The exam asks scenario questions where you must classify SR vs. NSR and identify the correct review path.

☐ Memorize the FDA centers and the expedited programs. CDER: small molecule drugs. CBER: biologics, vaccines, blood products, gene and cell therapies. CDRH: medical devices. CTP: tobacco products. Expedited programs: Fast Track (serious condition, unmet need), Breakthrough Therapy (preliminary clinical evidence of substantial improvement), Accelerated Approval (surrogate endpoint reasonably likely to predict clinical benefit), Priority Review (six-month FDA review instead of ten), RMAT (Regenerative Medicine Advanced Therapy for cell, tissue, and gene products), and Orphan Drug designation (condition affecting fewer than 200,000 US patients, with seven years of market exclusivity).

☐ Complete the Practice Questions for Part IV in your quiz bank. Review every rationale, correct and incorrect.

How to Use Your Templates

☐ Mind Map: Central node = Product Development and Regulation. Main branches: Drug Development Lifecycle (discovery → preclinical → Phase 1-4 → NDA/BLA → Phase 4 surveillance) → Device Classification (Class I, II, III) → Device Marketing Pathways (510(k), De Novo, PMA, HDE) → IND (components, 30-day review, clinical hold) → IDE (SR vs. NSR) → FDA Centers (CDER, CBER, CDRH, CTP) → FDA Decision Letters → Key Regulatory Citations (21 CFR 50, 56, 312, 812; 45 CFR 46) → ICH GCP E6(R3) → Combination Products & BLA → Expedited Programs (Orphan Drug, Fast Track, Breakthrough, Accelerated Approval, Priority Review, RMAT).

Comparison Charts:

☐ Chart 1, IND vs. IDE: Product type, governing regulation (21 CFR 312 vs. 21 CFR 812), components of application, FDA review window, default effective date, and what triggers a hold.

☐ Chart 2, Class I vs. Class II vs. Class III Devices: Risk level, regulatory controls, typical marketing pathway, representative product example, and whether premarket review is required.

☐ Chart 3, 510(k) vs. De Novo vs. PMA vs. HDE: Required showing (substantial equivalence vs. novel classification vs. safety/effectiveness vs. humanitarian use), typical review time, clinical data requirement, and patient population threshold.

☐ Chart 4, Fast Track vs. Breakthrough Therapy vs. Accelerated Approval vs. Priority Review: Eligibility criteria, FDA interaction benefit, evidentiary standard, and one example program for each.

Cornell Notes:

☐ Page 1, Cue questions: What is the difference between 21 CFR Parts 50, 56, 312, and 812, and which one applies to consent in an FDA-regulated drug study vs. a non-FDA-regulated NIH-funded study? What is the 30-day rule for an IND, and what is a clinical hold?

☐ Page 2, Cue questions: What are the three medical device classes, and which marketing pathway corresponds to each? When does the De Novo pathway apply, and how does it differ from 510(k)?

☐ Page 3, Cue questions: What does each FDA center regulate (CDER, CBER, CDRH, CTP), and where do combination products go for review? What are the five major expedited programs, and what eligibility criteria distinguish each?

Week 5, Part V: Clinical Trial Operations (Pre-Study and Start-Up)

Difficulty: Moderate to Heavy

What it covers:

• The site-side workflow from sponsor first contact through site activation, where missteps create downstream rework and findings

• Feasibility assessment: site capability, patient population, infrastructure, competing studies, and the consequences of inflated feasibility responses

• Confidentiality Disclosure Agreements (CDAs / NDAs): who signs, what is protected, how long obligations persist

• Pre-Study Visit (PSV) vs. Site Initiation Visit (SIV): purpose, attendees, qualification criteria evaluated

• The regulatory binder (Investigator Site File) organized by the ICH GCP essential documents framework

• ICH GCP essential documents required before, during, and after the trial, located correctly in the Trial Master File and Investigator Site File

• Form FDA 1572: accurate completion, common errors, when re-execution is required

• Financial disclosure under 21 CFR 54: who must disclose, what must be disclosed, and how long disclosures persist after study completion

• Delegation of Authority (DOA) log and Site Initiation Visit activities that transition the site from start-up to activation

Print: 1 Mind Map, 3 Comparison Charts, 2 Cornell Notes pages

Study Tasks

☐ Read the Study Guide first. Complete the High-Yield Objectives, Key Terms and Definitions, and Concept Overview sections before opening the chapter.

