Lec 3&4 Clinical Trials

Question 1

Define a clinical trial

Answer 1

Any form of PLANNED EXPERIMENT

which involves patients

and is designed to elucidate the MOST APPROPRIATE method of treatment

for FuTuRe PATIENTS with a given medical condition

Question 2

Purpose of a clinical trial

Answer 2

To provide evidence of treatment efficacy and safety

Efficacy- ability of a health care intervention to improve the health of a DEFINED GROUP under SPECIFIC CONDITIONS

SAFETY - the ability of a health care intervention not to harm a DEFINED GROUP under SPECIFIC CONDITIONS

Question 3

In order for a clinical trial to give a fair comparison of effect and safety it must be what?

Answer 3

Reproducible
Controlled
Fair

Question 4

What are the stages of drug development and monitoring?

Answer 4

Pre- clinical phase(lab studies) - pharmacology/ animal toxicology, cell cultures/ animals

Phase 1 (volunteer studies) - pharmacodynamics/ pharmacokinetics/ major side-effects, <100 healthy volunteers

Phase 2 (treatment studies) - effects and dosages/ common side effects, <1000 patients

Phase 3 (clinical trials) - comparison with standard treatments, <10000 patients

Phase 4 (post-marketing surveillance) - monitoring for adverse reactions/ potential new users, whole population

Question 5

What are non-randomised clinical trials and what are the disadvantages?

Answer 5

AllocTion of patients receiving a new treatment to compare with a group of patients receiving the standard treatment

• allocation bias (patient/ clinician/ investigator)
• confounding (known and unknown)

Question 6

What is comparison with historical controls and what are the disadvantages?

Answer 6

Comparison of group patients who had standard treatment with. Group receiving new treatment

• selection often less well defined
• treated differently from new treatment group
• less info about potential bias/ confounders
• unable to control confounders

Question 7

Steps involved in a randomised controlled trial

Answer 7

Define: disease of interest/ patients eligible/ patients excluded/ treatments to be compared/ outcomes to be measured/ possible bias and confounders

Conduct of the trial: identify a source of eligible patients, invite to trial, consent, allocate fairly to treatments, follow up identically, minimise losses, maximise adherence to treatments

Comparison of outcomes: observed difference, arisen by chance (statistically significant), how big is the difference (clinically important), is difference attributable to treatments (design and conduct good)

Question 8

Reasons for pre-defining outcomes

Answer 8

Define what/ when/ how outcomes measured before start of clinical trial

• prevent data dredging/ repeated analyses
• protocol for data collection
• agreed criteria for measurement and assessment of outcomes

Question 9

Compare primary and secondary outcomes

Answer 9

Primary:
Preferably only one, used in the sample size calculation

Secondary: other outcomes of interest, often includes occurrence of side-effects

Question 10

Types of outcomes

Answer 10

Patho-physiological e.g. tumour size, thyroxine level, ECG changes

Clinically defined e.g. mortality, morbidity, disability

Patient- focussed e.g. quality of life, psychological well-being, social well-being, satisfaction

Question 11

Features of an ideal outcome

Answer 11

Appropriate and relevant - to patient/ clinician/ society

Valid and attributable - any observed effect can be reasonably linked to treatments being observed

Sensitive and specific - chosen method of measurement can detect changes accurately

Reliable and robust - outcome measurable by different ppl in various settings -> similar result

Simple and sustainable - method of measurement easily carried out repeatedly

Cheap and timely - not excessively expensive to measure nor has a long lag time

Question 12

Timing of measurements

Answer 12

Baseline measurement of relevant factors (inadvertent differences in groups)

Monitoring outcomes during trial (possible/ adverse effects)

Final measurement of outcomes

Question 13

What is non-random allocation?

Answer 13

Allocation of participants to treatments by a

Person, historical basis, geographical location, convenience, numerical order etc.

Leads to a potential for allocation (selection) bias and confounding factors go unwittingly cause unidentified differences between the treatment groups

Question 14

What is random allocation And what are the benefits?

Answer 14

Allocate participants to the treatments fairly
E.g. random number tables, computer generated random number allocator

• minimal allocation bias
• minimal confounding (likely similar size and characteristics by chance)

Question 15

Benefits of blinding

Answer 15

Prevents:

• behaviour effect (patient May alter behaviour/ expect an outcome)
• non- treatment effect (clinician alter behaviour/ care/ interest in patient)
• measurement bias (alter approach)

Question 16

Single/ double/ triple blind

Answer 16

Single blind - one of patient/ clinician/ assessor doesn’t know treatment allocation

Double blind - 2 of patient/ clinician/ assessor doesn’t know treatment allocation

Triple blind - all don’t know allocation

Question 17

When might blinding be difficult?

Answer 17

Surgical procedures

Psychotherapy vs anti-depressant

Alternative medicine E.g. acupuncture vs western e.g. drugs

Lifestyle interventions

Prevention programmes

Question 18

Define the placebo effect

Answer 18

Even if therapy irrelevant to patients condition the patients attitude to illness and the illness may improve by a feeling something is being done

Question 19

Define placebo

Answer 19

Insert substance made to appear identical to active formulation with which it is compared

(Only when no standard treatment available) form of deception, need told may receive

Question 20

2 types of losses to follow-up and how to prevent

Answer 20

Appropriate - clinical condition

Unfortunate - choose to withdraw

- practical follow up and minimise 
Inconvenience
- honest about commitment 
- avoid coercion
- maintain contact

Question 21

What is explanatory ‘as treated’ analysis?

Answer 21

Anylses only those who complete follow-up and complied

Compares physiological effects

Loses effects randomisation

Non-compilers likely systematically different (selection bias and confounding)

Gives larger sizes of effect

Question 22

What is pragmatic trial or intention to treat analysis?

Answer 22

Analyses according to original allocation to treatment groups (regardless follow up or compliance)

Compared likely effects in routine clinical practice

Preserved randomisation

Smaller and more realises sizes of effect

Question 23

What is the declaration of Helsinki and international code of medical ethics?

Answer 23

The health of my patient will be my first consideration

A physician shall act only in the patients interest when providing medical care

Question 24

Collective vs individual ethics

Answer 24

Collective - all patients should have treatments properly tested for efficacy and safety
Randomised clinical trials aim properly test treatments efficacy/ safety

Individual - principle of beneficence/ non-Maleficence/ autonomy/ justice
RCTs do not guarantee benefit/ may cause harm/ treatment by chance/ burdens and confer benefits (for the benefit of future patients)

Question 25

Issues to consider for a clinical trial to be ethical

Answer 25

• clinical equipoise (reasonable uncertainty/ genuine ignorance about better treatment/ intervention)
• scientifically robust (relevant/ important issue, valid question, appropriate study design/ protocol, potential to reach sound conclusion, justify use of placebo, acceptable risks, monitoring safety provisions, arrangements appropriate reporting/ publication)
• ethical recruitment (communities likely benefit, low risk of harm compared benefits, included in analysis, people who differ ideal homogenous group, ppl difficult to gain valid consent from)
• valid consent (knowledgeable informant, appropriate information, competent decision maker, legitimate authoriser)
• voluntariness (pre requisite for consent, decision free (perceived) coercion/ manipulation)

Approval by research ethics committee

Question 26

What do reasearch ethics committees focus on?

Answer 26

Scientific design and conduct of study

Recruitment of research participants

Care and protection of research participants

Protection of confidentiality

I formed consent process

Community considerations