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Evidence Synthesis and Guideline Integration Guide

Overview

Evidence synthesis involves systematically reviewing, analyzing, and integrating research findings to inform clinical recommendations. This guide covers guideline sources, evidence hierarchies, systematic reviews, meta-analyses, and integration of multiple evidence streams for clinical decision support.

Major Clinical Practice Guidelines

Oncology Guidelines

NCCN (National Comprehensive Cancer Network)

Scope: 60+ cancer types, supportive care guidelines
Update Frequency: Continuous (online), 1-3 updates per year per guideline
Evidence Categories:
- Category 1: High-level evidence, uniform NCCN consensus
- Category 2A: Lower-level evidence, uniform consensus (appropriate)
- Category 2B: Lower-level evidence, non-uniform consensus (appropriate)
- Category 3: Major disagreement or insufficient evidence
Access: Free for patients, subscription for providers (institutional access common)
Application: US-focused, most widely used in clinical practice

ASCO (American Society of Clinical Oncology)

Scope: Evidence-based clinical practice guidelines
Methodology: Systematic review, GRADE-style evidence tables
Endorsements: Often endorses NCCN, ESMO, or other guidelines
Focused Topics: Specific clinical questions (e.g., biomarker testing, supportive care)
Guideline Products: Full guidelines, rapid recommendations, endorsements
Quality: Rigorous methodology, peer-reviewed publication

ESMO (European Society for Medical Oncology)

Scope: European guidelines for cancer management
Evidence Levels:
- I: Evidence from at least one large RCT or meta-analysis
- II: Evidence from at least one well-designed non-randomized trial, cohort study
- III: Evidence from well-designed non-experimental study
- IV: Evidence from expert committee reports or opinions
- V: Evidence from case series, case reports
Recommendation Grades:
- A: Strong evidence for efficacy, substantial clinical benefit (strongly recommended)
- B: Strong or moderate evidence, limited clinical benefit (generally recommended)
- C: Insufficient evidence, benefit not sufficiently well established
- D: Moderate evidence against efficacy or for adverse effects (not recommended)
- E: Strong evidence against efficacy (never recommended)
ESMO-MCBS: Magnitude of Clinical Benefit Scale (grades 1-5 for meaningful benefit)

Cardiovascular Guidelines

AHA/ACC (American Heart Association / American College of Cardiology)

Scope: Cardiovascular disease prevention, diagnosis, management
Class of Recommendation (COR):
- Class I: Strong recommendation - should be performed/administered
- Class IIa: Moderate recommendation - is reasonable
- Class IIb: Weak recommendation - may be considered
- Class III - No Benefit: Not recommended
- Class III - Harm: Potentially harmful
Level of Evidence (LOE):
- A: High-quality evidence from >1 RCT, meta-analyses
- B-R: Moderate-quality evidence from ≥1 RCT
- B-NR: Moderate-quality evidence from non-randomized studies
- C-LD: Limited data from observational studies, registries
- C-EO: Expert opinion based on clinical experience
Example: "Statin therapy is recommended for adults with LDL-C ≥190 mg/dL (Class I, LOE A)"

ESC (European Society of Cardiology)

Scope: European cardiovascular guidelines
Class of Recommendation:
- I: Recommended or indicated
- II: Should be considered
- III: Not recommended
Level of Evidence: A (RCTs), B (single RCT or observational), C (expert opinion)

Other Specialties

IDSA (Infectious Diseases Society of America)

Antimicrobial guidelines, infection management
GRADE methodology
Strong vs weak recommendations

ATS/ERS (American Thoracic Society / European Respiratory Society)

Respiratory disease management
GRADE methodology

ACR (American College of Rheumatology)

Rheumatic disease guidelines
Conditionally recommended vs strongly recommended

KDIGO (Kidney Disease: Improving Global Outcomes)

Chronic kidney disease, dialysis, transplant
GRADE-based recommendations

GRADE Methodology

Assessing Quality of Evidence

Initial Quality Assignment

Randomized Controlled Trials: Start at HIGH quality (⊕⊕⊕⊕)

Observational Studies: Start at LOW quality (⊕⊕○○)

Factors Decreasing Quality (Downgrade)

Risk of Bias (-1 or -2 levels)

Lack of allocation concealment
Lack of blinding
Incomplete outcome data
Selective outcome reporting
Other sources of bias