☐ Highlight as you read using the Made Easy Highlighting System (Red, Purple, Blue, Orange, Green, Yellow as defined in Week 1).

☐ Master the PSV vs. SIV distinction. The Pre-Study Visit happens AFTER feasibility and BEFORE site selection. Its purpose is sponsor qualification of the site: facilities, staff, patient population, regulatory standing. The Site Initiation Visit happens AFTER all regulatory documents are complete and IRB approval is in hand, immediately BEFORE the first subject is enrolled. Its purpose is to train the site on the protocol, IP handling, data capture, and reporting workflows. The exam pairs these visits with the wrong activities as distractors.

☐ Build a memorized list of Form FDA 1572 contents and re-execution triggers. The 1572 is the investigator's commitment to the FDA, signed under penalty of perjury. It identifies the principal investigator, sub-investigators (Section 6), the clinical site, the IRB, the protocol, and the investigator's qualifications (CV, license). The 1572 must be re-executed when there is a change in principal investigator, addition or removal of sub-investigators in Section 6, change of site location, or substantive change in protocol identification. Address corrections, IRB updates, and CV updates typically do not require re-execution but must be documented. This is heavily tested.

☐ Memorize 21 CFR 54 financial disclosure cold. Required for clinical investigators (PI and any sub-I listed on the 1572) in FDA-regulated studies supporting a marketing application. Four disclosable arrangements: (1) compensation tied to study outcome, (2) significant equity interest in the sponsor (publicly traded > $50,000 or any equity in non-publicly-traded sponsor), (3) significant payments of other sorts (> $25,000) for activities related to the study or sponsor, (4) proprietary interest (patent, trademark, copyright, licensing arrangement). Obligations extend for one year after study completion.

☐ Build a clean regulatory binder map organized by ICH GCP E6(R3) essential documents. Before the trial: protocol and amendments, investigator's brochure, financial agreement, insurance, sample CRF, signed protocol, IRB approval, 1572, CV, lab certifications, sample label. During: ongoing IRB correspondence, updated CVs and certifications, monitoring visit logs, drug accountability, deviation logs, signed consents, source documents. After: final IRB report, final IP reconciliation, audit certificates, final closeout letter, archive plan. The essential documents framework is the spine of every regulatory inspection.

☐ Master the Delegation of Authority log. The DOA log documents which study staff are delegated which study tasks by the PI, with the start and end date of each delegation and the PI's signature authorizing each. It is one of the first documents an FDA inspector requests. Common findings: tasks performed by staff not delegated for them, expired delegations, missing PI signature, vague task descriptions ("study procedures" instead of "obtain consent, perform vitals, complete CRFs").

☐ Complete the Practice Questions for Part V in your quiz bank. Review every rationale, correct and incorrect.

How to Use Your Templates

☐ Mind Map: Central node = Pre-Study and Start-Up. Main branches: Feasibility Assessment → CDA/NDA → Pre-Study Visit (PSV) → Site Selection & Regulatory Package → ICH GCP Essential Documents (before/during/after) → Investigator Site File & Trial Master File → Form FDA 1572 (contents, re-execution triggers) → Financial Disclosure (21 CFR 54) → Delegation of Authority Log → Site Initiation Visit (SIV) → Site Activation.

Comparison Charts:

☐ Chart 1, Pre-Study Visit vs. Site Initiation Visit: When in the timeline, sponsor purpose, site purpose, typical attendees, documents reviewed, and what marks visit completion.

☐ Chart 2, Investigator Site File vs. Trial Master File: Who maintains each, where each is kept, what each contains, retention obligations, and how they reconcile at closeout.

