S1) Developing Medicines and Clinical Trials Flashcards
1
Q
Identify the different stages in drug development as well as their associated duration
A
- Discovery research (4 years)
- Phase 1 (1 year)
- Phase 2 (2 years)
- Phase 3 (4 years)
- Regulatory review (1 year)
- Phase 4
2
Q
Describe what is involved in the 4 years of discovery research in drug development
A
- Medicinal chemistry
- Biological testing
- Pharmacology
- Toxicology
3
Q
Describe what is involved in the phase 1 of drug development
A
- Evaluates pharmacokinetics and safety with 50 healthy volunteers
- Lasts 1 year
4
Q
Describe what is involved in the phase 2 of drug development
A
- Evaluates pharmacology in disease in 200 - 400 patients with target disease
- Lasts 2 years
5
Q
Describe what is involved in the phase 3 of drug development
A
- Comparison with standard treatments
- Evaluates efficacy in target population and provides longer term safety data using 1000 - 3000 patients
- Lasts 4 years
6
Q
Describe what is involved in the regulatory review in drug development
A
- Authority review of efficacy and safety
- Lasts 1 years
7
Q
Describe what is involved in the phase 4 of drug development
A
- Monitoring for adverse reactions
- New indications or formulations in < 10 000 patients
8
Q
Name the five processes which occur in discovery research in drug development
A
- Idea/concept phase
- Feasibility
- Target validation
- Identification of potential compounds (leads)
- Selection of candidate drug
9
Q
What is involved in the idea/concept phase of discovery research in drug development?
A
- Therapeutic indication identified (disease approach)
- Potential molecular targets identified (mechanism approach)
- Assessment of medical/scientific/commercial opportunity
10
Q
What is involved when considering the feasibility of discovery research in drug development?
A
- Model development
- Hypotheses generation
- Relevance to humans
- Screen evaluation
11
Q
What is involved in the target validation of discovery research in drug development?
A
- Screens developed and validated
- Screening
- Hits (potential drugs) identified and evaluated
- Synthetic feasibility assessed (chemistry)
- Lead drug development and optimisation approach determined
12
Q
What is involved when identifying potential compounds in discovery research in drug development?
A
- Potency and selectivity optimised
- PK and metabolism optimised
- Early assessment of toxicity
- Physical chemical properties and technical issues assessed
13
Q
What is involved when selecting a candidate drugs in discovery research in drug development?
A
- Animal toxicology and preclinical safety pharmacology
- Toxicology studies (1 month/or longer) to support next phase
- Pre-formulation package and drug product supply
- Clinical and regulatory development plan & methodology studies
14
Q
With reference to drug action, what does the statement ‘scientifically proven to work’ mean?
A
“It is better than the other treatment” i.e. more people receiving this treatment are cured than those on the other treatment
15
Q
What is a clinical trial?
A
A clinical trial is 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
16
Q
What is the purpose of a clinical trial?
A
The purpose of a clinical trial is to provide reliable evidence of treatment efficacy and safety
17
Q
What is efficacy?
A
Efficacy is the ability of a healthcare intervention to improve the health of a defined group under specific conditions
18
Q
What is safety?
A
Safety is the ability of a health care intervention not to harm a defined group under specific conditions
19
Q
In order to be able to give a fair comparison of effect and safety, which three features must a clinical trial have?
A
- Reproducible – in experimental conditions
- Controlled – comparison of interventions
- Fair – unbiased without confounding
20
Q
What are non-randomised clinical trials?
A
Non-randomised clinical trials involve the allocation of patients receiving a new treatment to compare with a group of patients receiving the standard treatment
21
Q
What are the two disadvantages of non-randomised clinical trials?
A
- Allocation bias – by patient, clinician or investigator
- Confounding – known and unknown
22
Q
What are the three steps involved in a randomised controlled trial (RCT)
A
- Definition of factors
- Conduct of the trial
- Comparison of outcomes
23
Q
Identify the 6 factors which need to be defined in an RCT
A
- The disease of interest
- The treatments to be compared
- The outcomes to be measured
- Possible bias and confounders
- The patients eligible for the trial
- The patients to be excluded from the trial
24
Q
What are the seven sub-steps in conducting a RCT?
A
⇒ 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 compliance with treatments
25
Which four questions might one ask when comparing outcomes in an RCT?
- 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?
26
Provide 3 reasons for pre-defining outcome measures before the start of a clinical trial
- **Prevent ‘data dredging’**, ‘repeated analyses’
- Protocol for **data collection**
- **Agreed criteria** for measurement and assessment of outcomes
27
Identify three types of clinical outcomes and provide examples for each
- Patho-physiological *e.g. tumour size, thyroxine level, ECG changes*
- Clinically defined *e.g. mortality, morbidity, disability*
- Patient-focused *e.g. quality of life, psychosocial well-being, satisfaction*
28
Describe the timing of measurements in a clinical trial
- **Baseline measurement of relevant factors** – monitoring for inadvertent differences in groups
- **Monitoring outcomes during the trial** – monitoring for possible effect / adverse effects
- **Final measurement of outcomes** – comparing final effect of treatments in trial
29
What are the two advantages of random allocation?
- **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
30
Blinding/masking is a method to ensure minimal allocation bias.
What are the two types of blinding?
