Steps in a Randomised Controlled Trial (RCT)

Definition

Steps in Conducting an RCT

Step 1: Formulation of the Research Question (Hypothesis)

• Define a clear, specific, testable hypothesis.
• State the PICO framework: Population, Intervention, Comparison, Outcome.
• Example: "Does Drug X reduce blood pressure more than placebo in hypertensive adults?"

Step 2: Study Protocol and Ethical Approval

• Write a detailed study protocol specifying design, sample size, eligibility criteria, duration, endpoints, and statistical plan.
• Submit to an Institutional Ethics Committee (IEC) or Institutional Review Board (IRB) for approval.
• Register the trial in a public trial registry (e.g., CTRI in India, ClinicalTrials.gov).
• Obtain informed written consent from all participants.

Step 3: Selection of Study Population

• Define strict inclusion criteria (who qualifies).
• Define strict exclusion criteria (who is left out - e.g., pregnant women, severe comorbidities, children if not applicable).
• Participants must be eligible, willing, and able to comply with the protocol.

Step 4: Sample Size Calculation

• Calculate the minimum number of participants required to detect a clinically meaningful difference (effect size) with adequate:
  • Power (usually 80% or 90%) - probability of detecting a true effect.
  • Significance level (alpha = 0.05) - acceptable probability of false positive.
• Inadequate sample size leads to underpowered trials (false negatives).

Step 5: Randomisation (Allocation)

Step 6: Allocation Concealment

• The randomisation sequence must be concealed from the person recruiting/enrolling participants until the moment of allocation.
• Prevents selection bias even when randomisation has occurred.
• Methods: Sequentially Numbered Opaque Sealed Envelopes (SNOSE), central telephone randomisation, web-based systems.
• Allocation concealment ≠ blinding; it occurs before allocation, blinding occurs after.

Step 7: Blinding (Masking)

• Use of identical placebo (same appearance, taste, smell) is required for drug trials.

Step 8: Implementation of Intervention

• Administer the intervention (drug, vaccine, procedure) to the experimental group.
• Administer a placebo or standard treatment to the control group.
• Ensure protocol adherence and monitor for protocol deviations.
• Maintain a run-in period if needed (to exclude non-compliant participants before randomisation).

Step 9: Follow-up and Data Collection

• Follow all participants for a pre-specified duration.
• Collect outcome data at defined time points.
• Monitor for:
  • Adverse events and side effects
  • Drop-outs and withdrawals (document reasons)
  • Cross-overs (control participants receiving intervention)
• Minimise loss to follow-up (should ideally be <20%).

Step 10: Outcome Assessment

• Measure primary outcomes (the main endpoint, e.g., mortality, cure rate).
• Measure secondary outcomes (additional endpoints, e.g., hospitalisations, quality of life).
• Use pre-defined, objective, validated outcome measures.
• Outcome assessors should be blinded to group assignment.

Step 11: Statistical Analysis

• Intention-to-treat (ITT) analysis - analyse all participants in the group they were originally randomised to, regardless of compliance. This preserves the benefit of randomisation and reflects real-world effectiveness.
• Per-protocol (PP) analysis - analyse only those who completed the trial per protocol. Gives a measure of efficacy under ideal conditions.
• Compare outcomes between groups using appropriate statistical tests (t-test, chi-square, log-rank, etc.).
• Calculate Relative Risk (RR), Relative Risk Reduction (RRR), Absolute Risk Reduction (ARR), and Number Needed to Treat (NNT).

Step 12: Reporting of Results

• Report results following the CONSORT (Consolidated Standards of Reporting Trials) checklist and flow diagram.
• The CONSORT flow diagram shows: enrolled -> randomised -> allocated -> followed-up -> analysed in each group, with reasons for exclusion at every step.
• Publish in a peer-reviewed journal with full disclosure of conflicts of interest and funding.