☐ Chart 3, Form FDA 1572 vs. Financial Disclosure (21 CFR 54): Regulatory citation, who must complete each, signature requirement, what triggers re-execution or update, and how long obligations persist.

Cornell Notes:

☐ Page 1, Cue questions: What is the difference in timing, purpose, and attendees between a PSV and an SIV? What are the four most common Form FDA 1572 re-execution triggers, and what changes typically do not require re-execution?

☐ Page 2, Cue questions: What are the four disclosable arrangements under 21 CFR 54, and how long do financial disclosure obligations persist after study completion? What are the most common Delegation of Authority log findings during FDA inspections, and how should each be prevented?

Week 6, Part VI: Clinical Trial Operations (Conduct)

Difficulty: Heavy, High Yield

What it covers:

• The largest and most clinically applied Part: the day-to-day operational workflow from first subject enrolled to last subject last visit

• Recruitment strategy design that balances enrollment goals with equitable selection and noncoercion, and IRB-approved recruitment materials

• Pre-screening vs. full screening: documentation, consent timing, HIPAA implications

• Eligibility determination against inclusion and exclusion criteria, screen failure workflow, and re-screening rules

• Randomization workflows, Interactive Response Technology (IRT/IWRS/IVRS), and emergency unblinding procedures that preserve trial integrity

• Investigational product accountability from shipment through reconciliation: temperature monitoring, dispensing, return, destruction

• Sample collection, processing, and shipping under protocol, central lab requirements, and IATA rules for biological substances (UN3373 vs. Category A)

• Concomitant medication tracking, protocol-defined prohibited and permitted meds, and drug-drug interactions

• Visit windows, compliance tracking, protocol deviations vs. violations, and subject retention strategies

Print: 1 Mind Map, 4 Comparison Charts, 3 Cornell Notes pages

Study Tasks

☐ Read the Study Guide first. Complete the High-Yield Objectives, Key Terms and Definitions, and Concept Overview sections before opening the chapter.

☐ Highlight as you read using the Made Easy Highlighting System (Red, Purple, Blue, Orange, Green, Yellow as defined in Week 1).

☐ Lock down the pre-screening vs. screening distinction. Pre-screening occurs BEFORE informed consent and is limited to activities that do not require the subject's individually identifiable health information to be accessed under HIPAA. Pre-screening can include reviewing publicly available information, posting ads, or asking a few general questions about interest. Full screening occurs AFTER informed consent and includes protocol-specified procedures (labs, imaging, eligibility checks). Conducting screening-level procedures before consent is one of the most common GCP findings.

☐ Master eligibility documentation. Each inclusion and exclusion criterion must be assessed and documented, with source documents supporting each. A screen failure is a consented subject who fails eligibility before randomization; the screen failure log records the date, the criterion failed, and whether re-screening is permitted by protocol. Re-screening rules vary by protocol: some allow re-screening once a temporary exclusion (lab value, washout) resolves; others prohibit it. The exam tests this directly.

☐ Memorize the emergency unblinding procedure. Emergency unblinding is permitted when knowing the subject's treatment assignment is essential for medical management (a suspected SAE requiring treatment differentiation, an overdose, pregnancy). The decision is made by the investigator or treating physician, not the coordinator alone. The IRT/IWRS system records who unblinded, when, and why. Sponsor notification follows immediately. Unnecessary unblinding compromises trial integrity and is a major protocol deviation.

☐ Build a clean IP accountability workflow. Receipt: verify shipment matches packing slip, log temperature in transit, store per label. Dispensing: per protocol, with dose, date, time, lot, expiration, dispenser, and subject ID recorded. Return: subjects return all containers (used and unused) at each visit; reconcile against dispensed amount. Destruction: per sponsor instruction, with witness signatures. IP accountability is reconciled to zero at study closeout. The IP log is among the first documents reviewed in a sponsor monitoring visit or FDA inspection.