Inconsistency (-1 or -2 levels)

Unexplained heterogeneity in results across studies
Wide variation in effect estimates
Non-overlapping confidence intervals
High I² statistic in meta-analysis (>50-75%)

Indirectness (-1 or -2 levels)

Different population than target (younger patients in trials, applying to elderly)
Different intervention (higher dose in trial than used in practice)
Different comparator (placebo in trial, comparing to active treatment)
Surrogate outcomes (PFS) when interested in survival (OS)

Imprecision (-1 or -2 levels)

Wide confidence intervals crossing threshold of benefit/harm
Small sample size, few events
Optimal information size (OIS) not met
Rule of thumb: <300 events for continuous outcomes, <200 events for dichotomous

Publication Bias (-1 level)

Funnel plot asymmetry (if ≥10 studies)
Known unpublished studies with negative results
Selective outcome reporting
Industry-sponsored studies only

Factors Increasing Quality (Upgrade - Observational Only)

Large Magnitude of Effect (+1 or +2 levels)

+1: RR >2 or <0.5 (moderate effect)
+2: RR >5 or <0.2 (large effect)
No plausible confounders would reduce effect

Dose-Response Gradient (+1 level)

Clear dose-response or duration-response relationship
Strengthens causal inference

All Plausible Confounders Would Reduce Effect (+1 level)

Observed effect despite confounders biasing toward null
Rare, requires careful justification

Final Quality Rating

After adjustments, assign final quality:

High (⊕⊕⊕⊕): Very confident in effect estimate
Moderate (⊕⊕⊕○): Moderately confident; true effect likely close to estimate
Low (⊕⊕○○): Limited confidence; true effect may be substantially different
Very Low (⊕○○○): Very little confidence; true effect likely substantially different

Systematic Reviews and Meta-Analyses

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)

Search Strategy

Databases: PubMed/MEDLINE, Embase, Cochrane Library, Web of Science
Search Terms: PICO (Population, Intervention, Comparator, Outcome)
Date Range: Typically last 10-20 years or comprehensive
Language: English only or all languages with translation
Grey Literature: Conference abstracts, trial registries, unpublished data

Study Selection

PRISMA Flow Diagram:

Records identified through database searching (n=2,450)
Additional records through other sources (n=15)
                ↓
Records after duplicates removed (n=1,823)
                ↓
Records screened (title/abstract) (n=1,823)  → Excluded (n=1,652)
                ↓                                 - Not relevant topic (n=1,120)
Full-text articles assessed (n=171)              - Animal studies (n=332)
                ↓                                 - Reviews (n=200)
Studies included in qualitative synthesis (n=38) → Excluded (n=133)
                ↓                                 - Wrong population (n=42)
Studies included in meta-analysis (n=24)          - Wrong intervention (n=35)
                                                  - No outcomes reported (n=28)
                                                  - Duplicate data (n=18)
                                                  - Poor quality (n=10)

Data Extraction

Study characteristics: Design, sample size, population, intervention
Results: Outcomes, effect sizes, confidence intervals, p-values
Quality assessment: Risk of bias tool (Cochrane RoB 2.0 for RCTs)
Dual extraction: Two reviewers independently, resolve disagreements

Meta-Analysis Methods

Fixed-Effect Model

Assumption: Single true effect size shared by all studies
Weighting: By inverse variance (larger studies have more weight)
Application: When heterogeneity is low (I² <25%)
Interpretation: Estimate of common effect across studies

Random-Effects Model

Assumption: True effect varies across studies (distribution of effects)
Weighting: By inverse variance + between-study variance
Application: When heterogeneity moderate to high (I² ≥25%)
Interpretation: Estimate of average effect (center of distribution)
Wider CI: Accounts for heterogeneity, more conservative

Heterogeneity Assessment

I² Statistic

Percentage of variability due to heterogeneity rather than chance
I² = 0-25%: Low heterogeneity
I² = 25-50%: Moderate heterogeneity
I² = 50-75%: Substantial heterogeneity
I² = 75-100%: Considerable heterogeneity

Q Test (Cochran's Q)

Test for heterogeneity
p<0.10 suggests significant heterogeneity (liberal threshold)
Low power when few studies, use I² as primary measure

Tau² (τ²)