Summary Flowchart

Hypothesis → Protocol & Ethics Approval → Eligibility Criteria
→ Sample Size Calculation → Enrolment of Participants
→ RANDOMISATION
          ↙               ↘
 Experimental Group     Control Group
 (Intervention)         (Placebo/Standard Rx)
          ↓                   ↓
       Follow-up & Outcome Assessment (Blinded)
          ↓
    Statistical Analysis (ITT)
          ↓
    Reporting (CONSORT)

Common Biases in RCTs and How Steps Address Them

Important Terminologies

• Phase I trial: Safety and dosage - small group of healthy volunteers.
• Phase II trial: Efficacy and side effects - small group of patients.
• Phase III trial: Definitive efficacy vs. control in large population - this is the classic RCT.
• Phase IV trial: Post-marketing surveillance after drug approval.
• Run-in period: Pre-randomisation period to check compliance and exclude non-responders.
• Wash-out period: Period between arms in crossover trials to eliminate carry-over effects.
• Cross-over RCT: Same participant receives both intervention and control in sequence (with wash-out in between); each participant is their own control.

Key Points for Exam

1. Randomisation is the defining feature of an RCT - it eliminates confounding.
2. Allocation concealment prevents selection bias at enrolment.
3. Blinding prevents bias after allocation.
4. Intention-to-treat analysis is the standard; it preserves the benefits of randomisation.
5. CONSORT checklist is the reporting standard for RCTs.
6. Phase III trials are the classic RCT used for drug/vaccine approval.
7. RCT has highest internal validity among analytical study designs but may have limited external validity due to strict eligibility criteria.

• The RANDOMISATION box is the central/highlighted step - examiners always look for this
• Show the split into two parallel arms (Experimental vs Control) clearly with branching arrows
• Write Intention-to-Treat (ITT) Analysis specifically in the analysis step - it's a common viva point
• End with CONSORT - shows awareness of reporting standards
• You can add a side note: "Allocation concealment prevents selection bias; Blinding prevents performance and detection bias"

Recent RCT Examples from PubMed

VACCINE TRIALS

• Reference: Wilson E et al., N Engl J Med, Dec 2023 - PMID: 38091530
• Design: Double-blind, placebo-controlled Phase II/III RCT
• Intervention: mRNA-based RSV PreF vaccine vs placebo in adults aged 60+
• Key finding: Significant reduction in RSV-associated lower respiratory tract disease
• PSM relevance: Classic example of vaccine RCT with blinding, Phase III design, and elderly population

• Reference: Tricou V et al., Lancet Global Health, Feb 2024 - PMID: 38245116
• Design: Phase III, randomised, double-blind, placebo-controlled, long-term follow-up
• Intervention: Tetravalent dengue vaccine TAK-003 vs placebo
• Key finding: Sustained efficacy over 4.5 years, good safety profile
• PSM relevance: Excellent example of long-term follow-up in an RCT; dengue is a major PSM topic in India

• Reference: Kallás EG et al., N Engl J Med, Feb 2024 - PMID: 38294972
• Design: Phase III RCT, live attenuated tetravalent vaccine
• Key finding: Efficacious in dengue-naive and pre-immune individuals
• PSM relevance: Shows stratified randomisation by serostatus; covers both adults and children

• Reference: Simões EAF et al., Obstet Gynecol, Feb 2025 - PMID: 39746212
• Design: Phase III, multicenter, randomised, double-blind
• Intervention: RSV PreF protein vaccine given during pregnancy (maternal immunisation)
• PSM relevance: Demonstrates special population RCT design (pregnant women), maternal-neonatal protection - links to MCH/immunisation programs

DRUG TRIALS

• Reference: Zhao L et al., JAMA, Aug 2024 - PMID: 38819983
• Design: Phase III, multicenter, randomised, placebo-controlled
• Intervention: Tirzepatide (GLP-1/GIP dual agonist) vs placebo in Chinese adults with obesity
• Key finding: Significant weight reduction
• PSM relevance: NCD prevention, obesity as a public health problem, drug trial example with dose-response arms

• Reference: Wharton S et al., N Engl J Med, 2025 - PMID: 40960239
• Design: Phase III, multicenter RCT
• Intervention: Oral small-molecule GLP-1 receptor agonist (no injection needed)
• PSM relevance: Very recent trial; shows evolution of drug delivery - relevant to NCD burden

• Reference: Piazza G et al., N Engl J Med, 2025 - PMID: 40888734
• Design: Phase IV RCT (post-marketing)
• PSM relevance: Perfect example of a Phase IV / post-marketing surveillance trial - a commonly asked exam distinction

How to Use These in Your Exam

Exam tip: When citing an example RCT, mention: trial name (if any), drug/vaccine, journal, year, phase, and key design feature (double-blind, placebo-controlled, multicenter). This impresses examiners and shows you read current literature.