1
Q
What are the 4 stages of answering an MI enquiry?
A
- Understand the question
- Carry out your research
- Prepare your answer
- Feedback your answer
2
Q
What are the 5 reasons why documentation is important in MI?
A
- So others can see what advice you’ve given
- In case you’re asked the same question again
- So you can demonstrate that the advice you gave was correct and up-to-date at the time
- To record your workload
- To avoid forgetting important details or duplicating searches
3
Q
What are the 3 components of EBP?
A
- Individual clinical expertise
- Best external evidence
- Patient’s values & expectations
4
Q
What are the 4 As for deciding on a medicine?
A
- Ask good questions
- Acquire evidence which answers this question
- Appraise the quality of this evidence
- Apply the best evidence to your patient
5
Q
What does PICO stand for?
A
For converting a problem into a question
P- Patient and problem
I - Intervention
C - Comparison
O - Outcome
6
Q
What is incidence rate?
A
Number of new cases of disease / Mid-year population
7
Q
A
8
Q
What is point prevalence?
A
The proportion of people who have a disease at a specific point in time
9
Q
What is period prevalence?
A
The number of people who have the disease in a time period divided by the population at the mid-point of the period
10
Q
What is risk ratio?
A
incidence (exposed) / incidence (unexposed)
11
Q
What is absolute risk difference?
A
incidence (exposed) - incidence (unexposed)
12
Q
What is the number needed to treat?
A
1/Absolute risk difference
(always round up)
13
Q
What does the value of NNT mean?
A
The Number Needed to Treat (NNT) is the number of patients you need to treat to prevent one additional bad outcome. If NNT = 5, you have to treat 5 people with the drug to prevent one additional bad outcome.
14
Q
What are phase 1 clinical trials?
A
- 1st application of new treatment in humans
- In severe diseases, the aim is to find the maximum tolerated dose
- Usually single dose or only a few weeks of treatment
15
Q
Why do we have phase 1 clinical trials?
A
To generate preliminary PK/PD data
16
Q
Who takes part in phase 1 clinical trials?
A
- Usually have 20-50 participants
- Conducted in healthy subjects when expected toxicity is minor and extremely ill patients if therapy is toxic
17
Q
What are phase 2 clinical trials?
A
- First time patients are exposed to therapeutic dose drug
- Small study of efficacy
- Sample size <100 people
18
Q
Why do we have phase 2 clinical trials?
A
- Outcome is a measure of trt efficacy
- Short to moderate follow-up times (few weeks to 1 year)
- Aim to find out more about PK/PD and common adverse reactions
- Determine daily dosage and trt regimen to be tested more rigorously in phase III
- Provides experience with trt and administration
19
Q
What are phase 3 clinical trials?
A
- Aim to give a definitive assessment of intervention against a control
- Aim to evaluate an intervention’s toxicity and efficacy
- Classified according to how the control is selected
- Between 500 and 3000 patients exposed
- Interventions can include new drugs, devices, trt methods e.g. surgical techniques
20
Q
What are the 3 types of blinding?
A
Single blind
- Sometimes necessary
- Patient or assessing physician does not know which treatment is being taken
Double blind
- Ideal
- Protects against information bias
- Neither patient or physician/researcher knows the treatment being taken
Triple blind
- analyst is also blind to prevent their biases entering the mix
21
Q
What is randomisation?
A
Viewed as gold standard because possible error is just chance
Benefits
- Comparable groups with respect to measured and unmeasured risk factors
- Eliminates confounding: trt is independent of outcome – any association is either causal or the result of chance
Equipoise (neither better than the other)
22
Q
What is the purpose of inclusion + exclusion criteria?
A
Inclusion and exclusion criteria affect the extent to which the results of the trial can be generalised
23
Q
What is study power?
A
Power = probability of detecting a true difference between groups studied (usually >80%)
Significance level (either 1% or 5%)
24
Q
What are the 4 areas of data typically collected during a clinical trial?
A
- Baseline data collected prior to start of trt
- Efficacy
- Safety data including serious and non-serious adverse events or toxicities
- Follow-up status
25
What are the primary endpoints?
