Game 8 · Clinical trials
Which trial design answers this question?
Phases of trials, placebo, crossover and factorial designs, superiority and non-inferiority.
Read with: Clinical trials, Equivalence and non-inferiority113 DNB questions
Play
Pick the design, read the margin, set the washout
Rounds ask you to classify a non-inferiority result from its confidence interval, find the smallest difference that still shows non-inferiority, set a crossover washout from a half-life, match a research question to its design, and judge a placebo arm. You have three lives.
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Drug development
Phases 0 to IV
| Phase | Also called | Who takes part | Main question |
|---|---|---|---|
| 0 | Exploratory IND study | A few volunteers or patients | Does the drug reach and act on its target, at subtherapeutic doses? |
| I | Human pharmacology | Healthy volunteers, or patients when the drug is toxic (cytotoxics) | Safety and tolerability at first use in humans, dose range, pharmacokinetics |
| II | Therapeutic exploratory | Patients with the condition, a fairly uniform group | Does it work, what are the short-term side effects, which dose for phase III? |
| III | Therapeutic confirmatory | Larger groups, often in many centres | Confirm benefit and safety, as a basis for marketing approval |
| IV | Therapeutic use, post-marketing | Patients using the approved drug | Uncommon adverse effects, interactions, mortality and morbidity studies |
In India, the New Drugs and Clinical Trials Rules, 2019 (First Schedule, paragraph 3(2)) describe four phases, I to IV, in these terms. Phase 0 is not one of them. It comes from the US FDA exploratory IND guidance. ICH E8 notes that phases describe the usual order of development and are not the same thing as study types.
Type of comparison
Superiority, non-inferiority and equivalence
Δ (delta) is the margin: the largest difference that is clinically acceptable, fixed in the protocol and smaller than the differences seen in superiority trials of the active comparator (ICH E9). Read the 95% confidence interval for the difference (new minus standard) against 0 and against the margin.
Non-inferiority shown when: lower 95% limit > −Δ
Superiority shown when: lower 95% limit > 0
Equivalence shown when: −Δ < whole interval < +Δ
- Δ
- non-inferiority or equivalence margin, set before the trial
- lower 95% limit
- lower end of the two-sided 95% CI, which matches a one-sided α of 2.5% for non-inferiority
An interval that crosses −Δ is inconclusive. An interval entirely below −Δ shows the new treatment is worse by more than the margin. A superiority trial with p > 0.05 does not show equivalence: ICH E9 calls that conclusion inappropriate. A non-inferiority trial makes sense only when the new treatment has another advantage, such as cost, safety or an oral route.
Margins, M1 and M2, and two one-sided tests are in the equivalence and non-inferiority chapter.
Designs
Crossover, factorial, cluster and n-of-1
| Feature | Parallel group | Crossover |
|---|---|---|
| Each patient receives | One treatment | Both treatments, in random order |
| Comparison | Between patients | Within patients, so fewer patients are needed |
| Suits | Most confirmatory trials, curable conditions, death as outcome | Chronic stable conditions, effects that wear off |
| Main problem | Needs more patients | Carryover from period 1 into period 2 |
A washout separates the two periods so the first drug wears off. Each elimination half-life halves the amount left.
Fraction left after the washout = 0.5^(washout ÷ half-life)
- half-life
- time for the drug level to fall by half
- washout
- time between the last dose of period 1 and the first of period 2
After 5 half-lives about 3% remains, and bioequivalence crossovers usually use a washout of at least 5 elimination half-lives (EMA, 2010). ICH E9 notes that in the 2 × 2 design carryover cannot be told apart from the treatment × period interaction, and the test for it lacks power, so prevent carryover with the washout. A factorial trial tests two treatments at once (A or not A, B or not B). A cluster trial randomises whole groups such as villages and needs a larger sample size. An n-of-1 trial is a randomised crossover in a single patient. An adaptive trial makes changes that were planned in the protocol, such as dropping a futile arm.
Ethics
When can the control group receive a placebo?
The Declaration of Helsinki (2024, paragraph 33) requires a new intervention to be tested against the best proven intervention. A placebo is acceptable when no proven intervention exists, or when there are compelling scientific reasons and participants will not be subject to additional risks of serious or irreversible harm. ICMR 2017 (section 7.4) allows placebo when there is no established effective therapy, when withholding therapy causes only temporary discomfort, when the disease is self-limited, or when an active comparator would not give reliable results and placebo adds no risk of serious harm.
Safeguards include rescue medication, clear withdrawal criteria, close monitoring, the add-on design (placebo or new drug added to standard care) and unequal allocation such as 2 : 1. The NDCT Rules 2019 define a placebo as an inactive substance visually identical to the drug being tested, and count failure to give available standard care in a placebo-controlled trial as trial-related injury (rule 41).
