# Recommendation Strength Guide

## GRADE Framework for Clinical Recommendations

### Components of a Recommendation

Every clinical recommendation should address:

1. **Population**: Who should receive the intervention?
2. **Intervention**: What specific treatment/action?
3. **Comparator**: Compared to what alternative?
4. **Outcome**: What are the expected results?
5. **Strength**: How strong is the recommendation?
6. **Quality of Evidence**: How confident are we in the evidence?

### Recommendation Strength (Grade 1 vs Grade 2)

#### Strong Recommendation (Grade 1)

**When to Use**:
- Desirable effects clearly outweigh undesirable effects (or vice versa)
- High or moderate quality evidence
- Values and preferences: Little variability expected
- Resource implications: Cost-effective or cost considerations minor

**Wording**: "We recommend..." or "Clinicians should..."

**Implications**:
- Most patients should receive the recommended intervention
- Adherence to recommendation could be a quality indicator
- Policy-makers can adapt as performance measure

**Examples**:

```
STRONG RECOMMENDATION FOR (Grade 1):

"We recommend osimertinib 80 mg daily as first-line therapy for adults with 
advanced NSCLC harboring EGFR exon 19 deletion or L858R mutation (Strong 
recommendation, High-quality evidence - GRADE 1A)."

Rationale:
- Large PFS benefit: 18.9 vs 10.2 months (HR 0.46, p<0.001)
- OS benefit: 38.6 vs 31.8 months (HR 0.80, p=0.046)  
- Better tolerability: Lower grade 3-4 AEs
- Evidence: High-quality (large RCT, low risk of bias)
- Benefits clearly outweigh harms
```

```
STRONG RECOMMENDATION AGAINST (Grade 1):

"We recommend against using bevacizumab in the first-line treatment of newly 
diagnosed glioblastoma to improve overall survival (Strong recommendation against, 
High-quality evidence - GRADE 1A)."

Rationale:
- No OS benefit: HR 0.88 (0.76-1.02), p=0.10 (AVAglio trial)
- Toxicity: Increased grade ≥3 AEs (66% vs 52%)
- Evidence: High-quality (two large phase 3 RCTs)
- Harms outweigh lack of survival benefit
```

#### Conditional/Weak Recommendation (Grade 2)

**When to Use**:
- Desirable and undesirable effects closely balanced
- Low or very low quality evidence
- Values and preferences: Substantial variability
- Resource implications: High cost or limited access

**Wording**: "We suggest..." or "Clinicians might..."

**Implications**:
- Different choices will be appropriate for different patients
- Shared decision-making essential
- Policy-making requires substantial debate and stakeholder involvement

**Examples**:

```
CONDITIONAL RECOMMENDATION FOR (Grade 2):

"We suggest considering maintenance pemetrexed after first-line platinum-pemetrexed 
chemotherapy for advanced non-squamous NSCLC in patients without disease progression 
(Conditional recommendation, Moderate-quality evidence - GRADE 2B)."

Rationale:
- Modest PFS benefit: 4.0 vs 2.0 months (HR 0.62)
- No OS benefit: 13.9 vs 11.0 months (HR 0.79, p=0.23)
- Toxicity: Continued chemotherapy burden
- Quality of life: Trade-off between symptom control and treatment side effects
- Patient values: Some prioritize time off treatment, others prioritize disease control
- Shared decision-making essential
```

```
CONDITIONAL RECOMMENDATION - EITHER OPTION ACCEPTABLE (Grade 2):

"We suggest either pembrolizumab monotherapy OR pembrolizumab plus platinum-doublet 
chemotherapy as first-line treatment for PD-L1 ≥50% NSCLC, based on patient 
preferences and clinical factors (Conditional recommendation, High-quality evidence - 
GRADE 2A)."

Rationale:
- Both regimens NCCN Category 1 preferred
- Monotherapy: Less toxicity, oral vs IV, better quality of life
- Combination: Higher ORR (48% vs 39%), numerically longer PFS
- OS: Similar between strategies
- Patient values: Varies widely (tolerability vs response rate priority)
```