- Trial designed with a single primary question
26
What are secondary endpoints?
- There may be secondary questions of interest e.g. symptom relief, adverse events, QoL, health economics
- Complicates things if primary is not significant but secondary is
27
What are the 5 different ways to measure patient response?
- Unequivocal (death)
- Time to event (time to reoccurrence or death or full recovery)
- Measured (blood pressure, blood calcium level)
- Objective clinical assessment - objective (hamilton depression rating scale, disappearance of symptoms)
- Patient opinion - subjective (pain, side effects)
28
What are the other types of end points?
Clinical endpoints
- Reflect survival or symptomatic status of patient
Surrogate endpoints
- Associated with clinical endpoints but do not directly reflect survival or clinical status of the subject
29
What is per protocol analysis?
- Includes only those events that occur while participant is complying with intervention
- May be performed in addition to ITT
- Vulnerable to bias
- Self-selected healthy population?
30
What is intention to treat?
- All included regardless of adherence, all outcomes must be ascertained regardless of whether the trt has been discontinued
31
What are the 4 objections to intention to treat?
- Subjects who discontinue no longer receive the benefit from the trt
- Adverse events occurring after trt discontinuation bias analysis
- Study may lack power (and credibility) where nonadherence is significant
- Nonadherence can be beneficial in non-inferiority or equivalence trials
32
What are the two responses to the ITT objections?
- Non-adherence reflects real-life usage
- Excluding subjects would produce biased estimates
33
What is non-inferiority design?
- Aims to evaluate whether new treatment is not inferior to standard treatment
- New treatment may be less toxic, less expensive, less invasive than standard
- Trial design is more challenging
34
What are the challenges of non-inferiority design?
- What control should be used?
- Is there an agreed current best treatment?
- How to determine non-inferiority?
35
What is adaptive design?
Changes possible:
- Refining the sample size
- Abandoning doses or treatments
- Changing allocation ratio to trial arms
- Identifying patients most likely to benefit
- Stopping early due to success or lack of efficacy
Flexible design
- Scheduled flexible looks at the data
- Trial can be changed while it is running
- Once endpoint criteria met, trial is ended
36
What are the 4 steps of literature searching?
Define the question (PICO)
Identify search terms
Review papers
Summarise results
- Descriptively for a systematic review
- Quantitatively for a meta-analysis (together with checks for heterogeneity
37
What is heterogeneity?
Studies are heterogeneous when their underlying target parameters differ
38
How do you test for heterogeneity?
Often use Cochran’s Q test, a chi-squared test that determines if there is a significant difference between each study OR and the fixed effect OR is it just due to random error
this is a percentage of chi-squared not explained by the variation in studies
39
What is the importance of heterogeneity?
I^2 introduced as a percentage of chi-squared not explained by variation in the studies
I^2 25% = low
I^2 50% = medium
I^2 75% = high
40
What is health economics?
The study of attempts to allocate limited health care resources among unlimited wants and needs to achieve the maximum health benefit for society
41
What is pharmacoeconomics?
The application of the theories, techniques and concepts of health economics to the study of pharmaceutical interventions
42
What is economic evaluation?
- Comparison of two or more alternative treatments in terms of costs and benefits
- Measure differences in costs and benefits
- Quantify trade-offs between alternative treatments
- Framework for rational decision making to ensure maximum utility from scarce resources
43
What are 3 examples of unidimensional benefits?
e.g.
- Cases treated successfully
- Heart attacks prevented
- Number of patients alive after 5 years
44
What are QALYs?
Quality-adjusted life years
(How many years someone lives after treatment and their quality of life measured from 0 (death) to 1 (full health) )
45
What is cost-minimisation analysis?
- A comparison of the least costly interventions that are assumed to produce equivalent health outcomes
- Compares the costs of the interventions
- Intervention which achieves the desired outcome at the lowest price is the preferred choice
46
What is cost-consquence analysis?
- Lists costs and benefits
- Costs and benefits are not compared mathematically
- People then make their own judgement on which intervention is better
47
What is cost-effectiveness analysis?