Estimate of between-study variance
Used in random-effects weighting

Subgroup Analysis

Explore sources of heterogeneity
Pre-specified subgroups: Disease stage, biomarker status, treatment regimen
Test for interaction between subgroups

Forest Plot Interpretation

Study               n     HR (95% CI)          Weight
─────────────────────────────────────────────────────────────
Trial A 2018        450   0.62 (0.45-0.85)     ●───┤      28%
Trial B 2019        320   0.71 (0.49-1.02)      ●────┤     22%
Trial C 2020        580   0.55 (0.41-0.74)    ●──┤       32%
Trial D 2021        210   0.88 (0.56-1.38)        ●──────┤  18%

Overall (RE model)  1560  0.65 (0.53-0.80)      ◆──┤
Heterogeneity: I²=42%, p=0.16

                          0.25  0.5  1.0  2.0  4.0
                                Favors Treatment  Favors Control

Guideline Integration

Concordance Checking

Multi-Guideline Comparison

Recommendation: First-line treatment for advanced NSCLC, PD-L1 ≥50%

Guideline    Version   Recommendation                               Strength
─────────────────────────────────────────────────────────────────────────────
NCCN         v4.2024   Pembrolizumab monotherapy (preferred)       Category 1
ESMO         2023      Pembrolizumab monotherapy (preferred)       I, A
ASCO         2022      Endorses NCCN guidelines                    Strong
NICE (UK)    2023      Pembrolizumab approved                      Recommended

Synthesis: Strong consensus across guidelines for pembrolizumab monotherapy.
Alternative: Pembrolizumab + chemotherapy also Category 1/I-A recommended.

Discordance Resolution

Identify differences and reasons (geography, cost, access, evidence interpretation)
Note date of each guideline (newer may incorporate recent trials)
Consider regional applicability
Favor guidelines with most rigorous methodology (GRADE-based)

Regulatory Approval Landscape

FDA Approvals

Track indication-specific approvals
Accelerated approval vs full approval
Post-marketing requirements
Contraindications and warnings

EMA (European Medicines Agency)

May differ from FDA in approved indications
Conditional marketing authorization
Additional monitoring (black triangle)

Regional Variations

Health Technology Assessment (HTA) agencies
NICE (UK): Cost-effectiveness analysis, QALY thresholds
CADTH (Canada): Therapeutic review and recommendations
PBAC (Australia): Reimbursement decisions

Real-World Evidence (RWE)

Sources of RWE

Electronic Health Records (EHR)

Clinical data from routine practice
Large patient numbers
Heterogeneous populations (more generalizable than RCTs)
Limitations: Missing data, inconsistent documentation, selection bias

Claims Databases

Administrative claims for billing/reimbursement
Large scale (millions of patients)
Outcomes: Mortality, hospitalizations, procedures
Limitations: Lack clinical detail (labs, imaging, biomarkers)

Cancer Registries

SEER (Surveillance, Epidemiology, and End Results): US cancer registry
NCDB (National Cancer Database): Hospital registry data
Population-level survival, treatment patterns
Limited treatment detail, no toxicity data

Prospective Cohorts

Framingham Heart Study, Nurses' Health Study
Long-term follow-up, rich covariate data
Expensive, time-consuming

RWE Applications

Comparative Effectiveness

Compare treatments in real-world settings (less strict eligibility than RCTs)
Complement RCT data with broader populations
Example: Effectiveness of immunotherapy in elderly, poor PS patients excluded from trials

Safety Signal Detection

Rare adverse events not detected in trials
Long-term toxicities
Drug-drug interactions in polypharmacy
Postmarketing surveillance

Treatment Patterns and Access

Guideline adherence in community practice
Time to treatment initiation
Disparities in care delivery
Off-label use prevalence

Limitations of RWE

Confounding by indication: Sicker patients receive more aggressive treatment
Immortal time bias: Time between events affecting survival estimates
Missing data: Incomplete or inconsistent data collection
Causality: Association does not prove causation without randomization

Strengthening RWE

Propensity score matching: Balance baseline characteristics between groups
Multivariable adjustment: Adjust for measured confounders in Cox model
Sensitivity analyses: Test robustness to unmeasured confounding
Instrumental variables: Use natural experiments to approximate randomization