☐ Master IATA classification for sample shipping. UN3373 (Biological Substance, Category B): the default for most clinical trial samples, including most patient blood, urine, and tissue samples. Triple packaging required (primary watertight container, secondary watertight container with absorbent material, rigid outer packaging marked UN3373). Category A (UN2814 for human-affecting agents, UN2900 for animal-affecting): infectious substances capable of causing permanent disability, life-threatening, or fatal disease. Far more restrictive shipping requirements. Most CCRC trials handle Category B; Category A appears in vaccine and infectious disease trials.

☐ Memorize the protocol deviation vs. violation distinction. A protocol deviation is any departure from the IRB-approved protocol. A protocol violation is a deviation that affects subject rights, safety, or welfare, or the integrity of the study data. All violations are deviations; not all deviations are violations. Visit window deviations (one day late) may be deviations only; missed safety lab that should have triggered drug discontinuation is a violation. IRB and sponsor reporting requirements differ for deviations vs. violations.

☐ Complete the Practice Questions for Part VI in your quiz bank. Review every rationale, correct and incorrect.

How to Use Your Templates

☐ Mind Map: Central node = Trial Conduct. Main branches: Recruitment (IRB-approved materials, equitable selection) → Pre-Screening vs. Screening (HIPAA, consent timing) → Eligibility Determination & Screen Failure Workflow → Randomization & IRT/IWRS/IVRS → Emergency Unblinding → Investigational Product Accountability (receipt, dispensing, return, destruction) → Sample Collection, Processing & Shipping (IATA UN3373 vs. Category A) → Concomitant Medications & Drug-Drug Interactions → Visit Windows & Compliance Tracking → Protocol Deviations vs. Violations → Subject Retention.

Comparison Charts:

☐ Chart 1, Pre-Screening vs. Screening: Timing relative to consent, activities permitted, HIPAA implications, documentation requirement, and one example activity that is and is not permitted in each.

☐ Chart 2, IATA UN3373 (Category B) vs. UN2814/UN2900 (Category A): Type of substance, examples, packaging requirements, labeling requirements, training requirements, and which category most CCRC studies use.

☐ Chart 3, Protocol Deviation vs. Protocol Violation: Definition, impact on subject safety or data integrity, examples of each, IRB reporting requirement, sponsor reporting requirement, and prevention strategies.

☐ Chart 4, Investigational Product Accountability at Each Step: Receipt, storage, dispensing, return, destruction. For each: what is logged, who signs, what discrepancies trigger action, and what document records the step.

Cornell Notes:

☐ Page 1, Cue questions: What activities are permitted in pre-screening before informed consent, and what activities require full screening after consent? What are the HIPAA implications of each?

☐ Page 2, Cue questions: When is emergency unblinding permitted, who makes the decision, and what documentation is required? What is the impact of unnecessary unblinding on trial integrity?

☐ Page 3, Cue questions: What is the difference between a protocol deviation and a protocol violation, with one clinical example of each? What are the four steps of investigational product accountability, and what document records each?

Week 7, Part VII: Study and Site Management

Difficulty: Moderate to Heavy

What it covers:

• The business and oversight side of running a clinical research site: how the site sustains itself, how it withstands inspection, and how it responds when findings occur

• Study budget construction: direct, indirect, and per-procedure costs, with coverage analysis separating routine care from research-only costs

• Clinical Trial Agreement (CTA) clauses that matter operationally: payment terms, indemnification, publication rights, intellectual property, confidentiality, termination

• Subject stipends and compensation as participation support, not undue influence, under IRB and institutional standards

• Site staffing, workload, and protocol portfolio management across multiple concurrent studies

• The three external oversight visit types: sponsor monitoring visits, sponsor audits, and FDA Bioresearch Monitoring (BIMO) inspections

• Corrective and Preventive Action (CAPA) plans: root cause, correction, prevention, effectiveness check

• FDA Form 483 observations and Warning Letters: differences, response timelines, escalation

• Site-level Quality Management System (QMS) under ICH GCP E6(R3): risk-based monitoring at the site level, continuing education, document control

Print: 1 Mind Map, 3 Comparison Charts, 2 Cornell Notes pages

Study Tasks

☐ Read the Study Guide first. Complete the High-Yield Objectives, Key Terms and Definitions, and Concept Overview sections before opening the chapter.

