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Clinical Trial Reporting Standards

ICH-E3: Structure and Content of Clinical Study Reports

The International Council for Harmonisation (ICH) E3 guideline defines the structure and content of clinical study reports (CSRs) for regulatory submission.

CSR Overview

Purpose:

Provide comprehensive description of study design, conduct, and results
Support regulatory decision-making
Document evidence of safety and efficacy

Audience:

Regulatory authorities (FDA, EMA, PMDA, etc.)
Medical reviewers
Statistical reviewers
Clinical pharmacology reviewers

Length: Typically 50-300 pages (main text), with extensive appendices

Main Sections of ICH-E3 CSR

Section 1: Title Page

Required elements:

Full study title
Protocol number and version
Sponsor name and address
Compound/drug name and code
Study phase
Indication
Report date and version number
Report authors
Confidentiality statement

Section 2: Synopsis

Length: 5-15 pages

Content:

Brief summary of entire CSR
Must be understandable as standalone document
Cover all major sections

Standard synopsis elements:

Study identifier and title
Study objectives
Methodology:
- Study design
- Number and description of patients
- Diagnosis and main criteria for inclusion
- Study treatments
- Duration of treatment
- Criteria for evaluation
- Statistical methods
Results:
- Number of patients enrolled, completed, discontinued
- Efficacy results
- Safety results
Conclusions

Section 3: Ethics

3.1 Independent Ethics Committee/Institutional Review Board

Names and locations of all IRBs
Dates of initial approval
Dates of protocol amendment approvals
Documentation of continuing review

3.2 Ethical Conduct of Study

Statement of compliance with GCP and Declaration of Helsinki
Protocol adherence
Informed consent process

3.3 Patient Information and Consent

Description of informed consent procedures
Consent form versions used
Process for re-consent if applicable

Section 4: Investigators and Study Administrative Structure

4.1 Investigators

List of principal investigators by site
Site addresses and enrollment
Coordinating investigator (if applicable)

4.2 Administrative Structure

Sponsor personnel and roles
CRO involvement (if applicable)
Monitoring procedures
Data management organization
Statistical analysis organization

4.3 Study Monitoring and Quality Assurance

Monitoring procedures and frequency
Source document verification
Quality control procedures
Audits performed

Section 5: Introduction

5.1 Background

Disease or condition being studied
Current treatment landscape
Unmet medical need

5.2 Investigational Product

Pharmacology and mechanism of action
Nonclinical findings
Prior clinical experience
Known safety profile

5.3 Non-Investigational Therapy

Comparator drugs or placebo
Concomitant medications allowed/prohibited

Section 6: Study Objectives

6.1 Primary Objective

Main research question
Clearly stated and specific
Example: "To evaluate the efficacy of Drug X compared to placebo in reducing HbA1c in patients with type 2 diabetes mellitus over 24 weeks of treatment"

6.2 Secondary Objectives

Additional research questions
Supportive efficacy endpoints
Safety objectives
Exploratory objectives

6.3 Endpoints

Primary endpoint definition and measurement
Secondary endpoints
Safety endpoints
Pharmacokinetic endpoints (if applicable)
Biomarker endpoints (if applicable)

Section 7: Investigational Plan

7.1 Overall Study Design and Plan

Study design type (parallel, crossover, factorial, etc.)
Randomization and blinding
Study phases or periods
Duration of treatment and follow-up
Dosing regimen
Study flow diagram (patient flowchart)

7.2 Sample Size

Target enrollment
Sample size justification
Power calculation assumptions:
- Expected effect size
- Variability estimates
- Type I error (alpha)
- Power (1 - beta)
- Drop-out rate assumptions

7.3 Statistical Methods

Analysis populations (ITT, PP, safety)
Handling of missing data
Interim analyses (if planned)
Multiplicity adjustments
Subgroup analyses
Sensitivity analyses

7.4 Changes to Protocol

Protocol amendments and rationale
Impact on study conduct and analysis

Section 8: Study Patients

8.1 Inclusion and Exclusion Criteria

Key inclusion criteria
Key exclusion criteria
Rationale for criteria

8.2 Demographic and Baseline Characteristics

Age, sex, race/ethnicity
Disease severity or stage
Prior therapies
Baseline values of key endpoints
Comparability across treatment groups

8.3 Patient Disposition

Number screened
Number randomized
Number completing study
Number withdrawn (by reason)
Number lost to follow-up
CONSORT flow diagram

