Session 1

Question 1

Ethical pillars of NHS

Answer 1

Beneficence

Non-maleficence

Autonomy

Justice

Question 2

Aims of good prescribing?

Answer 2

Maximise effectiveness

Respect patient choice

Minimise cost

Minimise risk

Question 3

Sources of prescribing error?

Answer 3

Question 4

Types of prescibing error?

Answer 4

Question 5

How does number of drugs affect compliance

Answer 5

Generally increasing number of drugs causes a reduction in compliance as it becomes more difficult for the patient to follow.

Question 6

How to minimise prescibing risk?

Answer 6

• Recognise this is a high risk activity
• Aim to give the task the attentionand focusit deserves
• Ask for help from the team
• Check: 

Medication History/Allergies 

Drug/dose/route/frequency/duration 

Interactions and Side effects 

Correct instructions and monitoring 

Local/national guidance/policies

• Shared decision making - Talk to the patient and other healthcare proffesionals to find best treament option
• Ask the patient to check the prescription and drugs dispensed
• Double check
• Consider non prescribing alternatives

Question 7

Define what a clinical trial is

Answer 7

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 8

What is the purpose of a clinical trial?

Answer 8

“To provide reliable evidence of treatment efficacy and safety”

• Efficacy=the ability of a health care intervention to improve the health ofa defined group under specific conditions
• Safety=the ability of a health care intervention not to harma defined group under specific conditions

Question 9

In order to be able to give a fair comparison of effect and safety, a clinical trial needs to be what?

Answer 9

• Reproducible – in experimental conditions
• Controlled – comparison of interventions
• Fair–unbiased without confounding

N.B. –clinical trials are subject to random variation differences observed in small trials (<1,000) are more prone to ‘chance’

Question 10

What’s the difference between efficacy and effectiveness in clincal trials?

Answer 10

• Efficacy = ideal clinical conditions
• Effectiveness = real world clinical experience
• Effectiveness estimates are more realistic

Question 11

What are the different phases in drug development and trials?

Answer 11

insert slide 13

Question 12

Explain the disadvantages of non-randomised clinical trials and the use of historical controls

Answer 12

Non-randomised clinical trials involve the allocation of patients receiving a new treatment to compare with a group of patients receiving the standard treatment BUT there’s:

Allocation bias–by patient, clinician or investigator

•Confounding–known and unknown

Comparison with historical controls involves the comparison of a group of patients who had the standard treatment with a group of patients receiving a new treatment BUT for the ‘standard treatment’ group: •selection often less well defined, less rigorous •treated differently from ‘new treatment’ group •less information about potential bias/confounders •unable to control for confounders

Question 13

Outline the steps involved in a randomised controlled trial (RCT)

Answer 13

–Definition of key study variables

–Conduct of the trial

–Comparison of outcomes

•Define:

–The disease of interest

• The patients eligible for the trial
• The patients to be excluded from the trial

–The treatments to be compared

–The outcomes to be measured

–Possible bias and confounders

Conduct of the Trial

• Identify a source of eligible patients
• Invite eligible patients to be in the trial
• Consent patients willing to be in the trial
• Allocate participants to the treatments fairly, i.e. without bias or confounding
• Follow-up participants in identical ways
• Minimise losses to follow-up
• Maximise adherence to treatments

Comparison of Outcomes

•Compare the outcomes fairly to see:

–Is there an observed difference in outcome between the treatment groups?

–Could the observed difference have arisen by chance, i.e. is it statistically significant?

–How big is the observed difference between the treatment groups, i.e. is it clinically important?

–Is the observed difference attributable to the treatments compared in the trial? i.e.was the design & conduct of trial ‘good’?

Question 14

Explain the 95% Confidence Interval and the p-value

Answer 14

•If the null hypothesis value is consistent with the observed data, then any observeddifference from the null hypothesis may be due to chance: –null hypothesis value inside 95% CI p ≥ 0.05 nu hypothesis value outside 95% CI ⇒ p < 0.05

N.B. –the observed value is ALWAYS within the 95% Confidence Interval, in fact in the middle

Question 15

Describe suitable ‘outcome measures’ for clinical trials

–Reasons for pre-defining outcomes –Primary and secondary outcomes –Types of outcomes –Features of an ideal outcome –Timing of measurements

Answer 15

Reasons for Pre-Defining Outcomes

•Need to define what, when and how outcomes are to be measured before start of the clinical trial:

–prevent ‘data dredging’, ‘repeated analyses’

–protocol for data collection

–agreed criteria for measurement and assessment of outcomes

Primary and Secondary Outcomes

•Primary outcome

–preferably only one primary outcome

–used in the sample size calculation

•Secondary outcomes

–other outcomes of interest

–often includes occurrence of side-effects

Types of Outcomes

• Patho-physiological, e.g.–tumour size –thyroxine level –ECG changes
• Clinically defined, e.g. –death (mortality) –disease (morbidity) –disability
• Patient-focused, e.g.–quality of life –psychological well-being –social well-being –satisfaction