☐ Highlight as you read using the Made Easy Highlighting System (Red, Purple, Blue, Orange, Green, Yellow as defined in Week 1).

☐ Master coverage analysis before touching the budget. Coverage analysis is the document that separates routine care (billable to insurance/Medicare under the Medicare Clinical Trial Policy and the Qualifying Clinical Trial criteria) from research-only costs (billable to the sponsor). Misclassification creates double-billing, which is fraud. Items typically research-only: study drug, study-only labs, study-only procedures, research staff time. Items typically routine: standard-of-care visits, standard-of-care labs that would have been ordered anyway. The exam tests recognition of which is which.

☐ Memorize the three external oversight visit types and the correct site response to each. Sponsor monitoring visit: scheduled (typically), focused on protocol compliance, data quality, and IP accountability, follow-up letter expected. Sponsor audit: less frequent, broader and deeper, independent of routine monitoring, audit report with findings. FDA BIMO inspection: unscheduled or short-notice, conducted under FDA authority, focused on regulatory compliance and data integrity, may result in Form 483 observations and/or a Warning Letter. The exam pairs the wrong visit type with the wrong scope as a distractor.

☐ Lock down Form 483 vs. Warning Letter. Form 483 is issued at the close of an FDA inspection listing observations of conditions that, in the investigator's judgment, may constitute violations. It requires a written response within 15 business days. A Warning Letter is a more serious formal communication, typically issued after Form 483 response is found inadequate, alleging significant violations and requiring corrective action within 15 working days. Repeated Warning Letters can lead to consent decrees, injunctions, or disqualification.

☐ Master the CAPA structure. A complete CAPA has four parts. Root cause: the specific systemic reason the finding occurred (not "human error" but the system that allowed human error). Correction: the immediate fix to the affected work. Corrective action: changes that prevent recurrence at all subjects/studies affected. Preventive action: system-level changes that prevent similar findings across the site. Effectiveness check: how and when you will verify the CAPA worked. A CAPA that stops at "we retrained staff" without a system change is incomplete and will fail follow-up.

☐ Understand the ICH GCP E6(R3) shift to risk-based, proportionate, technology-neutral quality management. The 2025 revision moves the framework away from prescriptive 100% source data verification toward risk-based monitoring focused on critical-to-quality factors and critical data and processes. At the site level, this means a written QMS, defined critical processes, risk-based source review, and proportionate documentation. The exam will test E6(R3) principles, not the older E6(R2) prescriptive framework.

☐ Complete the Practice Questions for Part VII in your quiz bank. Review every rationale, correct and incorrect.

How to Use Your Templates

☐ Mind Map: Central node = Study and Site Management. Main branches: Study Budget (direct, indirect, per-procedure) → Coverage Analysis (routine vs. research-only) → Clinical Trial Agreement (payment, indemnification, publication, IP, termination) → Subject Stipends & Undue Influence → Site Staffing & Protocol Portfolio → Sponsor Monitoring Visits → Sponsor Audits → FDA BIMO Inspections → Form 483 & Warning Letters → CAPA (root cause, correction, prevention, effectiveness check) → ICH GCP E6(R3) Site-Level QMS → Continuing Education & Document Control.

Comparison Charts:

☐ Chart 1, Sponsor Monitoring Visit vs. Sponsor Audit vs. FDA BIMO Inspection: Triggering authority, frequency, scope, notice given, site response protocol, deliverable (visit letter vs. audit report vs. Form 483/EIR), and consequence of significant findings.

☐ Chart 2, Form 483 vs. Warning Letter: Issuing authority, what each alleges, response timeline, written response requirement, escalation path, and what each predicts about future FDA action.

☐ Chart 3, Routine Care Costs vs. Research-Only Costs in Coverage Analysis: Definition, billing destination (insurance/Medicare vs. sponsor), example items in each category, Medicare Qualifying Clinical Trial criteria, and the fraud risk created by misclassification.

Cornell Notes:

☐ Page 1, Cue questions: What is the difference between a sponsor monitoring visit, a sponsor audit, and an FDA BIMO inspection, and what is the correct site response to each? How long does the site have to respond in writing to a Form 483 vs. a Warning Letter?

