Week 8 Lecture: Clinical Trials (both the lecture slides & part two recording)

Question 1

What is a clinical trial, as defined why the WHO?

Answer 1

‘any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes’.

Question 2

What are prospective studies in health research?

Answer 2

a study or clinical trial in which participants are identified and then followed forward in time.

Question 3

What are examples of health-related interventions?

Answer 3

• experimental drugs
• cells and other biological products
• vaccines
• medical devices
• surgical and other medical treatments and procedures
• psychotherapeutic and behavioural therapies
• health service changes
• preventive care strategies and
• educational interventions.
• diagnostic and screening tests

Question 4

What are some examples of outcome markers? (how to measure progress in a field)

Answer 4

• Drugs – mortality or markers of recovery
• Vaccines – protection from disease
• Medical devices – lower rate of revision surgery over time or
  better function.
• Health Service Changes – higher rates of satisfaction or reduced
  waiting times.
• Preventive care strategies – reduced injury or disease rates
• Diagnostic and screening tests – sensitivity and specificity

Question 5

What are the benefits of clinical trials?

Answer 5

Methodology is rigorous and the results are generally trusted.
Clinical trials offer patients access to medications and services that are not yet available in the open market. This is particularly important for difficult-to-treat patients.

Question 6

Provide an overview of the history of clinical trials

Answer 6

562 BC King Nebuchadnezzar of Babylon conducted the first documented clinical trial / scientific research used to inform public health: (this part is just for interest, don’t have to memorise) he compared the health of those who ate meat/alcohol (c`ontrol as this was the diet by law) and legumes/water (outlaws were vegetarian) - then realised that the vegetarian diets yielded healthier people (so he changed the law to allow people to be legally vegetarian)

1747: Dr James Lind Britain - cured scurvy through lemons

1863 Austin Flint - first placebo controlled trial (used herbal remedy as the placebo for rheumatism)

1940s Philip Hart - first double blind controlled trial - patulin for common cold (2 placebo, 2 patulin groups, double blinding)

1946 Bradford Hill - first randomised controlled trial - Streptomycin in pulmonary tuberculosis by MRC of the UK; introduced randomised allocation order (random sampling numbers) and also allocation concealment.

Question 7

Outline the Salk vaccine clinical trials (case study)

Answer 7

Context: to find polio vaccine
In 1935, John Kolmer (trialled the live vaccine) and Maurice Brodie (trialled a formaldehyde-killed vaccine) failed clinical trials.
In 1952, Jonas Salk conducted a clinical trial of his polio vaccine (‘killed’) - sequentially.
Phase I - on a small group of adults and children
Phase II - 4000 primary school children
Phase III - 1.8 million people - 1.2 nothing, 440000 vaccine, 210000 placebo.
Was effective against various forms of polio -> licensed -> cases fell.
Phase IV - post-release monitoring + safety

Question 8

Outline the Salk vaccine case of post-licensing safety

Answer 8

In 1955 mass vaccination commenced but reports of patients contracting paralytic polio about a week after being vaccinated with Salk polio vaccine. Discovered that two laboratories had not killed the virus adequately. 250 cases of polio had occurred. After this all vaccine lots were tested before release.

Question 9

List 10 hallmarks of a competent clinical trial

Answer 9

1. A clear statement of the aims of the investigation with stated hypotheses.
2. Methods include strategies to minimize bias
3. Personnel are led by experienced trialist
4. Good Governance – competence/safety
5. An appropriate outcome measure or endpoint (One primary ‘endpoint’ or multiple primary endpoints? Direct ‘clinical’ endpoints or indirect ‘surrogate’ endpoints?)
6. Involvement of a statistician/methodologist
7. Stopping rules
8. Adequately powered
9. A priori analysis plan
10. Realistic recruitment rates based on evidence.

Question 10

What should a good aim contain?

Answer 10

(Aim should include Population, Intervention, Comparison, Outcome)

Question 11

List five types of bias in clinical trials

Answer 11

• Selection bias
• Performance bias
• Detection bias
• Attrition bias
• Reporting bias

Question 12

What is selection bias? What is a strategy to prevent it?

Answer 12

What it is: the introduction of systematic differences between baseline characteristics of the groups that are being compared.
Strategy: Randomization prevents selection bias in the way it allocates interventions to participants ensuring the highest likelihood of equivalence between groups.

Question 13

What is detection bias? What is a strategy to prevent it?

Answer 13

Detection bias refers to systematic differences between groups in how outcomes are determined.
Strategy: Blinding of outcome assessors can reduce the risk that knowledge of the intervention rather than the intervention will affect the measure.
e.g. Postoperative pain measurement (0-10) might be sensitive to suggestion – “are you sure?”

Question 14

What is performance bias? What is a strategy to prevent it?