- **Single blind** – one of patient, clinician, assessor does not know the treatment allocation
- **Double blind** – two of patient, clinician, assessor does not know the treatment allocation (usually patient + clinician/assessor)
| (usually patient)
31
Identify five situations where blinding is difficult to achieve
- Surgical procedures
- Psychotherapy vs. anti-depressant
- Alternative medicine vs. Western medicine
- Lifestyle interventions
- Prevention programmes
32
What is the effect of 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**
33
What is the placebo effect?
**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**”
34
What is a 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*
35
What is the purpose of a placebo?
The aim of a ‘**placebo**’ is to cancel out any ‘placebo effect’ that may exist in the active treatment
36
The use of a placebo is a form of deception.
Hence, what are the ethical implications for this?
- A placebo should only be used when **no standard treatment is available**
- Participants in a placebo-controlled trial are **informed that they may receive a placebo**
37
What leads to losses to follow-up i.e. not every participant remains in the clinical trial?
- Their **clinical condition** may necessitate their removal from the trial (appropriate)
- They may **choose to withdraw** from the trial (unfortunate)
38
Suggest four ways that might help minimise losses to follow up in clinical trials
- Make the follow-up practical and **minimise inconvenience**
- **Be honest** about the commitment required from participants
- **Avoid** **coercion** or inducements
- **Maintain** **contact** with participants
39
What leads to non-compliance to treatment in patients?
- 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**
40
Suggest four ways that might help 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*
41
Explain how one might conduct an explanatory trial – 'as-treated’ analysis
- Analyses only those who **completed follow-up** and **complied with treatments**
- Compares the **physiological effects** of the treatments
- Loses effects of **randomisation** → selection bias and confounding
42
Explain how one might conduct an pragmatic trial – 'intention-to-treat’ analysis
- Analyses according to the **original allocation** to treatment groups, **regardless of compliance/completion**
- Compares the **likely effects** of using the treatments in r**outine clinical practice**
- Preserves effects of **randomisation** → minimal selection bias and confounding
43
Clinical trials should normally be analysed on an ‘intention-to-treat’ basis.
Why is this?
- **'As-Treated’** analyses tend to give larger sizes of effect
- **‘Intention-to-Treat’** analyses tend to give smaller and more realistic sizes of effect
44
What is the principle of collective ethic?
**Collective ethic** – all patients should have treatments that are properly tested for efficacy and safety
45
What are the principles of individual ethic?
- The principle of **beneficence**
- The principle of **non-maleficence**
- The principle of **autonomy**
- The principle of **justice**
46
Explain collective ethic in terms of randomised controlled trials
**Collective ethic** – RCTs aim to properly test treatments for efficacy and safety
47
Explain individual ethic in terms of randomised controlled trials
- RCTs do not **guarantee benefit**
- RCTs may result in **harm**
- RCTs allocate treatment **by chance**
- RCTs place **burdens** and confer **benefits**
48
Which issues should be considered for a clinical trial to be ethical?
- Clinical equipoise
- Scientifically robust
- Ethical recruitment
- Valid consent
- Voluntariness
49
What is clinical equipoise?
**Clinical equipoise** is when there is reasonable uncertainty or genuine ignorance about the better treatment or intervention (including non-intervention)
50
Which 8 features make a trial scientifically robust?
- Addresses a **relevant issue**
- Asks a **valid question**
- Has an **appropriate study design** and protocol
- Has the potential to **reach sound conclusions**
- Can justify the use of the **comparator treatment or placebo**
- Has **acceptable risks of possible harm** compared to anticipated benefits
- Has provision for **monitoring the safety** participants
- Has **arrangements for appropriate reporting** and publication
51
Identify two issues with ethical recruitment
- Inappropriate exclusion
- Inappropriate inclusion
52
In terms of ethical recruitment, provide two scenarios demonstrating inappropriate exclusion
- People who differ from an **ideal homogenous group** *e.g. non-White people, women, co-morbidities (usually elderly)*
- People who are difficult to get **valid consent from** *e.g. immigrants, mentally ill, children, prisoners*
53
In terms of ethical recruitment, provide two scenarios demonstrating inappropriate inclusion
- Participants from communities that are **unlikely to benefit** *e.g. AIDS drugs trials in LEDCs*
- Participants with a **high risk of harm with respect to potential benefits**
* e.g. pregnant women*
- Participants likely to be **excluded from analysis** *e.g. a small sub-group of Chinese*
54
Describe the six steps involved to attain valid consent
⇒ Knowledgeable **informant**
⇒ Appropriate **information** (verbal, written, freedom to opt out)
⇒ Informed **participant**
⇒ Competent **decision-maker**
⇒ Legitimate **authoriser**
⇒ Signed **consent form** as evidence of valid consen
55
What is voluntariness?
**Voluntariness** is a pre-requisite for consent to be valid, i.e. the decision should be free from *coercion or manipulation*
56
Perceived coercion or manipulation invalidates consent as much as actual coercion or manipulation.
Provide some examples of coercion
- Non-access to ‘best’ treatment
- Lower quality of care
- Disinterest by clinician
57
Perceived coercion or manipulation invalidates consent as much as actual coercion or manipulation.
Provide some examples of manipulation
- Exploitation of emotional state
- Distortion of information
- Financial inducements
58
What is the purpose of a research ethics committee?
- Research governance
- Financial management
- Resource implications