☐ Page 2, Cue questions: What are the four components of a complete CAPA, and how does each differ in scope (immediate vs. systemic)? What is the central shift introduced by ICH GCP E6(R3) at the site level, and how does risk-based monitoring change site documentation expectations?

Week 8, Part VIII: Data Management, Informatics, and Study Closeout

Difficulty: Moderate to Heavy

What it covers:

• The final operational arc of a trial: how data flows from the source document to the locked database, and how the site closes when the last subject completes the last visit

• Case Report Form (CRF) design and data flow under ALCOA-C principles (Attributable, Legible, Contemporaneous, Original, Accurate, plus Complete, Consistent, Enduring, Available)

• Electronic Data Capture (EDC) operation: data entry, query response, electronic signature, access control

• 21 CFR Part 11 requirements for electronic records and signatures: audit trails, system validation, access control, signature manifestation

• Database lock workflow: final query resolution, source data verification closure, data freeze, lock

• HIPAA in research: Authorization, Limited Data Set, Waivers, the de-identification standard (Safe Harbor and Expert Determination), and the Common Rule's privacy provisions

• Record retention under FDA (21 CFR 312.62 for drugs, 21 CFR 812.140 for devices), ICH GCP, HIPAA, and institutional policy, with attention to media format and access over time

• Electronic Patient-Reported Outcomes (ePRO) and decentralized trial data capture (eConsent, wearables, telemedicine, direct-to-patient shipping) under E6(R3) principles

• Site closeout: final drug and device reconciliation, archive setup, final IRB and sponsor reports, and the ClinicalTrials.gov reporting, subject notification, and publication obligations under ICMJE authorship criteria

Print: 1 Mind Map, 4 Comparison Charts, 3 Cornell Notes pages

Study Tasks

☐ Read the Study Guide first. Complete the High-Yield Objectives, Key Terms and Definitions, and Concept Overview sections before opening the chapter.

☐ Highlight as you read using the Made Easy Highlighting System (Red, Purple, Blue, Orange, Green, Yellow as defined in Week 1).

☐ Master ALCOA-C cold. Every source data and CRF question on the CCRC traces back to one of these letters. Attributable: who recorded it (initials, signature, electronic ID). Legible: readable, with corrections done by single line strikethrough, initial, date, never erased or whited out. Contemporaneous: recorded at the time of the observation, not later from memory. Original: first capture of data (the source), or a certified copy. Accurate: factually correct, with any corrections explained. Complete: nothing missing, no blank fields, "N/A" or "0" written explicitly. Consistent: same observation reported the same way across forms. Enduring: lasts the required retention period in the chosen medium. Available: retrievable on demand during inspection.

☐ Memorize 21 CFR Part 11. Part 11 governs electronic records and electronic signatures in FDA-regulated research. Required components: audit trail (who, what, when, why, with old and new values), system validation, access controls (unique user IDs, password requirements, role-based access), electronic signatures (with name, date, time, and meaning displayed at signing), and signature manifestation in printed reports. The audit trail must be computer-generated, time-stamped, and unalterable. A system that allows backdating or anonymous changes does not meet Part 11.

☐ Lock down HIPAA in research. The three main pathways for using PHI in research: (1) Authorization (the subject's signed permission to use specific PHI for specific research, with required elements), (2) Waiver of Authorization by the IRB (requires minimal privacy risk, infeasibility without the waiver, and a written justification), (3) Limited Data Set with Data Use Agreement (PHI stripped of 16 direct identifiers, used under DUA). The Safe Harbor de-identification standard requires removal of 18 specific identifiers; the Expert Determination standard requires a qualified expert to certify low re-identification risk.

☐ Memorize record retention requirements. FDA: 21 CFR 312.62(c) requires investigators to retain records for 2 years after the marketing application is approved or 2 years after the investigation is discontinued and FDA is notified. 21 CFR 812.140 for devices is similar (2 years after PMA approval or 2 years after investigation is discontinued). ICH GCP: 2 years after the last marketing approval or 2 years after formal discontinuation. HIPAA: 6 years from the date of creation or last effective date. Sponsor contracts often require longer (15 to 25 years). The longest applicable rule controls.