Answer 14

Performance bias refers to systematic differences between the care or exposure that each group experiences.
Strategy: Blinding of the participant and personnel ensures that the compared groups receive a similar amount of attention, treatment and investigations. This can be very difficult in surgical trials but has been done. Single, double, triple, quadruple blinded

Question 15

What is attrition bias? What is a strategy to prevent it?

Answer 15

Attrition bias refers to systematic differences between groups in withdrawals from a study.
Strategy: Intention to treat analysis. Because anything that happens after randomisation can affect the participant,it is important that all patients are analysed in the groups to which they were allocated.

Question 16

What is reporting bias? What is a strategy to prevent it?

Answer 16

Reporting bias refers to systematic differences between between reported and unreported findings.
Statistically significant differences between intervention groups are more likely to be reported than non-significant differences.
Strategy: Trial Registries have been designed to ensure that data is not buried AFTER the trial is completed.

Question 17

What does good governance mean? What are three phases of good governance?

Answer 17

Good governance means that the trial is optimized for successful completion and protection of the participants.

Phases:

1. Well developed idea and argument.
2. Ethics approvals
3. Facilities budget, insurance, legislative compliance and
   contracts.

Question 18

List factors to consider as part of governance, related to accountability and risk management

Answer 18

• Finance – study budget (site fees, HREC and RGO approvals,
  study visit costs, participant reimbursements)
• Insurances
• Legislation
• Intellectual property
• Contracts/ Agreements
• Monitoring protocol amendments/ serious adverse events
• Protocol deviations
• Regular Reporting

Question 19

What is the primary endpoint used to determine?

Answer 19

This endpoint used to determine:
* sample size determination,
* interim data monitoring,
* final analyses, and the
* reporting of the trial result.
The primary endpoint should be the most clinically relevant measure
to address the primary objective of a trial.

Question 20

When should we use multiple primary endpoints?

Answer 20

When they may provide a more complete picture.
* In complex diseases multiple primary endpoints may be preferable.
* However, statistical adjustments are needed in order to defend against TYPE 2 error which is finding a difference when it isn’t there – just because you are looking in lots of places

Question 21

What is a direct outcome measure?

Answer 21

measure of how a patient feels, functions or survives (“clinical” endpoint)
ie. ∗ Mortality ∗ Ability to perform in daily life (function) ∗ Symptoms of disease ∗

Question 21

What is an indirect outcome measure?

Answer 21

physical signs, observations or laboratory test used as a substitute for direct outcome measure (surrogate endpoint)

→ note: A surrogate endpoint by itself does not indicate direct clinical benefit to the patient e.g. For an HIV treatment the clinical endpoint might be death/no death, but the surrogate might be viral load.

Question 22

What are stopping rules? Why are stopping rules established?

Answer 22

Stopping rules allow clinicians to review the safety and efficacy at certain points during the clinical trial. If the impact of the drug or treatment is too large for patients, then the clinical trial will be stopped.

Stopping rules are established to:

1. Ensure that excessive adverse events are not left
   undetected until the end of the trial.
2. Ensure that a group which has clearly superior outcomes
   is not undetected until the end of the trial.

These are a feature of adaptive trial designs.

Question 23

What is power analysis (sample size prediction)

Answer 23

• Mathematical calculations based on previous data which predict how many participants are required to ensure that enough participants are included for the trial to have enough power to determine whether there is a difference between groups.

Question 24

A priori analysis plan

Answer 24

Occurs when a detailed analysis plan should be designed prior to commencement of the study.
* This way, the preferably blinded statistician receives the data in a pre-designed format and can enter it into previously agreed algorithms.
* Manages reporting bias

Question 25

Phase I clinical trial

Answer 25

Tests a new intervention for the first time in a small group of people to evaluate safety (e.g. a safe dosage range and to identify side effects).

Question 26

Phase II clinical trial

Answer 26

Phase II clinical trials study an intervention in a larger group of people to determine efficacy (that is, whether it works as intended) and to further evaluate its safety.

Question 27

Phase III clinical trial

Answer 27

Phase III trials are fully powered to study the efficacy of an intervention with large groups of participants in an intervention group and a control group and/or non-interventional standard care. Adverse effects are monitored to evaluate safety.

Question 28

Phase IV clinical trial

Answer 28

Phase IV studies are done after an intervention has been marketed. These studies are designed to monitor the effectiveness of the approved intervention in the general population and to collect information about any adverse effects associated with widespread use over longer periods of time.

Question 29

What are the 3 main functions of a Phase IV clinical trial?

Answer 29

1. To support pharmacoviligance systems in monitoring the safety of new interventions used in large populations and in specific groups who were not studied adequately in the premarketing phases such as children, pregnant women, the elderly, or those with co morbidities
2. to determine the effectiveness of an intervention in a routine health system, as opposed to within a carefully controlled trial
3. to assess new strategies of use of approved products or interventions, such as the evaluation of anti-malarials when used for intermittent presumptive treatment, rather than either for malaria prophylaxis or for treatment of a diagnosed malarial infection.

