Clinical Trials

Question 1

Define clinical trial

Answer 1

A specialised assay designed to measure therapeutic efficacy and detect adverse effects

Planned experiment involving patients to elucidate most appropriate treatment of future patients with a given medical condition (limited sample, inferences on general population)

Question 2

Phase 1a

Answer 2

• Exploaratory, safe, tolerability
• Healthy subjects, single dose - placebo, random, double-blind
• Adverse events, PK parameters
• 20-100 subjects
• 6 months

Question 3

Phase 1b

Answer 3

• Exploratory, safety, tolerability
• Healthy subjects, repeat dose - placebo, random, double-blind
• Adverse events, PK parameters
• 20-100 subjects
• 6 months

Question 4

Phase IIa

Answer 4

• Exploratory, safety, efficacy
• Patients given clinical dose - placebo, random, double-blind
• Adverse events - PK parameters, efficacy ‘proof-of-concept’
• 50-200
• 6 months-2 years

Question 5

Phase IIb

Answer 5

• Confirmatory, dose selection
• Patients given selected dose levels - placebo, random, double-blind
• Statistical analysis of dose response, confirmation of dose
• 200-500 subjects
• 2-3 yrs

Question 6

Phase III

Answer 6

• Confirmatory, efficacy, safety
• Patients in target indications - selected dose level, placebo, random, double-blind
• Statistical measurements demonstrating safety and efficacy
• 300-3000+
• 1-4 years

Question 7

Phase IV

Answer 7

• Obligatory post marketing surveillance
• Treated patients
• Adverse events
• 10000+
• 2-4 yrs

Question 8

2 important principles underpinning the integrity of the scientific method

Answer 8

SIZE

• The trial must recruit enough patients to obtain a reasonably precise estimate of response on each treatment

AVOIDANCE OF BIAS

• The selection, ancillary care and evaluation of patients should not differ between treatments, so that the treatment comparison is not affected by factors unrelated to treatments themselves

Question 9

Organisation and planning of clinical trials

Answer 9

Which patients are eligible

Which treatments are to be evaluated

How each patient’s response is to be assessed

Question 10

3 sources of funding for clinical trials

Answer 10

1. Pharmaceutical companies - majority
2. National Health Organisations - justified for trials of major treatment issues
3. Locally based trials - no external backing - can provide important source of new therapeutic ideas but many are poorly organised

Question 11

Most important regulatory authorities

Answer 11

• Investigational New Drug (IND) for first human studies
• New Drug Application (NDA) for launching on to the market
• Food and Drug Administration (FDA)
• Health Products Regulatory Authority (HPRA - Ireland)
• European Medicines Evaluation Agency (EMEA) - mutual recognition
• Japan insists on clinical trials within Japan

Question 12

Randomised control trials problems

Answer 12

• Uncontrolled trials - no direct comparison with a similar group of patients on more standard therapy
• Historical trials - potential incompatibility with patient selection and patient environment
• Concurrent non-randomised controls - systematic assignment and judgement assignment

Question 13

Justification for placebo trials

Answer 13

To make patient attitudes to the trial as similar as possible in treatment and control groups

Question 14

Define double-blind trials

Answer 14

Neither the patient nor those responsible for care and evaluation know which treatment they are receiving

Question 15

Ethics of double-blind testing

Answer 15

Double-blind procedure should not result in any harm or undue risk to a patient

Strong connection between ethics and high scientific and organisational standards

Question 16

Practicality of double-blind testing

Answer 16

It might be impossible in some trials

Question 17

Avoidance of bias with double-blind testing

Answer 17

One needs to assess just how serious the bias would be without blinding

Question 18

Compromise with double-blind testing

Answer 18

Sometimes partial blinding (e.g. independent blinded evaluators) can be sufficient to reduce bias in treatment comparison

Question 19

How are patients protected in clinical trials

Answer 19

• Respect for persons, the requirement to treat individuals as autonomous agents , and the requirement to protect those with diminished autonomy
• Beneficence, maximising possible benefits and minimising possible harms
• Justice, as demonstrated by fairness in distribution of the opportunity to participate in research

Question 20

What should a trial avoid

Answer 20

1. BIAS - exaggeration of benefit of new therapy - too few patients
2. NOT PUBLISHING THE FINDINGS - publication no matter the outcome furthers medical knowledge
3. Each trial requires a balance between individual and collective ethics - informed patient consent is essential

Question 21

How is the size of a clinical trial determined

Answer 21

Statisitical methods (power calculations) can be used to determine the required number of patients to meet the trial’s principal scientific objectives

Question 22

Advantages of multi-centre trials

Answer 22

Patient accrual faster

Any conclusions have a broader more representative base, collaboration should raise standards

Question 23

Disadvantages of multi-centre trials

Answer 23

Planning is more complex

Expensive

All must follow the same protocol

Standardised training

A well-organised centre for data essential

Motivation of all participants

Question 24

Critical evaluation of results

Answer 24

Check that the conclusion are justified from the results given

Potential for distorting results (trial size, failure to account for all, inappropriate stats methods, confusing presentation of results)

Question 25

Overall conclusion of clinical trials

Answer 25

Weighing up the efficacy (therapeutic benefits) and safety (harms) of the treatment

Sufficient evidence to enable reg. authorities to grant licence

Follow up in postmarketing surveillance