☐ Build a closeout checklist organized by domain. Subjects: last subject last visit complete, all consents signed, final safety assessment documented. IP: final drug/device reconciliation to zero, destruction or return documented. Data: all queries resolved, source verified, database locked. Regulatory: final IRB report, final sponsor closeout letter, final 1572 (if required), Form 482 if FDA-inspected, archive plan executed. ClinicalTrials.gov: results posted within 12 months of primary completion date (FDAAA 801 requirement). Publication: results submitted per protocol publication policy with ICMJE-compliant authorship.

☐ Complete the Practice Questions for Part VIII in your quiz bank. Review every rationale, correct and incorrect.

How to Use Your Templates

☐ Mind Map: Central node = Data Management, Informatics, and Closeout. Main branches: Source Documents & CRFs → ALCOA-C → Electronic Data Capture (EDC) → 21 CFR Part 11 (audit trail, validation, access, signature) → Query Management → Database Lock & Data Freeze → HIPAA in Research (Authorization, Waiver, Limited Data Set, Safe Harbor, Expert Determination) → Record Retention (FDA, ICH GCP, HIPAA, institutional) → ePRO & Decentralized Trial Data → Site Closeout (subjects, IP, data, regulatory) → ClinicalTrials.gov Reporting (FDAAA 801) → Publication & ICMJE Authorship.

Comparison Charts:

☐ Chart 1, ALCOA-C Elements: Each of the nine letters (Attributable, Legible, Contemporaneous, Original, Accurate, Complete, Consistent, Enduring, Available). For each: definition, one common source document error that violates it, and the correct documentation practice.

☐ Chart 2, 21 CFR Part 11 Compliant System vs. Non-Compliant System: Audit trail, validation status, access control, electronic signature meaning, signature manifestation in printed reports, and what a non-compliant system would lack.

☐ Chart 3, HIPAA Authorization vs. Waiver vs. Limited Data Set: When each is used, what PHI may be released, IRB/Privacy Board approval requirement, subject signature requirement, identifiers permitted, and one representative research scenario for each.

☐ Chart 4, Record Retention by Regulation: FDA (21 CFR 312.62 and 812.140), ICH GCP, HIPAA, institutional policy, sponsor contract. For each: retention period rule, the trigger event that starts the clock, and which rule controls when they conflict (longest applicable).

Cornell Notes:

☐ Page 1, Cue questions: What are the nine elements of ALCOA-C, and what is one common source document error that violates each? How are corrections to a paper source document made correctly?

☐ Page 2, Cue questions: What are the five core requirements of 21 CFR Part 11 for electronic records and signatures, and what makes a system non-compliant? What is the difference between an electronic signature and a digital signature in regulatory practice?

☐ Page 3, Cue questions: What are the three HIPAA pathways for using PHI in research, and what are the elements required for each? What is the longest applicable record retention rule when FDA, ICH GCP, HIPAA, and a sponsor contract all apply to the same study, and what is the trigger event that starts the clock?

Week 9: Full Review and Exam Simulation

Your final week is not about learning new material. It is about consolidating everything you have built and proving it under exam conditions.

Review Tasks

☐ Re-draw one Mind Map from memory for each Part you feel least confident about. Check it against your original.

☐ Work through your Cornell Notes cue columns for every Part. Cover the right-hand notes and answer from memory.

☐ Re-do any quiz bank questions you got wrong across all Parts. Focus on the rationales.

☐ Review the Common Mistakes, Rapid Review, and Self-Assessment Checklist sections for your two or three weakest Parts.

Exam Simulation

☐ Take the full-length CCRC practice exam using the QR code in the back matter of this book. Complete it in one sitting, timed, as close to real exam conditions as possible.

☐ Review your emailed score report. Identify which Parts you missed most and spend your remaining time on those Parts' Rapid Review and clinical scenarios only.