Question 30

What is good clinical practice (GCP)?

Answer 30

GCP is the international and scientific quality standard for designing, conducting, recording and reporting trials that involve human participants, including research on identifiable human material and data.

Question 31

What is the history of the GCP?

Answer 31

1947 Nuremberg Code -> 1964 declaration of Helsinki -> Good Clinical Practice Principles harmonised in 1996 and 1998
* Protect the rights of human participants participating in clinical trials
* To ensure the scientific validity and credibility of the data collected in human clinical studies
→ to be an investigator, you need a GCP certificate

Question 32

Brief overview of ethical approval required for clinical trials

Answer 32

All clinical trials in Australia require review and approval of trial proposals by a Human
Research Ethics Committee (HREC). HRECs in Australia provide a combined ethical and
scientific review process.
* In undertaking this role, HRECs are guided by relevant standards, such as those set out in
the National Statement on Ethical Conduct in Human Research (the National Statement),
which is issued by the National Health and Medical Research Council (NHMRC)

Question 33

List three types of randomisation:

Answer 33

1. Simple randomization.
2. Block randomization.
3. Stratified randomization.

Question 34

simple randomisation

Answer 34

• randomisation based on a single sequence of random assignments
• complete and most basic form of randomisation
• very appropriate for large trials
• can be problematic in smaller samples, resulting in uneven numbers
• so it is recommended to be used in sample sizes > 100 participants

Question 35

block randomisation

Answer 35

• usually used for smaller sample sizes, randomisation occurs in blocks
• experimental units are first organized into homogeneous blocks and then the treatments are assigned at random to these units within these blocks.

Question 36

stratified randomisation

Answer 36

participants first grouped into strata according to clinical features that may influence outcome risk. Within each stratum, patients are then assigned to a treatment according to separate randomization schedules

Question 37

intention to treat

Answer 37

Intention to treat means that no matter what happens to participants after randomization, their outcomes are assessed according to their allocation (if you don’t understand here’s a good video https://www.youtube.com/watch?v=nnxg0FJwPjY)

• More reliable estimate of true treatment effectiveness by replicating what happens in the ‘real world’ (e.g. noncompliance and protocol violations commonly affect therapies).
• treatment effectiveness is not the same as the effectiveness of an assigned treatment in an RCT

Question 38

What is per protocol analysis?

Answer 38

Per-protocol analysisis a comparison of treatment groups that includes only those patients who completed the treatment originally allocated.

Question 39

What are the three steps of traditional research design?

Answer 39

1. The trial is designed.
2. The trial is conducted as prescribed by the design.
3. Once the data are ready, they are analysed according to
   a pre-specified analysis plan.

Question 40

What are adaptive research designs?

Answer 40

Adaptive designs (ADs) add a review–adapt loop to the linear design–conduct–analysis sequence.

Question 41

why use an adaptive research design?

Answer 41

In conventional trials critical parameters are best estimates but there is
always some uncertainty leading to inefficiencies and increased expense
e.g uncertainty in optimal dose, best duration, target population
* This creates uncertainty in the optimal design
* Traditionally, all key trial parameters are defined and held constant during
execution of a trial
* Adaptive designs can modify doses as the data comes in to inform the trialist
of the optimal dose.
* Adaptive designs can include futility criteria so that they can be stopped.
* Adaptive designs can ensure an adequate sample size

central advantage = the ability to
include prospectively planned opportunities for
modifying study design elements and hypotheses based
upon interim data analyses.
However, such modifications must be prospectively planned
in the protocol and any interim analyses need to control for
statistical bias.

Question 42

what can be modified in an adaptive research design

Answer 42

• Adaptations to randomization procedures, which can lead
  to more subjects being assigned to more promising
  treatment arms
• Abandoning or adding treatment arms or doses
• Adaptations to the sample size based on interim results
• Adaptive enrichment to the patient population
• Pre-specified stopping rules for efficacy or futility

Question 43

list some things to consider in an adaptive research design

Answer 43

• Controlling the chance of erroneous conclusions
• Estimating treatment effects (methods for adjusting the estimates and reducing

the bias must be prospectively planned.)
* Trial planning - prospective planning should be rigorous
* Maintaining trial conduct and integrity (interim analysis conducted by an independent statistician, avoiding sponsors)

Question 44

why do adaptive clinical trials?

Answer 44

• To avoid getting the wrong answer!
  – Drawing an incorrect qualitative conclusion
• To avoid taking too long to draw the right
  conclusion
  – Time, human subjects, and resources

Question 45

potential challenges of an adaptive design

Answer 45

• Trade off between decreased time and time to consider.
• Not ideal for short studies (2-8 weeks) in easy to recruit
  populations
• Not ideal where a lot of uncertainty about a lot of
  parameters