Meta-Analysis Techniques

Binary Outcomes (Response Rate, Event Rate)

Effect Measures

Risk Ratio (RR): Ratio of event probabilities
Odds Ratio (OR): Ratio of odds (less intuitive)
Risk Difference (RD): Absolute difference in event rates

Example Calculation

Study 1:
- Treatment A: 30/100 responded (30%)
- Treatment B: 15/100 responded (15%)
- RR = 0.30/0.15 = 2.0 (95% CI 1.15-3.48)
- RD = 0.30 - 0.15 = 0.15 or 15% (95% CI 4.2%-25.8%)
- NNT = 1/RD = 1/0.15 = 6.7 (treat 7 patients to get 1 additional response)

Pooling Methods

Mantel-Haenszel: Common fixed-effect method
DerSimonian-Laird: Random-effects method
Peto: For rare events (event rate <1%)

Time-to-Event Outcomes (Survival, PFS)

Hazard Ratio Pooling

Extract HR and 95% CI (or log(HR) and SE) from each study
Weight by inverse variance
Pool using generic inverse variance method
Report pooled HR with 95% CI, heterogeneity statistics

When HR Not Reported

Extract from Kaplan-Meier curves (Parmar method, digitizing software)
Calculate from log-rank p-value and event counts
Request from study authors

Continuous Outcomes (Quality of Life, Lab Values)

Standardized Mean Difference (SMD)

Application: Different scales used across studies
SMD = (Mean₁ - Mean₂) / Pooled SD
Interpretation: Cohen's d effect size (0.2 small, 0.5 medium, 0.8 large)

Mean Difference (MD)

Application: Same scale/unit used across studies
MD = Mean₁ - Mean₂
More directly interpretable than SMD

Network Meta-Analysis

Purpose

Compare multiple treatments simultaneously when no head-to-head trials exist

Example Scenario

Drug A vs placebo (Trial 1)
Drug B vs placebo (Trial 2)
Drug C vs Drug A (Trial 3)
Question: How does Drug B compare to Drug C? (no direct comparison)

Methods

Fixed-Effect Network Meta-Analysis

Assumes consistency (transitivity): A vs B effect = (A vs C effect) - (B vs C effect)
Provides indirect comparison estimates
Ranks treatments by P-score or SUCRA

Random-Effects Network Meta-Analysis

Allows heterogeneity between studies
More conservative estimates

Consistency Checking

Compare direct vs indirect evidence for same comparison
Node-splitting analysis
Loop consistency (if closed loops in network)

Interpretation Cautions

Transitivity assumption: May not hold if studies differ in important ways
Indirect evidence: Less reliable than direct head-to-head trials
Rankings: Probabilistic, not definitive ordering
Clinical judgment: Consider beyond statistical rankings

Evidence Tables

Constructing Evidence Summary Tables

PICO Framework

P (Population): Patient characteristics, disease stage, biomarker status
I (Intervention): Treatment regimen, dose, schedule
C (Comparator): Control arm (placebo, standard of care)
O (Outcomes): Primary and secondary endpoints

Evidence Table Template

Study         Design  n    Population      Intervention vs Comparator   Outcome            Result                Quality
────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
Smith 2020    RCT     450  Advanced NSCLC  Drug A 10mg vs               Median PFS         12 vs 6 months        High
                           EGFR+           standard chemo               (95% CI)           (10-14 vs 5-7)        ⊕⊕⊕⊕
                                                                        HR (95% CI)        0.48 (0.36-0.64)
                                                                        p-value            p<0.001

                                                                        ORR                65% vs 35%            
                                                                        Grade 3-4 AEs      42% vs 38%

Jones 2021    RCT     380  Advanced NSCLC  Drug A 10mg vs               Median PFS         10 vs 5.5 months      High
                           EGFR+           placebo                      HR (95% CI)        0.42 (0.30-0.58)      ⊕⊕⊕⊕
                                                                        p-value            p<0.001

Pooled Effect                                                          Pooled HR          0.45 (0.36-0.57)      High
(Meta-analysis)                                                        I²                 12% (low heterogeneity) ⊕⊕⊕⊕

Evidence to Decision Framework

Benefits and Harms

Magnitude of desirable effects (ORR, PFS, OS improvement)
Magnitude of undesirable effects (toxicity, quality of life impact)
Balance of benefits and harms
Net benefit calculation