Features of an Ideal Outcome

• Appropriate and Relevant–to patient, clinician, society, etc.
• Valid and Attributable–any observed effect can be reasonably linked to the treatments being compared
• Sensitive and Specific–chosen method of measurement can detect changes accurately
• Reliable and Robust–outcome measurable by different people in various settings → similar result
• Simple and Sustainable–method of measurement is easily carried out repeatedly
• Cheap and Timely–not excessively expensive to measure nor has a long lag time

Timing of Measurements

•Baseline measurement of relevant factors

–monitoring for inadvertent differences in groups

•Monitoring outcomes during the trial

–monitoring for possible effect, i.e. is one group being disadvantaged?

–monitoring for adverse effects, i.e. are individual patients being harmed?

•Final measurement of outcomes

–comparing final effect of treatments in trial

Question 16

Discuss the advantages of ‘random allocation’ and ‘blinding’ to minimise confounding and bias in the estimation of treatment effects
–Non-random allocation –Random allocation and randomisation –Knowing the treatment allocation –Blinding (or masking)

Answer 16

Non-Random Allocation
Allocation of participants to treatments by a person, historical basis, geographical location, convenience, numerical order, etc. leads to the potential for allocation [aka. selection]biasand confounding factorsto unwittingly cause unidentified differences between the treatment groups being compared

Random Allocation

“Allocate participants to the treatments fairly”

• Minimal allocation bias–randomisation gives each participant an equal chance of being allocated to each of the treatments in the trial
• Minimal confounding–in the long run, randomisation leads to treatment groups that are likely to be similar in size and characteristics by chance

N.B. –this applies to both knownand unknown confounder factors

Randomisation

• Toss a coin (best as an explanation) –if ‘heads’:allocate to ‘new treatment’ –if ‘tails’:allocate to ‘standard treatment’
• Random number tables –if ‘even’:allocate to ‘new treatment’ –if ‘odd’:allocate to ‘standard treatment’
• The best trials use an external unit to create a computer generated random numberthat is accessed remotely, e.g. phone, secure website

Knowing the Treatment Allocation (or Open Label)
•Knowledge of which participant is receiving which treatment may bias the results of a clinical trial, e.g. –Patient may alter their behaviour, other treatment, or even expectation of outcome (behaviour effect) –Clinician may alter their treatment, care and interest in the patient (non-treatment effect) –Investigator may alter their approach when making measurements and assessing outcomes (measurement bias)

Question 17

Avoiding biases

• Selection bias –how can we avoid?
• Recall or reporting bias–how can we avoid?
• Observer bias–how can we avoid?

Answer 17

Blinding (or Masking)

“Allocate participants to the treatments fairly”

•Minimal allocation bias–by ensuring that randomisation gives each participant an equal chance of being allocated to each of the treatments in the trial

“Follow-up participants in identical ways”

• Single blind –one of patient, clinician, assessor does not know the treatment allocation (usually patient)
• Double blind –two of patient, clinician, assessor does not know the treatment allocation (usually patient + clinician/assessor)
• Triple blind (term rarely used as ‘double blind’ usually implies all do not know the allocation)

Example of Blinding (or Masking)
•Aim to make the treatments appear identical in every way, e.g. appearance, taste, texture, dosage regime, warnings •Use a designated pharmacy to label identical containers for the treatments with code numbers, and to have a code sheet detailing which code number corresponds to which treatment

Examples where Blinding is difficult
•Surgical procedures •Psychotherapy vs. anti-depressant •Alternative medicine, e.g. acupuncture, vs. Western medicine, e.g. drug •Lifestyle interventions •Prevention programmes

Question 18

Describe the ‘placebo effect’, what a ‘placebo’ is, and how a ‘placebo’ addresses the ‘placebo effect’
–Comparing with ‘no treatment’ –The placebo effect –Placebo –Ethical implications of placebo

Answer 18

Comparing with ‘No Treatment’
The effect of comparing a ‘new treatment’ group with a group receiving no treatment is to leave one unsure as to whether any observed difference was due to the ‘new treatment’ or to the fact that the group was receiving care.