8.4 Protocol Deviations

Major protocol deviations
Minor protocol deviations
Impact on efficacy and safety analyses
Corrective actions taken

8.5 Demographic and Other Baseline Characteristics

Detailed demographic tables
Baseline disease characteristics
Stratification factors
Medical history
Prior/concomitant medications

Section 9: Efficacy Evaluation

9.1 Data Sets Analyzed

Intent-to-treat (ITT) population
Per-protocol (PP) population
Modified ITT
Other analysis sets
Justification for population definitions

9.2 Demographic and Baseline Characteristics

Demographics by analysis population
Baseline comparability

9.3 Measurements of Treatment Compliance

Drug accountability
Pill counts or diary compliance
Plasma drug levels (if measured)
Percent of planned dose received

9.4 Efficacy Results

9.4.1 Primary Endpoint

Results for primary endpoint
Statistical analysis
Effect size and confidence intervals
P-values
Subgroup analyses

9.4.2 Secondary Endpoints

Results for each secondary endpoint
Statistical analyses
Hierarchy of testing (if applicable)

9.4.3 Other Efficacy Endpoints

Exploratory endpoints
Post-hoc analyses
Responder analyses

9.5 Dropouts and Missing Data

Patterns of missing data
Reasons for dropout
Sensitivity analyses for missing data

Section 10: Safety Evaluation

10.1 Extent of Exposure

Duration of exposure
Dose intensity
Dose delays or reductions
Treatment discontinuations due to adverse events

10.2 Adverse Events

10.2.1 Overview of Adverse Events

Summary tables (any AE, treatment-related, serious, leading to discontinuation)
Percentage of patients with AEs
Comparison across treatment groups

10.2.2 Common Adverse Events

AEs occurring in ≥5% or ≥10% of patients
Sorted by frequency
Preferred terms and system organ class (MedDRA)

10.2.3 Serious Adverse Events

Definition of SAE
Summary table of SAEs
Individual narratives for each SAE
Causality assessment
Outcome

10.2.4 Adverse Events Leading to Discontinuation

AEs leading to study drug discontinuation
Frequency and type
Relationship to study drug

10.2.5 Deaths

All deaths during study and follow-up
Detailed narratives for each death
Relationship to study drug
Autopsy findings (if available)

10.3 Clinical Laboratory Evaluations

Laboratory abnormalities
Shift tables (normal to abnormal, abnormal to normal)
Mean changes from baseline
Laboratory values meeting protocol-defined criteria
Hepatotoxicity monitoring (if applicable)

10.4 Vital Signs and Physical Findings

Vital signs (BP, HR, temperature, respiratory rate)
Mean changes from baseline
Clinically significant changes
Physical examination findings

10.5 ECG Evaluation

QTc interval changes
Other ECG abnormalities
Clinically significant ECG findings

10.6 Special Safety Evaluations

Immunogenicity (for biologics)
Pregnancy outcomes (if applicable)
Abuse potential (if applicable)
Withdrawal or rebound effects
Dependency potential

Section 11: Discussion and Overall Conclusions

11.1 Efficacy Discussion

Interpretation of efficacy results
Clinical significance of findings
Consistency with prior studies
Limitations

11.2 Safety Discussion

Safety profile overview
Notable safety findings
Comparison to known safety profile
Risk-benefit assessment

11.3 Benefit-Risk Assessment

Overall benefit-risk conclusion
Subpopulations with favorable/unfavorable benefit-risk
Implications for dosing or patient selection

11.4 Clinical Implications

Place in therapy
Target patient population
Comparison to existing therapies

Section 12: Tables, Figures, and Graphs

Comprehensive set of tables and figures for efficacy and safety data.

Common tables:

Demographic and baseline characteristics
Patient disposition
Extent of exposure
Efficacy results (primary and secondary endpoints)
Adverse event summary
Common adverse events
Serious adverse events
Deaths
Laboratory abnormalities
Vital signs

Common figures:

Study design schematic
Patient disposition flowchart (CONSORT)
Kaplan-Meier curves (survival, time to event)
Forest plots (subgroup analyses)
Mean change over time plots

Section 13: References

Publications cited in CSR
Relevant literature
Regulatory guidelines
Prior study reports

Section 14: Appendices

Required appendices:

Study protocol and amendments
Sample case report forms
Investigator list with IRB information
Patient information and informed consent forms
List of patients receiving study drug
Randomization scheme
Audit certificates (if applicable)
Documentation of statistical methods
Publications based on study

Optional appendices:

Individual patient data listings
SAE narratives
Laboratory normals and conversion factors
Investigator signatures

Statistical Analysis Plan (SAP)

SAP Components:

Analysis populations
Handling of missing data
Statistical tests to be used
Adjustment for multiplicity
Interim analysis plan
Subgroup analyses
Sensitivity analyses
Safety analyses

SAP Timing:

Finalized before database lock
Amendments documented with rationale

CONSORT (Consolidated Standards of Reporting Trials)

CONSORT guidelines promote transparent and complete reporting of randomized controlled trials.

CONSORT 2010 Checklist

Title and Abstract

1a. Title: Identification as randomized trial in title
1b. Abstract: Structured summary covering trial design, methods, results, conclusions

Introduction

2a. Background: Scientific background and explanation of rationale
2b. Objectives: Specific objectives or hypotheses

Methods - Participants

3a. Eligibility: Eligibility criteria for participants
3b. Settings: Settings and locations of data collection

Methods - Interventions

4a. Interventions: Details of interventions for each group
4b. Details: Sufficient details to allow replication

Methods - Outcomes

5. Outcomes: Clearly defined primary and secondary outcome measures
6a. Sample size: How sample size was determined
6b. Interim analyses: When applicable, explanation of interim analyses

Methods - Randomization

7a. Sequence generation: Method of random sequence generation
7b. Allocation concealment: Mechanism of allocation concealment
8a. Implementation: Who generated allocation, enrolled, and assigned participants
8b. Blinding: Whether participants, care providers, outcome assessors were blinded

Methods - Statistical

9. Statistical methods: Methods for primary and secondary outcomes
10. Additional analyses: Subgroup or adjusted analyses

Results - Participant Flow

11a. Enrollment: Numbers screened, randomized, allocated
11b. Losses and exclusions: For each group, losses and exclusions after randomization
12. Recruitment: Dates defining recruitment and follow-up periods
13a. Baseline: Baseline demographic and clinical characteristics
13b. Baseline comparability: Numbers analyzed in each group

Results - Outcomes and Estimation

14a. Outcomes: For primary and secondary outcomes, results for each group
14b. Binary outcomes: For binary outcomes, effect sizes and confidence intervals
15. Ancillary analyses: Results of other analyses performed

Results - Harms

16. Harms: All important harms or unintended effects in each group

Discussion

17a. Limitations: Trial limitations, addressing biases, imprecision
17b. Generalizability: Generalizability (external validity) of trial findings
18. Interpretation: Interpretation consistent with results, balancing benefits and harms
19. Registration: Registration number and name of trial registry
20. Protocol: Where full trial protocol can be accessed
21. Funding: Sources of funding, role of funders

CONSORT Flow Diagram

Standard format showing patient flow through trial:

Assessed for eligibility (n=)
    ↓
Randomized (n=)
    ├─ Allocated to intervention (n=)
    │   ├─ Received intervention (n=)
    │   └─ Did not receive intervention (n=)
    │       Give reasons
    ├─ Allocated to control (n=)
    │   ├─ Received control (n=)
    │   └─ Did not receive control (n=)
    │       Give reasons
    ↓
Lost to follow-up (n=)
    Give reasons
Discontinued intervention (n=)
    Give reasons
    ↓
Analyzed (n=)
Excluded from analysis (n=)
    Give reasons

Serious Adverse Event (SAE) Reporting

Definition of Serious Adverse Event

An adverse event or suspected adverse reaction is considered serious if it:

Results in death
Is life-threatening
Requires inpatient hospitalization or prolongation of existing hospitalization
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
Requires intervention to prevent permanent impairment or damage (device-related)
Other medically important events (based on medical judgment)

SAE Report Components

1. Administrative Information

Report type (initial, follow-up, final)
Report number
Date of report
Reporter information
Sponsor information
Study identifier (protocol number, NCT number)

2. Patient Information (De-identified)

Subject ID or randomization number
Initials (if permitted)
Age or date of birth (year only)
Sex
Race/ethnicity
Weight
Height

3. Study Information

Study phase (I, II, III, IV)
Study design (randomized, open-label, etc.)
Treatment arm or randomization
Date of first study drug
Date of last study drug