- Typically has a health service perspective
- Measures costs and benefits of two interventions
- Calculate the cost of each extra ‘unit of benefit’
This is calculated using the incremental cost-effectiveness ratio (ICER)
ICER = (C1 – C0) / (E1 – E0)
C1 and E1 are costs and effects (benefits) in a study intervention group
C0 and E0 are costs and effects (benefits) in a study control group
48
What is cost-utility analysis?
Incremental cost-effectiveness ratio cannot be compared if benefits have different units
CUA is a sub-type of CEAs where the benefits are measured as QALYs
The ICER therefore calculates how many £ for each extra QALY
ICER = (C1 – C0)
(E1 – E0)
C1 and E1 are costs and QALYs in a study intervention group
C0 and E0 are costs and QALYs in a study control group
Results of CUA can be compared between different treatments
Committees can also set a cost-effectiveness threshold for how much it is prepared to pay for one extra QALY
Treatments with a lower ICER are funded
Treatments with a higher ICER are not funded
49
What is cost-benefit analysis?
- Typically has a societal perspective
- Measures costs and benefits of two interventions
- Benefits are measured in monetary terms
- Various methods are used to work out how much the public is willing to pay for a certain benefit
Can then directly compare costs and benefits to see if you get more benefits than you pay for
Difficult method
50
How do you evaluate economic methods?
Trial-based evaluation:
- Collect costs alongside an RCT
- The RCT already collects data on benefits
- Can collect robust data
- Follow up rarely long enough
- Can only compare treatments used in the trial
- Costs can vary between countries
- Does not use all the available information
- Two main ways to carrying out an economic evaluation
Economic modelling:
- Systematic, mathematical way of combining best available evidence
- To compare all relevant alternatives
- Over a clinically relevant time period
Two main types of model:
- Decision tree model
- Markov model
51
What are the NICE commitees?
- NICE publications are overseen by a range of committees
- Relevant health professionals and patient/public representatives
- Evidence reviewed by EBP experts and health economists
- Either employed by NICE or submitted by industry
- Committee reviews evidence, hears from witnesses and makes decisions
52
What are technology appraisals?
Review the clinical and cost-effectiveness of new treatments
NHS is required to fund approved treatments within 3 months
Single technologies - clinical and economic evidence is supplied by the manufacturer
Evidence review group critiques this evidence
Multiple technologies – evidence is generated by technology assessment group
ICER threshold of £20,000-£30,000 per QALY
53
How do technology appraisals differ for end of life care?
Where:
- The treatment is indicated for patients with a short life expectancy, normally less than 24 months and;
- There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared to current NHS treatment
ICER threshold of ~£50,000
54
What are highly specialised technology appraisals?
- Single technology for a single, very rare indication (<500 people in England)
- Key, new and emerging technologies
- ICER threshold depends on incremental QALYs gained per person:
<10 QALYs gained: £100,000 per QALY
11-29 QALYs gained: £100,000-300,000 per QALY
>30 QALYs gained: £300,000 per QALY
Examples:
Asfotase alfa for treating paediatric-onset hypophosphatasia
Birch bark extract for treating epidermolysis bullosa
55
What are managed access programs?
- There are sometimes uncertainties about the clinical or cost-effectiveness of some new treatments
- These programmes designed to allow people to use them, while collecting data to address these uncertainties:
- Patients: new treatments
- Industry: route to market
- Taxpayers: value for money
- Time limited agreements (max 5 years) about who is treated, the data collected and the cost
- After this time, NICE reviews new evidence and decides whether treatment can be routinely used
56
What are the two current managed access programs?
Cancer Drugs Fund: e.g. atezolizumab for adjuvant treatment of resected non-small-cell lung cancer
Innovative Medicines Fund: e.g. nusinersen for treating spinal muscular atrophy
57
What are cohort studies?
Typically a large group of people who share a common characteristic followed over a period of many years.
58
Why do you define exposure?
Must be clearly defined
Misclassification of exposure may lead to an underestimate or overestimate of association between exposure and outcome
59
What are the 5 strengths of cohort studies?