### Evidence Quality (⊕⊕⊕⊕ to ⊕○○○)

#### High Quality (⊕⊕⊕⊕)

- Further research very unlikely to change confidence in effect estimate
- Consistent results from well-designed RCTs
- No serious limitations
- Direct evidence (target population, intervention, outcomes)
- Precise estimate (narrow CI)

**Example**: FLAURA trial for osimertinib in EGFR+ NSCLC - Large RCT, consistent results, low risk of bias, direct outcomes

#### Moderate Quality (⊕⊕⊕○)

- Further research likely to impact confidence and may change estimate
- RCTs with some limitations OR very strong evidence from observational studies
- Some inconsistency, indirectness, imprecision, or publication bias

**Example**: Single RCT with some limitations, or multiple RCTs with moderate heterogeneity

#### Low Quality (⊕⊕○○)

- Further research very likely to have important impact on confidence in estimate
- Observational studies OR RCTs with serious limitations
- Serious issues with consistency, directness, precision, or bias

**Example**: Well-conducted cohort study, or RCT with high attrition and unclear allocation concealment

#### Very Low Quality (⊕○○○)

- Estimate of effect very uncertain
- Case series, expert opinion, mechanistic reasoning
- Very serious limitations

**Example**: Retrospective case series, expert consensus without systematic review

## Combining Strength and Quality

### All Nine Possible Combinations

| Evidence Quality | Strong For (↑↑) | Weak For (↑) | Strong Against (↓↓) | Weak Against (↓) |
|-----------------|----------------|--------------|---------------------|------------------|
| **High (⊕⊕⊕⊕)** | Grade 1A | Grade 2A | Grade 1A (against) | Grade 2A (against) |
| **Moderate (⊕⊕⊕○)** | Grade 1B | Grade 2B | Grade 1B (against) | Grade 2B (against) |
| **Low (⊕⊕○○)** | Grade 1C* | Grade 2C | Grade 1C (against)* | Grade 2C (against) |
| **Very Low (⊕○○○)** | Grade 1D* | Grade 2D | Grade 1D (against)* | Grade 2D (against) |

*Rare: Strong recommendations usually require at least moderate-quality evidence

### Unusual Combinations (When They Occur)

**Strong Recommendation with Low Quality Evidence (Grade 1C)**

Rare, but can occur when:
- Large magnitude of effect from observational data (RR >5 or <0.2)
- Low quality evidence, but clear benefit-harm balance
- Example: Anticoagulation for atrial fibrillation (before RCTs, strong observational data)

**Weak Recommendation with High Quality Evidence (Grade 2A)**

Occurs when:
- Benefits and harms closely balanced
- Patient values highly variable
- Example: Aspirin for primary prevention in low-risk individuals (benefits small, bleeding risk present, patient values vary)

## Wording Templates

### Strong Recommendations

**FOR (↑↑)**:
- "We recommend [intervention] for [population]."
- "Clinicians should [action]."
- "[Intervention] is recommended."

**AGAINST (↓↓)**:
- "We recommend against [intervention] for [population]."
- "Clinicians should not [action]."
- "[Intervention] is not recommended."

### Conditional/Weak Recommendations

**FOR (↑)**:
- "We suggest [intervention] for [population]."
- "Clinicians might consider [action]."
- "[Intervention] may be considered for selected patients."

**AGAINST (↓)**:
- "We suggest not using [intervention] for [population]."
- "Clinicians might avoid [action]."
- "[Intervention] is generally not recommended."

**EITHER ACCEPTABLE**:
- "We suggest either [option A] or [option B] based on patient preferences."
- "Either approach is reasonable."