4. Event Information

Reported term (verbatim)
MedDRA preferred term
System organ class
Date of onset
Time of onset (if relevant)
Date of resolution (or ongoing)
Duration

5. Seriousness Criteria

Death: Yes/No
Life-threatening: Yes/No
Hospitalization required: Yes/No
Hospitalization prolonged: Yes/No
Disability/incapacity: Yes/No
Congenital anomaly: Yes/No
Medically significant: Yes/No

6. Severity

Mild: Noticeable but does not interfere with daily activities
Moderate: Interferes with daily activities but manageable
Severe: Prevents usual daily activities, requires intervention

Note: Severity ≠ Seriousness

7. Outcome

Recovered/resolved
Recovering/resolving
Not recovered/not resolved
Recovered/resolved with sequelae
Fatal
Unknown

8. Causality Assessment

Relationship to study drug:
- Not related
- Unlikely related
- Possibly related
- Probably related
- Definitely related
Relationship to study procedures
Relationship to underlying disease
Relationship to concomitant medications
Reasoning for determination

9. Expectedness

Expected (per Investigator's Brochure or protocol)
Unexpected (not in IB or more severe than documented)

10. Action Taken with Study Drug

No change
Dose reduced
Dose increased
Drug interrupted (temporarily held)
Drug discontinued
Not applicable (event occurred after discontinuation)

11. Treatments/Interventions for Event

Medications administered
Procedures performed
Hospitalization details
ICU admission
Surgical intervention

12. Event Narrative

Detailed description of event
Timeline of events
Clinical course
Relevant medical history
Concomitant medications
Diagnostic test results
Treatment and response
Outcome and current status

Example narrative:

A 58-year-old male (Subject ID: 12345) enrolled in Study XYZ-301, a Phase 3
randomized trial of Drug X vs. placebo for heart failure. On Day 42 of treatment
(15-Feb-2024), the patient presented to the emergency department with sudden onset
severe chest pain, diaphoresis, and dyspnea. ECG showed ST-segment elevation in
leads V2-V4. Troponin I was elevated at 12.5 ng/mL (normal <0.04). The patient was
diagnosed with acute ST-elevation myocardial infarction and underwent emergent
cardiac catheterization revealing 95% occlusion of the left anterior descending
artery. Percutaneous coronary intervention with drug-eluting stent placement was
performed successfully. The patient was admitted to the cardiac intensive care unit.
Study drug was permanently discontinued on Day 42. The patient recovered and was
discharged on Day 47 (20-Feb-2024) in stable condition. This event was assessed as
unlikely related to study drug by the investigator, as the patient had significant
underlying coronary artery disease risk factors including diabetes, hypertension,
and smoking history.

Regulatory Reporting Timelines

FDA IND Safety Reporting (21 CFR 312.32):

Fatal or life-threatening unexpected SAEs: 7 calendar days for preliminary report, 15 days for complete report
Other serious unexpected events: 15 calendar days
Annual safety reports: Within 60 days of anniversary of IND

EMA Expedited Reporting:

Fatal or life-threatening unexpected events: 7 days initial, 8 additional days for complete report
Other unexpected serious events: 15 days

IRB Reporting:

Per institutional policy
Typically 5-10 days for serious unexpected events
Some institutions require reporting within 24-48 hours

MedDRA Coding

MedDRA (Medical Dictionary for Regulatory Activities):

Standardized medical terminology for regulatory communication
Hierarchical structure:
- SOC (System Organ Class) - highest level
- HLGT (High Level Group Term)
- HLT (High Level Term)
- PT (Preferred Term) - used for coding AEs
- LLT (Lowest Level Term) - verbatim terms

Example:

Verbatim term: "bad headache"
LLT: Headache
PT: Headache
HLT: Headaches NEC
HLGT: Neurological disorders NEC
SOC: Nervous system disorders

Causality Assessment Methods

WHO-UMC Causality Categories:

Certain: Event cannot be explained by other factors
Probable/Likely: Event more likely related to drug than other factors
Possible: Event could be related to drug, but other factors cannot be ruled out
Unlikely: Event likely explained by other factors
Conditional/Unclassified: More data needed
Unassessable/Unclassifiable: Information insufficient

Naranjo Algorithm (for ADRs): Scoring system based on 10 questions:

Score ≥9: Definite
Score 5-8: Probable
Score 1-4: Possible
Score ≤0: Doubtful

Data Safety Monitoring Board (DSMB)