MEDC0014 – Introduction to Clinical Trials

Introduction to Clinical Trials

Fundamentals of Clinical Trials

• Presented by Jemima Thompson & Hannah Plant on 25-Feb-2025.

Intended Learning Outcomes

• Recognize, define, and distinguish between different types of clinical studies:
  • Interventional studies
  • Observational studies
• Define the phases of clinical trials and understand the aims of each phase.
• Describe the fundamental principles of clinical trials.

Clinical Studies

• Clinical study: Research using human volunteers (participants) intended to add to medical knowledge.
• Two main types:
  1. Interventional studies
  2. Observational studies

Interventional Studies

• The investigator tests whether giving the study participants some kind of intervention alters the development or the course of an outcome.
• Example: Investigator gives a beta-blocker to patients with high blood pressure to see if it will reduce their blood pressure.
• Outcome: Health-related event of interest (e.g., patient’s blood pressure).
• Clinical trials are a type of interventional study.

Observational Studies

• Investigators observe the course of a disease or the relationship between risk factors (exposures) and outcomes.
• The investigator does not intervene or manipulate the situation; they simply observe.
• Example: Observing a group of older adults to investigate how different lifestyles affect blood pressure.

Hierarchies of Evidence

• Meta-analysis & Systematic Reviews
• Randomized Controlled Trials
• Cohort Studies
• Case-Control Studies
• Case Series, Case Reports
• Editorials, Expert Opinion

Types of Observational Study

• Cross-sectional studies
• Cohort studies
• Case-control studies
• Ecological studies

Cross-Sectional Study

• Aim: To describe a population or a subgroup within the population with respect to an outcome and a set of risk factors.
• Contact participants at a fixed point in time and obtain relevant information from them.
• Often carried out as a survey (prevalence survey).
• Provide information only – a ‘snapshot’ of the health experience of the population.
• Example: Survey the prevalence of hypertension in a population.

Cohort Study

• A group of subjects, selected to represent the population of interest, is studied over time.
• Select a study population.
• Measure particular baseline characteristics or exposures suspected of being related to the outcome under investigation.
• Follow the population up over time for the development of new events.
• Compare the incidence of the outcome in the exposed individuals with those not exposed.

Case-Control Study

• Select a ‘case’ group of patients who have the outcome of interest and a ‘control’ (or comparison) group without the outcome.
• Compare the proportions with the exposure of interest in each group.
• Example: The link between tobacco smoking and lung cancer demonstrated by Richard Doll and Bradford Hill.

Ecological Study

• A type of study in which at least one variable is measured at the group level.
• Measure disease rates and exposures in each of a series of populations and examine their relationship.
• Example: A comparison of treatment patterns and outcomes of patients living in different geographical regions or countries.
• Appropriate for the initial investigation of cause-and-effect relationships.

Clinical Trial

• A clinical trial is a type of interventional study.
• Investigator intervenes to prevent or change the course of an outcome.
• Simplest terms: Research studies (in people) that compare different treatments or treatment strategies to test whether one treatment is better or, at times, at least as good as another.
• One of the final stages in a long and careful research process.
• Often begins in the laboratory and usually involves animal testing to see how the approach affects a living body and whether it's harmful.
• Something that works well in the lab or in animals doesn't always work well in people.
• No matter how promising a new treatment or treatment strategy may appear, it must go through clinical trials before its benefits and risks can be really known.

Randomized Controlled Trials

• The gold standard for evaluation of an intervention.
• Randomisation:
  • Allocation of treatment between groups at random: like ‘tossing a coin.’
  • Avoids ‘selection bias.’
• Non-randomised interventional designs exist, but they can be prone to bias.
• However, they are appropriate and widely used for early phase trials.

Bias

• Dictionary definition: ‘a partiality that prevents objective consideration of an issue or situation.’
• In statistics: ‘a tendency of an estimate to deviate in one direction from a true value.’
• This systematic deviation can result in either underestimation or overestimation of the effects of an intervention.
• Last J. A dictionary of epidemiology, 2001: ‘Any trend in the collection, analysis, interpretation, publication or review of data that can lead to conclusions that are systematically different from the truth.’

Clinical Trial Phases

• Trials involving drug treatments are classically divided into four phases: I to IV.
• But:
  • Behavior, lifestyle, or surgical interventions don’t necessarily fit into phases I to IV.
  • Some drug trials don’t fit into a single phase.
  • More and more trials may blend from phase I to II and from II to III.
  • Sometimes we split trials into early and late phases.

Drug Development

• A lengthy and time-consuming process.
• Drug research
• Preclinical: Lab and animal experiments
• Clinical trials
  • Phase I: 20-100 healthy volunteers
  • Phase II: 100-500 patients → safety, dosing (up to 2 years)
  • Phase III: 1,000-10,000 patients → efficacy, adverse events
  • Phase IV studies (more than 2 years)
• Evaluation/Approval: 1 drug approved by health authorities
• 10,000 Test compounds → <250 Test compounds → <5 Test compounds → 1 drug approved
• >1 billion Euro
• Timeline: 0 - 12 years

Phase I Trials

• Sometimes called first-in-human studies.
• Useful clinical information can be obtained from in vitro studies or animal models, but early data must also be obtained in humans.
• Involve healthy volunteers or patients who have tried and failed on existing standard treatment.
• Usually less than 20 patients.