Writing the answer
How to write this in a 10-mark DNB answer
- For phases, draw a five-column table (phase, other name, participants, question, design) and cite the NDCT Rules 2019 First Schedule.
- For non-inferiority, draw the number line with 0 and −Δ and four confidence intervals: superior, non-inferior, inconclusive, inferior.
- Define the margin, say who sets it and when, and state the null hypothesis: the new treatment is worse by Δ or more.
- Add a line on analysis: ITT and per protocol both reported, because ITT is not conservative here.
- For crossover, draw the AB/BA diagram with a washout, and give the conditions: chronic stable disease, effect that wears off, washout of at least 5 half-lives.
- For placebo, quote Helsinki 2024 paragraph 33 and the ICMR 2017 conditions, with one example of an add-on design.
The one thing to remember
Decide before the trial what you want to show, better, not worse or the same, because the hypothesis, the margin and the sample size all follow from that choice.
Past papers
DNB questions this game helps you answer
Questions from NBE theory papers for DNB, DrNB and Diploma courses, most often asked first. The tag after each question is the specialty and the year it was set.
- ×4List the steps of a randomized controlled trial.
- ×2Randomized control trial.
- ×1Define randomized controlled trial. [2]
- ×1Describe descriptive and analytical study designs. Where does “clinical trial” fall in the above classification? Describe the various phases of a clinical trial and give some examples of its use in genetic disorders. [4+2+4]
- ×1What is the difference between case control study and randomized control study? [4]
- ×1Advantages and disadvantages of randomised control trial over other study types.
- ×1Describe briefly the various phases of clinical trials.
- ×1Mention the different types of COVID vaccines. Describe the phases of clinical trials for vaccine development.
- ×1Phase II clinical trial.
- ×1Phases of clinical trial.
- ×1Trial designs, differences and clinical implications.
- ×1What is Randomized Controlled Trial (RCT)? Describe its usefulness and limitations in clinical research.
- ×1What is a placebo? Discuss the role of placebo in clinical trials.
- ×1What is phase III clinical trial?
- ×1What is randomized controlled study? How would you do randomization?
- ×1You are having many patients with hypertension taking treatment in your family practice. Only 50% of them are controlled with medications. Rest of them are uncontrolled even after taking regular medications. You want to study whether drug A or drug B is effective for hypertension in your population. b) How will you plan and execute a Randomized Controlled Clinical Trial (RCT) in your population?
- ×1You are having many patients with hypertension taking treatment in your family practice. Only 50% of them are controlled with medications. Rest of them are uncontrolled even after taking regular medications. You want to study whether drug A or drug B is effective for hypertension in your population. c) What are the factors that affect the quality of an RCT?
- ×1Equivalence trials and Non-inferiority trials.
- ×1Describe in detail alongwith one example each the following research studies: a) Cross sectional study. b) Randomized control trial. c) Cohort studies.
- ×1Discuss Randomized Controlled Trials (RCT).
- ×1Enumerate the steps involved in a Phase III clinical trial and its impact on treatment guidelines.
- ×1Explain event-driven trial design in clinical research.
- ×1Name different types of clinical trials. Discuss randomised control trials.
- ×1Phase 0 clinical trials.
- ×1Define the steps of randomised controlled trial.
- ×1Describe role of concealment (blinding) in randomised control studies.
- ×1Describe the methodology of Randomised Control Trial (RCT).
- ×1Describe the phases of clinical trials.
- ×1Discuss Phase II clinical trials.
- ×1Enlist steps in conducting a randomized controlled trial. Describe intention to treat analysis and per protocol analysis.
- ×1Randomized controlled trials (RCT) - conduct and importance for clinical practice.
- ×1What are the current guidelines for reporting Randomised Controlled Trials in Radiation Oncology.
- ×1What are the different phases of a clinical trial? Define interim analysis, definitive analysis and secondary analysis giving one suitable example of each.
- ×1What is Randomised Controlled Double Blind trial? Give one example.
- ×1What is phase III trial? Give example of a Phase III trial in radiotherapy of breast cancer.
- ×1Write important features of sequential trial design.
- ×1a) Discuss about statistical considerations in analysis of a randomized controlled trial. [3] b) Write briefly about conventional design used in phase 1 trials of anticancer drugs and challenges of its applications in targeted drugs. [3] c) What are basket and umbrella trial designs? Write with some examples of known clinical trials using these designs.
- ×1Clinical research methodology: What are various Phases of clinical trials?
- ×1Compare and contrast blinding and concealment in randomised controlled trials.
- ×1Discuss Factorial design trial with an example.
- ×1Discuss briefly the adaptive clinical trial designs and its challenges.
