Clinical Trials: Protocol Design, Current Issues and Future Developments

30 question-and-answer flashcards covering definitions, key design features (control, randomisation, blinding, endpoints), common trial designs, phases, protocol contents, and current/future issues in clinical trial conduct.

What is a clinical trial?

An investigation in human subjects intended to discover or verify the clinical, pharmacological or pharmacodynamic effects of an investigational product, identify adverse reactions, or study its ADME, with the goal of establishing safety and/or efficacy.

What are Randomised Controlled Trials (RCTs) and why are they pivotal in drug development?

RCTs randomly assign participants to an experimental or control group to minimise bias; they are the standard design for most Phase I–III studies and many Phase IV studies.

In clinical trials, what are the two meanings of the word “control”?

(1) Overall adherence to a scientifically written protocol that minimises bias; (2) use of comparator treatments (active drug or placebo) against which the investigational product is benchmarked.

Name two common comparator controls used in clinical trials.

Active control (e.g., established therapy or lifestyle change) and placebo.

Why is placebo often considered the most credible control, and when might it be unethical to use?

It distinguishes drug effects from non-pharmacologic effects and minimises bias, but may be unethical in serious conditions like cancer or when effective therapy already exists.

Define randomisation in a clinical trial.

The process of assigning treatments to participants by chance to minimise selection bias and give each subject an equal probability of receiving any treatment.

What is simple randomisation?

Straightforward allocation where each participant is independently and randomly assigned to a treatment group with no constraints (e.g., coin toss for each subject).

What is block randomisation and its main purpose?

Participants are randomised within small blocks so that equal numbers are assigned to each treatment in every block, maintaining balance throughout enrolment.

What is stratified randomisation?

Participants are first grouped into strata based on prognostic factors (e.g., age group) and then randomised within each stratum to ensure balanced distribution of those factors across treatments.

What is blinding and what bias does it prevent?

Concealing treatment allocation from one or more parties (participants, investigators, assessors) to reduce performance and assessment bias.

Differentiate single-blind from double-blind trials.

Single-blind: typically participants are unaware of treatment identity; investigators know. Double-blind: both participants and investigators (and often assessors) are unaware of treatment assignments.

What is an open-label trial?

A study conducted without blinding; all parties know which treatment each participant receives.

Give two techniques that help maintain blinding when treatments look different.

Over-encapsulation of tablets/capsules and the double-dummy technique (each group receives active drug plus matching placebo of the comparator).

What is an endpoint in a clinical trial?

A specific, precisely defined outcome variable measured to assess whether a treatment achieves the study objective; can be primary or secondary.

What is a surrogate endpoint?

A biomarker that substitutes for a clinical endpoint (e.g., blood pressure used in place of cardiovascular events).

How do parallel group and crossover designs differ in variability and sample size?

Parallel: between-subject comparisons, higher variability, generally larger sample size. Crossover: within-subject comparisons, lower variability, smaller sample size.

What is a carry-over effect and in which design can it occur?

Residual influence of a treatment into the next study period; it can occur in crossover designs and is mitigated by washout intervals.

Phase I trials: primary goal, population, typical size and success rate.

Goal: assess safety, tolerability, pharmacokinetics; Population: healthy volunteers (or patients unlikely to benefit); Size: ~20–100; Success: ≈70 % advance to Phase II.

Phase II trials: primary goal and success rate.

Goal: evaluate safety and preliminary efficacy (proof of concept) in patients with the target disease; Success: ≈30 % move to Phase III.

Phase III trials: purpose and success rate.

Confirm efficacy and safety of one or more doses in large patient populations to support marketing application; Success: ≈25–30 % achieve approval.

Phase IV trials: objective and typical population.

Post-approval studies to monitor long-term safety/efficacy or explore new indications in patients using the marketed drug.

List at least five key elements that should appear in a clinical trial protocol.

Background and rationale, objectives/endpoints, trial design, eligibility criteria, treatment regimen, statistical analysis plan, quality control/assurance, ethics/regulatory information, data handling, publication policy.

Why are poorly designed trials considered unethical?

They may yield unreliable results, waste resources, expose participants to unnecessary risk, and potentially harm both participants and the public by leading to wrong conclusions.

What risks arise from eligibility criteria that are too loose or too stringent?

Too loose: heterogeneous data and potential safety concerns; Too stringent: slow recruitment and unrepresentative sample.

How can excessive trial complexity affect cost and data quality?

More procedures inflate per-visit costs, burden participants, increase errors, and generate non-core data that may not aid regulatory decisions.

According to Tufts CSDD, what proportion of Phase II and Phase III procedures may collect non-core data?

Roughly 20 % of Phase II and 33 % of Phase III protocol procedures collect data not tied to core endpoints or compliance requirements.

Name two innovative trial designs gaining traction.

Adaptive designs and master protocols such as umbrella, basket, or platform trials.

What are decentralised clinical trials and which technologies enable them?

Studies that conduct visits and assessments outside traditional sites (e.g., at home) using telemedicine, wearable sensors, and remote data capture.

Why is increasing the participation of under-represented populations important in trials?

It improves generalisability of results, addresses health disparities, and ensures treatments are safe and effective across diverse groups.

Give two future tools or approaches expected to enhance clinical trial efficiency.

Machine learning/AI for data analysis and patient selection, and greater adoption of patient-centric, home-based assessments.