The Placebo Effect
“Even if the therapy is irrelevant to the patient’s condition, the patient’s attitude to his or her illness, and indeed the illness itself, may be improved by a feeling that something is being done about it”

Placebo
A placebo is an inert substance made to appear identical in every way to the active formulation with which it is to be compared, e.g. appearance, taste, texture, dosage regime, warnings, etc.
The aim of a ‘placebo’ is to cancel out any ‘placebo effect’ that may exist in the active treatment

Ethical Implications of Placebo
•A placebo should only be used when no standard treatment is available

•Use of a placebo is a form of deception. Therefore, it is essential that participants in a placebo-controlled trial are informed that they may receive a placebo

Question 19

•Discuss how to deal with ‘losses to follow-up’ and ‘non-compliance’
–Losses to follow-up –Non-compliance with treatments –An issue for the analysis

Answer 19

Losses to Follow-Up
•Not every participant remains in the trial: –their clinical condition may necessitate their removal from the trial (appropriate) –they may choose to withdraw from the trial (unfortunate)

“Minimise losses to follow-up” •Make the follow-up practical and minimise inconvenience •Be honest about the commitment required from participants •Avoid coercion or inducements •Maintain contact with participants

Non-Compliance with Treatments
•Not every participant complies with their allocated treatment: –they may have mis-understood the instructions –they may not like taking their treatment –they may think their treatment is not working –they may prefer to take another treatment –they can’t be bothered to take their treatment –etc. i.e. all the usual reasons for non-compliance

“Maximise compliance with treatments” •Simplify the instructions •Ask about compliance •Ask about effects and side-effects •Monitor compliance, e.g. tablet count, urine level, blood level

An Issue for the Analysis
•In practice, it is never possible to have 100% follow-up and to guarantee that 100% compliance took place •Therefore, any analysis of outcomes should take these issues into account

Question 20

•Differentiate between ‘explanatory’ and ‘pragmatic’ trials and be able to explain the meaning of the term ‘intention-to-treat’ analysis
–Explanatory Trial: ‘As-Treated’ Analysis –Pragmatic Trial: ‘Intention-to-Treat’ Analysis –‘As-Treated’ vs. ‘Intention-to-Treat’

Answer 20

Is the ‘New Treatment’ Better than the ‘Standard Treatment’?
Two different interpretations: •Is the physiological actionof the new treatment better than the standard treatment? e.g. does drug A lower BP more than drug B? OR •Is the new treatment better than the standard treatment in routine clinical practice? e.g. if you prescribe drug A, is it better at lowering BP than drug B (e.g. will patients take it)?

slide 70 and 71

Explanatory Trial: ‘As-Treated’ Analysis
•Analyses only those who completed follow-up and complied with treatments •Compares the physiological effects of the treatments BUT loses effects of randomisation •Non-compliers are likely to be systematically different from compliers selection biasand confounding
Pragmatic Trial: ‘Intention-to-Treat’ Analysis
•Analyses according to the original allocation to treatment groups (regardless of whether they completed follow-up or complied with treatment) •Compares the likely effects of using the treatments in routine clinical practice ALSO preserves effects of randomisation → minimal selection bias and confounding
‘As-Treated’ vs. ‘Intention-to-Treat’
•‘As-Treated’ analyses tend to give larger sizes of effect •‘Intention-to-Treat’ analyses tend to give smaller and more realistic sizes of effect
Clinical trials should normally be analysed on an ‘Intention-to-Treat’ basis

Question 21

•Discuss the ethical principles involved in medical research involving human subjects
–‘Declaration of Helsinki’ 2013 (Paragraph 3) –Collective Ethic –Individual Ethic

Answer 21

Ethical Principles for Medical Research Involving Human Subjects (‘Declaration of Helsinki’ 2013)
Paragraph 3. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient will be my first consideration,” and the International Code of Medical Ethics declares that, “A physician shall act only in the patient’s interest when providing medical care.”

Collective and Individual Ethics
•Collective Ethic: –All patients should have treatments that are properly tested for efficacy and safety •Individual Ethic: –The Principle of Beneficence –The Principle of Non-Maleficence –The Principle of Autonomy –The Principle of Justice

Collective vs.Individual Ethics
•Collective Ethic: –RCTs aim to properly test treatments for efficacy and safety •Individual Ethic: –RCTs do not guarantee benefit –RCTs may result in harm –RCTs allocate treatment by chance –RCTs place burdens and confer benefits RCTs are for the benefit of future patients

Question 23

•Describe the role and function of a Research Ethics Committee
–NHS Trust/PCT R&D Office –Research Ethics Committee

Answer 23

Research Ethics Committee •NHS Trust/PCT R&D Office: –research governance –financial management –resource implications •Research Ethics Committee: “The dignity, rights, safety and well-being of participants must be the primary consideration in any research study.”

Research Ethics Committee Focus particularly on:

1. Scientific design and conduct of the study
2. Recruitment of research participants
3. Care and protection of research participants
4. Protection of research participants’ confidentiality
5. Informed consent process
6. Community considerations

A Moral Obligation to Participate in Research?

“Effective and responsive services depend on research. … Anyone using health and social care services should give serious consideration to becoming involved in developing or undertaking research studies.”
Since we all benefit from knowledge derived from research, do we not all have a moral obligation to participate in obtaining that knowledge?