Values and Preferences

How do patients value outcomes? (survival vs quality of life)
Variability in patient values
Shared decision-making importance

Resource Considerations

Cost of intervention
Cost-effectiveness ($/QALY)
Budget impact
Equity and access

Feasibility and Acceptability

Is treatment available in practice settings?
Route of administration feasible? (oral vs IV vs subcutaneous)
Monitoring requirements realistic?
Patient and provider acceptability

Guideline Concordance Documentation

Synthesizing Multiple Guidelines

Concordant Recommendations

Clinical Question: Treatment for HER2+ metastatic breast cancer, first-line

Guideline Summary:
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
NCCN v3.2024 (Category 1):
  Preferred: Pertuzumab + trastuzumab + taxane
  Alternative: T-DM1, other HER2-targeted combinations

ESMO 2022 (Grade I, A):
  Preferred: Pertuzumab + trastuzumab + docetaxel
  Alternative: Trastuzumab + chemotherapy (if pertuzumab unavailable)

ASCO 2020 Endorsement:
  Endorses NCCN guidelines, recommends pertuzumab-based first-line

Synthesis:
  Strong consensus for pertuzumab + trastuzumab + taxane as first-line standard.
  Evidence: CLEOPATRA trial (Swain 2015): median OS 56.5 vs 40.8 months (HR 0.68, p<0.001)
  
Recommendation:
  Pertuzumab 840 mg IV loading then 420 mg + trastuzumab 8 mg/kg loading then 6 mg/kg 
  + docetaxel 75 mg/m² every 3 weeks until progression.
  
  Strength: Strong (GRADE 1A)
  Evidence: High-quality, multiple RCTs, guideline concordance

Discordant Recommendations

Clinical Question: Adjuvant osimertinib for resected EGFR+ NSCLC

NCCN v4.2024 (Category 1):
  Osimertinib 80 mg daily × 3 years after adjuvant chemotherapy
  Evidence: ADAURA trial (median DFS not reached vs 28 months, HR 0.17)

ESMO 2023 (II, B):
  Osimertinib may be considered
  Note: Cost-effectiveness concerns, OS data immature

NICE (UK) 2022:
  Not recommended for routine use
  Reason: QALY analysis unfavorable at current pricing

Synthesis:
  Efficacy demonstrated in phase 3 trial (ADAURA), FDA/EMA approved.
  Guideline discordance based on cost-effectiveness, not clinical efficacy.
  
  US practice: NCCN Category 1, widely adopted
  European/UK: Variable adoption based on national HTA decisions

Recommendation Context-Dependent:
  US: Strong recommendation if accessible (GRADE 1B)
  Countries with cost constraints: Conditional recommendation (GRADE 2B)

Quality Assessment Tools

RCT Quality Assessment (Cochrane Risk of Bias 2.0)

Domains

Bias from randomization process: Sequence generation, allocation concealment
Bias from deviations from intended interventions: Blinding, protocol adherence
Bias from missing outcome data: Attrition, intention-to-treat analysis
Bias in outcome measurement: Blinded assessment, objective outcomes
Bias in selection of reported result: Selective reporting, outcome switching

Judgment: Low risk, some concerns, high risk (for each domain)

Overall Risk of Bias: Based on highest-risk domain

Observational Study Quality (Newcastle-Ottawa Scale)

Selection (max 4 stars)

Representativeness of exposed cohort
Selection of non-exposed cohort
Ascertainment of exposure
Outcome not present at start

Comparability (max 2 stars)

Comparability of cohorts (design/analysis adjustment for confounders)

Outcome (max 3 stars)

Assessment of outcome
Follow-up duration adequate
Adequacy of follow-up (low attrition)

Total Score: 0-9 stars

High quality: 7-9 stars
Moderate quality: 4-6 stars
Low quality: 0-3 stars

Translating Evidence to Recommendations

Recommendation Development Process

Step 1: PICO Question Formulation

Example PICO:
P - Population: Adults with type 2 diabetes and cardiovascular disease
I - Intervention: SGLT2 inhibitor (empagliflozin)
C - Comparator: Placebo (added to standard care)
O - Outcomes: Major adverse cardiovascular events (3P-MACE), hospitalization for heart failure