## Color Coding for Visual Documents

**Strong Recommendations (Green Background)**:
- RGB(0, 153, 76) or #009954
- Clear visual priority
- Use for Grade 1A, 1B

**Conditional Recommendations (Yellow Background)**:
- RGB(255, 193, 7) or #FFC107
- Indicates discussion needed
- Use for Grade 2A, 2B, 2C

**Research/Investigational (Blue Background)**:
- RGB(33, 150, 243) or #2196F3
- Clinical trial consideration
- Insufficient evidence for standard care

**Not Recommended (Red Border/Background)**:
- RGB(220, 20, 60) or #DC143C
- Strong recommendation against
- Evidence of harm or no benefit

## Common Scenarios

### Scenario 1: Strong Evidence, Clear Benefit-Harm Balance

**Example**: Pembrolizumab for PD-L1 ≥50% NSCLC

- Evidence: Large phase 3 RCT (KEYNOTE-024), n=305, well-designed
- Results: PFS HR 0.50 (0.37-0.68), OS HR 0.60 (0.41-0.89)
- Toxicity: Lower grade 3-5 AEs than chemotherapy (27% vs 53%)
- Patient values: Most prioritize efficacy and tolerability

**Recommendation**: STRONG FOR (Grade 1A)

### Scenario 2: Moderate Evidence, Balanced Trade-Offs

**Example**: Adjuvant immunotherapy for resected melanoma

- Evidence: RCT showing relapse-free survival benefit, OS data immature
- Results: Recurrence risk reduced but ongoing toxicity
- Toxicity: Immune-related AEs requiring steroids (some severe)
- Cost: High annual cost for 12 months treatment
- Patient values: Variable (some prioritize recurrence prevention, others avoid toxicity)

**Recommendation**: CONDITIONAL FOR (Grade 2B)

### Scenario 3: Low Evidence, but Severe Consequence

**Example**: Anticoagulation for prosthetic heart valve

- Evidence: No RCTs (would be unethical), observational data and mechanistic reasoning
- Consequence: Very high thromboembolic risk without anticoagulation
- Benefit-harm: Clear despite low quality evidence

**Recommendation**: STRONG FOR (Grade 1C)

### Scenario 4: High Evidence, but Patient Preferences Vary

**Example**: Breast reconstruction after mastectomy

- Evidence: High-quality data on outcomes and satisfaction
- Trade-offs: Cosmetic benefit vs additional surgery, recovery time
- Values: Highly personal decision, wide preference variability

**Recommendation**: CONDITIONAL (Grade 2A) - discuss options, patient decides

## Documentation Template

```
RECOMMENDATION: [State recommendation clearly]

Strength: [STRONG / CONDITIONAL]
Quality of Evidence: [HIGH / MODERATE / LOW / VERY LOW]
GRADE: [1A / 1B / 2A / 2B / 2C]

Evidence Summary:
- Primary study: [Citation]
- Design: [RCT / Observational / Meta-analysis]
- Sample size: n = [X]
- Results: [Primary outcome with effect size, CI, p-value]
- Quality assessment: [Strengths and limitations]

Benefits:
- [Quantified benefit 1]
- [Quantified benefit 2]

Harms:
- [Quantified harm 1]
- [Quantified harm 2]

Balance: [Benefits clearly outweigh harms / Close balance requiring discussion / etc.]

Values and Preferences: [Little variability / Substantial variability]

Cost Considerations: [If relevant]

Guideline Concordance:
- NCCN: [Category and recommendation]
- ASCO: [Recommendation]
- ESMO: [Grade and recommendation]
```

## Quality Checklist

Before finalizing recommendations, verify:

- [ ] Recommendation statement is clear and actionable
- [ ] Strength is explicitly stated (strong vs conditional)
- [ ] Quality of evidence is graded (high/moderate/low/very low)
- [ ] GRADE notation provided (1A, 1B, 2A, 2B, 2C)
- [ ] Evidence is cited with specific study results
- [ ] Benefits are quantified (effect sizes with CIs)
- [ ] Harms are quantified (AE rates)
- [ ] Balance of benefits/harms is explained
- [ ] Patient values consideration is addressed (if conditional)
- [ ] Alternative options are mentioned
- [ ] Guideline concordance is documented
- [ ] Special populations are addressed (elderly, renal/hepatic impairment)
- [ ] Monitoring requirements are specified