- Efficient for rare exposures
- Multiple effects can be studied
- Studies are less prone to bias
- Can calculate incidence rates, relative risks
- Temporal relationship easier to establish
60
What are the 2 limitations of cohort studies?
- Can have difficulties with following up
- May have problems with bias
61
What are hill's 9 aspects of association?
- Strength of association
- Consistency
- Specificity
- Temporality
- Biologic gradient
- Biologic plausibility
- Coherence
- Experimental evidence
- Analogy
62
What is the advantage of using hospitals to create study population?
easy to recruit
63
What is the disadvantages of using hospitals to create study population?
might not come from the same population; might be more likely to have risk factors such as smoking / alcohol / poor diet than the general population
64
What is the advantage of using community to create study population?
Might be more representative
65
What are the disadvantages of using community to create study population?
Harder to recruit (less interest in study?)
More issues with recall bias?
66
What is bias?
The introduction of a systematic error in the study
Introduced at the point of study design and cannot be eliminated at point of analysis
Can be in terms of
- Selection of study subjects
- Exposure classification
- Outcome classification
Can result in over or underestimated risks
67
What are the two types of misclassification?
Non-differential
- Misclassification to same degree for all groups
Differential
- Misclassification different between groups
68
What is confounding?
- The distortion of a risk estimate due to the mixture of the people in the study population
- A confounder is a risk factor for the disease and is correlated with the exposure independent of disease
69
What is an effect modifier?
Effect modification occurs when the effect of the exposure is different in different groups of the population
A factor that modifies the effect of a putative causal factor under study
There is no average ‘true value’
70
What are phase 4 trials?
Required by regulator to follow up drug once released to market
Trying to identify adverse events
Trying to determine any long term harm
Can give information about drug effects in those not included in phase III trials
71
What are the three types of adverse drug reaction?
Type A – drug effect
Type B – patient reaction
Type C – where drug increases the frequency of spontaneous disease
72
What is pharmacovigilance?
- the detection, assessment and prevention of adverse drug effects in humans’ (WHO)
- Detection of unknown adverse events and interactions
- Identification of risk factors and quantification of risk for known adverse reactions
- Detection of increases in frequency of adverse reactions
- Information dissemination
73
What is pharmacoepidemiology?
- The principles of chronic disease epidemiology applied to the area of clinical pharmacology
- How is the drug used?
- What are the predictors of use?
- What are the outcomes?
74
What were the 3 effects on infants of thalidomide?
- Despite rubella causing birth defects, little consideration given to drug effects on foetus until thalidomide
- One third of women using thalidomide gave birth to babies with defects
- Limb, bowel, ear, eye, heart, gallbladder, uterus malformations detected
75
What were the outcomes from thalidomide?
- Animal testing: mice usually used for safety screening but later found to be insensitive to thalidomide
- Now several species are used in in vivo testing
- Timing of exposure: if thalidomide was taken before the 34th day after LMP OR after the 50th day then no malformations were present
- Earlier exposure can lead to miscarriage; late exposure to brain damage
- Death before 1st birthday: 40% of thalidomide victims
76
What are the 5 challenges of studying drug safety in pregnancy?
- Pregnant women are often excluded from clinical trials
- Preclinical animal studies are often not predictive of human risk
- Not possible to assume a ‘class effect’
- Gaps in our knowledge of teratogenic mechanisms
- Information on pharmacology and toxicology is often of limited value
77
What is the importance of capturing pregnancy losses?
- Spontaneous losses or stillbirths might be the outcome of interest
- Advances in prenatal screening mean some women who are prenatally diagnosed with a severe birth defect may opt to have a pregnancy termination
78
What are pregnancy prevention plans?
- Some medicines are highly teratogenic when used during pregnancy
- For some individuals, however, the benefits of treatment with one of these products cannot be achieved from other products
PPPs aim to allow women of child bearing potential to use highly teratogenic products whilst ensuring they are not pregnant before during or after use
79
Why can't accutane be used in pregnancy?
Animal studies had identified concerns that there could be potential teratogenicity, found to be the case
However, it has a unique efficacy with a 5 month course often resulting in a cure and it has a short half life so the period of risk is limited
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