Step 2: Systematic Evidence Review

Identify all relevant studies
Assess quality using standardized tools
Extract outcome data
Synthesize findings (narrative or meta-analysis)

Step 3: GRADE Evidence Rating

Start at high (RCTs) or low (observational)
Downgrade for risk of bias, inconsistency, indirectness, imprecision, publication bias
Upgrade for large effect, dose-response, confounders reducing effect (observational only)
Assign final quality rating

Step 4: Recommendation Strength Determination

Strong Recommendation (Grade 1)

Desirable effects clearly outweigh undesirable effects
High or moderate quality evidence
Little variability in patient values
Intervention cost-effective

Conditional Recommendation (Grade 2)

Trade-offs: Desirable and undesirable effects closely balanced
Low or very low quality evidence
Substantial variability in patient values/preferences
Uncertain cost-effectiveness

Step 5: Wording the Recommendation

Strong: "We recommend..."
  Example: "We recommend SGLT2 inhibitor therapy for adults with type 2 diabetes and 
  established cardiovascular disease to reduce risk of hospitalization for heart failure 
  and cardiovascular death (Strong recommendation, high-quality evidence - GRADE 1A)."

Conditional: "We suggest..."
  Example: "We suggest considering GLP-1 receptor agonist therapy for adults with type 2 
  diabetes and CKD to reduce risk of kidney disease progression (Conditional recommendation, 
  moderate-quality evidence - GRADE 2B)."

Incorporating Emerging Evidence

Early-Phase Trial Data

Phase 1 Trials

Purpose: Dose-finding, safety
Outcomes: Maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics
Evidence level: Very low (expert opinion, case series)
Clinical application: Investigational only, clinical trial enrollment

Phase 2 Trials

Purpose: Preliminary efficacy signal
Design: Single-arm (ORR primary endpoint) or randomized (PFS comparison)
Evidence level: Low to moderate
Clinical application: May support off-label use in refractory settings, clinical trial enrollment preferred

Phase 3 Trials

Purpose: Confirmatory efficacy and safety
Design: Randomized controlled trial, OS or PFS primary endpoint
Evidence level: High (if well-designed and executed)
Clinical application: Regulatory approval basis, guideline recommendations

Phase 4 Trials

Purpose: Post-marketing surveillance, additional indications
Evidence level: Variable (depends on design)
Clinical application: Safety monitoring, expanded usage

Breakthrough Therapy Designation

FDA Fast-Track Programs

Breakthrough Therapy: Preliminary evidence of substantial improvement over existing therapy
Accelerated Approval: Approval based on surrogate endpoint (PFS, ORR)
- Post-marketing requirement: Confirmatory OS trial
Priority Review: Shortened FDA review time (6 vs 10 months)

Implications for Guidelines

May receive NCCN Category 2A before phase 3 data mature
Upgrade to Category 1 when confirmatory data published
Monitor for post-market confirmatory trial results

Updating Recommendations

Triggers for Update

New phase 3 trial results (major journal publication)
FDA/EMA approval for new indication or agent
Guideline update from NCCN, ASCO, ESMO
Safety alert or drug withdrawal
Meta-analysis changing effect estimates

Rapid Update Process

Critical appraisal of new evidence
Assess impact on current recommendations
Revise evidence grade and recommendation strength if needed
Disseminate update to users
Version control and change log

Conflicts of Interest and Bias

Identifying Potential Bias

Study Sponsorship

Industry-sponsored: May favor sponsor's product (publication bias, outcome selection)
Academic: May favor investigator's hypothesis
Independent: Government funding (NIH, PCORI)

Author Conflicts of Interest

Consulting fees, research funding, stock ownership
Disclosure statements required by journals
ICMJE Form for Disclosure of Potential COI

Mitigating Bias

Register trials prospectively (ClinicalTrials.gov)
Pre-specify primary endpoint and analysis plan
Independent data monitoring committee (IDMC)
Blinding of outcome assessors
Intention-to-treat analysis

Transparency in Evidence Synthesis

Pre-Registration

PROSPERO for systematic reviews
Pre-specify PICO, search strategy, outcomes, analysis plan
Prevents post-hoc changes to avoid negative findings

Reporting Checklists

PRISMA for systematic reviews/meta-analyses
CONSORT for RCTs
STROBE for observational studies

Data Availability

Individual patient data (IPD) sharing increases transparency
Repositories: ClinicalTrials.gov results database, journal supplements

Practical Application

Evidence Summary for Clinical Document

EVIDENCE SYNTHESIS: Osimertinib for EGFR-Mutated NSCLC

Clinical Question:
Should adults with treatment-naïve advanced NSCLC harboring EGFR exon 19 deletion 
or L858R mutation receive osimertinib versus first-generation EGFR TKIs?