- ×1Discuss the method of conducting and reporting of studies: Randomized control trial.
- ×1Discuss the phases of clinical trials of a new drug.
- ×1Discuss the various Bias while conducting a randomized controlled trial and ways to minimize them.
- ×1Discuss the various phases of clinical trial.
- ×1Give an account of phase 0 clinical trials. Discuss the advantages and limitations for conducting such trials?
- ×1Randomised control trial (RCT).
- ×1Randomized controlled trials. [RCT].
- ×1What are various types of research studies? Compare RCT with Case-control study.
- ×1What is a phase I clinical trial?
- ×1Clinical research methodology: Describe design of a phase-III randomized trial to test non-inferiority of oral metronomic chemotherapy compare to conventional intravenous chemotherapy in recurrent epithelial ovarian cancer.
- ×1Describe phase 0, Phase I and Phase IV clinical trials.
- ×1Describe steps in planning a Randomised Controlled Study.
- ×1Design of Randomized Control trials.
- ×1Double blind randomised controlled trial.
- ×1Enlist different types of Randomized Control Trials. Give any four examples of important risk factor intervention trials for coronary heart disease.
- ×1Phases of clinical trial and phases of anticancer drug development.
- ×1Randomized Controlled Trials.
- ×1What are adaptive clinical trials? Explain with example.
- ×1What is the purpose of randomization in a randomized controlled trial?
- ×1Why and how is allocation concealment done in a randomized controlled trial?
- ×1Blinding in randomized controlled trial.
- ×1Define precision oncology. Enumerate different precision oncology trial designs with examples.
- ×1Describe Randomized Controlled Trial. Give a flow chart depicting a Randomized Controlled Trial.
- ×1Describe different phases of clinical trials.
- ×1Phase II Randomized Control Trials.
- ×1Phase II trial.
- ×1Plan RCT on use of calcium supplementation for prevention of hypocalcaemia in apheresis donors.
- ×1Principles of randomized controlled study.
- ×1Randomized Controlled Trial (RCT).
- ×1Role of placebo in therapeutics.
- ×1What is a randomized control Trial? Discuss examples of any two of the trials done in the specialty of Respiratory Medicine.
- ×1What is null and alternate hypothesis in superiority and non-inferiority clinical trials? Explain type I and type II errors with examples.
- ×1Analysis in Randomized Control Trials.
- ×1Basic design of a Randomized Control Trial.
- ×1Basic requirements in a randomized controlled trial.
- ×1Describe the various phases of clinical trials.
- ×1Draw a CONSORT flow chart and describe the steps in a Randomized Controlled Trial.
- ×1Noninferiority trial design.
- ×1Phases of clinical trials.
- ×1Randomization in Randomized Control Trials.
- ×1You want to investigate the effectiveness of a single high dose of 10 azithromycin as compared to the usual treatment for outpatient management of community acquired pneumonia, using a randomized controlled trial. Write briefly on the steps involved in this.
- ×1Aims of RCT.
- ×1Key elements of a randomized controlled trial.
- ×1Outline a design of a phase 1 clinical trial.
- ×1What are the objectives of phase 1 clinical trial?
- ×1What is a “Randomized Control Trial”?
- ×1Characteristics of various phases of clinical trials
- ×1Discuss the various phases of a clinical trial.
- ×1Randomized control trials- Define and give examples in GI surgery.
- ×1Randomized controlled trials
- ×1What is a phase IV clinical trial?
- ×1Design & types of RCT.
- ×1Design of a randomized control trial (RCT).
- ×1Is evidence provided by Randomised Controlled Trial (RCT) better than Case Reports? Explain.
- ×1Outline the advantages and disadvantages of Randomized Control Trials.
- ×1Randomized controlled trial.
- ×1Randomized controlled trials.
- ×1Submit a plan of Randomized Control Trial with an 10 illustrative example.
- ×1What are Phase I, II, III trials?
- ×1What are Randomized Control Trials?
- ×1What are the types of RCT?
- ×1What is phase III clinical trial? Give example of a Phase III trial in radiotherapy of breast cancer.
- ×1What is ‘Randomized Control Trial’ (RCT)?
- ×1Advantages of conducting a Randomised control trial.
- ×1RCT (Randomized controlled trial).
- ×1Various phases of clinical trials.
- ×1What is a Randomized Control Trial (RCT)?
- ×1Different phases of clinical trials of a drug.
- ×1What are the various types of clinical trials? What are biomarkers driven adaptive clinical trials? What are Gene chip arrays?
- ×1What do you understand by double blind placebo controlled trial and its significance?
- ×1Randomized Control Trial (RCT)
- ×1What are the features of the different phases of clinical trials? What is the importance of randomization and stratification?
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