Phase II Trials

• Test of a new treatment in a larger group of people.
• Participants usually have the condition for which the treatment is to be used and are usually carefully selected with narrow inclusion criteria.
• Aim to see whether the treatment is safe and if it has any biological activity or effect.
• Usually performed to make a decision about whether to further develop a new drug or device.
• Often around 30-50 people.

Phase III Trials

• Involve larger numbers of patients (100s to 1000s).
• Participants are usually randomised to receive the new treatment or the best available current treatment (or sometimes a placebo).
• Aim to assess how well the new treatment works and so focuses on efficacy or effectiveness but will also continue to look at safety.
• Used to obtain regulatory approval for new treatments.
• Phase III RCT trials are the primary focus of this module.

Phase IV Trials

• Carried out after a drug has already been approved by regulatory authorities.
• Aim to gather information on a drug's effect in various populations and any side effects associated with long-term use.

Features of a ‘Good’ Clinical Trial

• The use of a control group
• Randomisation
• Blinding (when appropriate)
• Large enough sample size

Control Groups

• A group of clinical trial participants who do not receive the treatment being investigated as part of the trial.
• Serves as a standard or baseline.
• Can be an existing standard treatment (which could be observation) or a placebo.
• By comparing the groups, you can cancel out external factors that may be affecting the overall condition of the participants.
• Important when trying to work out whether a new treatment works.

Randomisation

• What is it?
  • Allocation of treatment between groups at random: like ‘tossing a coin.
• Neither doctors nor patients choose the treatment to which patients are allocated.
• Protects against selection bias: selection bias occurs when there are systematic differences between comparison groups in response to treatment or prognosis.
• Other means of selecting who receives the intervention (e.g., doctors or patients deciding) are more prone to bias because decisions about care can be related to prognosis and responsiveness to treatment.
• Important that the randomisation sequence is concealed.
• ‘Allocation concealment’ – you don’t want investigators to try and guess the next allocation.

Blinding/Masking

• Many trials are set up so that patients and/or doctors (or those evaluating the response to treatment) do not know which treatment a patient is receiving. This is blinding.
• Minimises observer bias.
• Blinding can be called masking.
• Unblinded trials are called ‘open’ or ‘open-label’ trials.
• Not always possible and may not be necessary.
• You’ll learn more about blinding in a later session.

Sample Size

• For a trial to be a fair test, the number of people taking part in it needs to be large enough.
• Trials that aren’t large enough may lack the statistical power or ability to detect clinically important differences between treatment groups.
• Getting the trial size right is important.
• Ethical consequences.
• Wasteful of resources if a trial is too large.

Summary

• A clinical trial may find that a new strategy, treatment, or device:
  • improves patient outcomes
  • offers no benefit
  • causes unexpected harm
• All of these results are important because they advance medical knowledge and help improve patient care.
• Doctors and other healthcare professionals and patients need evidence from clinical trials to know which treatments work best.
• Otherwise:
  • people could be given treatments that have no advantage and might even be harmful
  • we would waste healthcare resources
• A clinical trial that is properly planned and well conducted is the best experimental technique for testing the effectiveness of an intervention.
• It also contributes to the identification of possible harms.

Clinical Trials Can Help…

• Prevent illnesses
• Detect or diagnose illnesses by testing a scan or blood test
• Treat illnesses by testing new or existing medicines
• Find out how best to provide psychological support
• Find out how people can control their symptoms or improve their quality of life

Subsequent Sessions

• Sessions 2-10 cover a range of topics including outcome measures, randomisation, ethics, protocol development, patient involvement, trial management, systematic reviews, data management, health economics, and clinical trial reporting.

Formative Assessment

• A Multiple-Choice Questionnaire to test your knowledge of what you have learned so far.
• Set on: Tuesday 4th March 2025
• Due for completion by: Tuesday 11th March 2025, 5pm (GMT)

Summative Assessment

• 2 parts:
  • 30 question Multiple-Choice Questionnaire (25% weighting)
  • 15-minute group presentation (75%) weighting
• MCQ date: TBC
• Presentation set: Friday 20th March
• Submission: Tuesday 20th May/Thursday 22nd May 2025
• There will be an opportunity to ask questions about the Summative Assessment during week 5.

Expectations

• 100% attendance if possible
• Participate
• Contribute
• Share ideas
• Ask questions
• Tell us how we’re doing

Questions

• Use the discussion forums on the module Moodle page for questions.
• Contact Hannah and Jemima via email for anything that cannot be answered in a public forum; email addresses are available on Moodle.