Evidence Review:
┌──────────────────────────────────────────────────────────────────────┐
│ FLAURA Trial (Soria et al., NEJM 2018)                              │
├──────────────────────────────────────────────────────────────────────┤
│ Design: Phase 3 RCT, double-blind, 1:1 randomization                │
│ Population: EGFR exon 19 del or L858R, stage IIIB/IV, ECOG 0-1      │
│ Sample Size: n=556 (279 osimertinib, 277 comparator)                │
│ Intervention: Osimertinib 80 mg PO daily                            │
│ Comparator: Gefitinib 250 mg or erlotinib 150 mg PO daily           │
│ Primary Endpoint: PFS by investigator assessment                     │
│ Secondary: OS, ORR, DOR, CNS progression, safety                     │
│                                                                       │
│ Results:                                                             │
│ - Median PFS: 18.9 vs 10.2 months (HR 0.46, 95% CI 0.37-0.57, p<0.001)│
│ - Median OS: 38.6 vs 31.8 months (HR 0.80, 95% CI 0.64-1.00, p=0.046)│
│ - ORR: 80% vs 76% (p=0.24)                                          │
│ - Grade ≥3 AEs: 34% vs 45%                                          │
│ - Quality: High (well-designed RCT, low risk of bias)               │
└──────────────────────────────────────────────────────────────────────┘

Guideline Recommendations:
  NCCN v4.2024: Category 1 preferred
  ESMO 2022: Grade I, A
  ASCO 2022: Endorsed

GRADE Assessment:
  Quality of Evidence: ⊕⊕⊕⊕ HIGH
    - Randomized controlled trial
    - Low risk of bias (allocation concealment, blinding, ITT analysis)
    - Consistent results (single large trial, consistent with phase 2 data)
    - Direct evidence (target population and outcomes)
    - Precise estimate (narrow CI, sufficient events)
    - No publication bias concerns

  Balance of Benefits and Harms:
    - Large PFS benefit (8.7 month improvement, HR 0.46)
    - OS benefit (6.8 month improvement, HR 0.80)
    - Similar ORR, improved tolerability (lower grade 3-4 AEs)
    - Desirable effects clearly outweigh undesirable effects

  Patient Values: Little variability (most patients value survival extension)

  Cost: Higher cost than first-gen TKIs, but widely accessible in developed countries

FINAL RECOMMENDATION:
  Osimertinib 80 mg PO daily is recommended as first-line therapy for adults with 
  advanced NSCLC harboring EGFR exon 19 deletion or L858R mutation.
  
  Strength: STRONG (Grade 1)
  Quality of Evidence: HIGH (⊕⊕⊕⊕)
  GRADE: 1A

Keeping Current

Literature Surveillance

Automated Alerts

PubMed My NCBI (save searches, email alerts)
Google Scholar alerts for specific topics
Journal table of contents alerts (NEJM, Lancet, JCO)
Guideline update notifications (NCCN, ASCO, ESMO email lists)

Conference Monitoring

ASCO Annual Meeting (June)
ESMO Congress (September)
ASH Annual Meeting (December, hematology)
AHA Scientific Sessions (November, cardiology)
Plenary and press releases for practice-changing trials

Trial Results Databases

ClinicalTrials.gov results database
FDA approval letters and reviews
EMA European public assessment reports (EPARs)

Critical Appraisal Workflow

Weekly Review

Screen new publications (title/abstract)
Full-text review of relevant studies
Quality assessment using checklists
Extract key findings
Assess impact on current recommendations

Monthly Synthesis

Review accumulated evidence
Identify practice-changing findings
Update evidence tables
Revise recommendations if warranted
Disseminate updates to clinical teams

Annual Comprehensive Review

Systematic review of guideline updates
Re-assess all recommendations
Incorporate year's evidence
Major version release
Continuing education activities

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