Clinical Trial Design COPY

Question 1

Why are clinical trials important

Answer 1

They provide evidence and most medical practice is evidence based

Question 2

Name some drug treatments which are based on clinical trial evidence

Answer 2

Treatment of:
Myocardial infarction
Stroke
Many cancers
Rheumatoid arthritis

Question 3

What type of questions should be asked when developing a new drug/clinical trial

Answer 3

Does it work?
What dose is therapeutic?
What dose is toxic?
Is it safe?
Is it necessary?

Question 4

Name some drugs used today that were developed before clinical trials

Answer 4

Digoxin

Warfarin

Question 5

Name some false positives which have occurred with observational studies

Answer 5

High cholesterol diet and rectal cancer
Smoking and breast cancer
Vasectomy and prostate cancer
Red meat and colon cancer
Red meat and breast cancer
Drinking water frequently and bladder cancer
Not consuming olive oil (reduces bp in women) and breast cancer
HRT and cardiovascular risk

Question 6

What are observational studies difficult to replicate

Answer 6

Due to bias/different criteria

Question 7

Why should robust clinical trials be conducted

Answer 7

What works in theory may not be best in practice

Question 8

Give some examples of treatments which have changed due to robust clinical trials

Answer 8

Intermittent positive pressure ventilation (IPPV) - reduced use as no benefit
Tonsillectomy -
unnecessary in most cases

Question 9

What acts and regulations are in place for clinical trials

Answer 9

UK Medicines Act 1968

The Medicines for Human Use (Clinical Trials) Regulations 2004

Question 10

What should clinical trials test

Answer 10

Efficacy

Saftey

Question 11

What should the drug efficacy be compared with in clinical trials

Answer 11

Placebo

Another drug

Question 12

What are the stages in development

Answer 12

Drug discovery
Pre-clinical development
Clinical development

Question 13

Name some drugs and how they were discovered

Answer 13

Fox gloves and digoxin
Poppies and morphine
Dogs and insulin

Question 14

What is done in pre-clinical development

Answer 14

Animal pharmacology
Animal toxicology
Tissue culture

Question 15

What does animal pharmacology test

Answer 15

Dose

Adverse effects

Question 16

What does animal toxicology test

Answer 16

Teratogenicity
Fertility
Mutagenicity

Question 17

How many phases are there in clinical trials

Answer 17

4

Question 18

What does phase 1 (volunteer studies) in clinical development involve

Answer 18

Clinical pharmacology in normal volunteers generating pharmacokinetic, metabolic and pharmacodynamic data.
Usually involves around 100 subjects

Question 19

What type of drugs can bypass phase 1

Answer 19

Cytotoxics

Question 20

Give an example of a phase 1 trial

Answer 20

Tegenero drug which used 8 volunteers
Six given active drug intravenously
Two given placebo
Given in regulated environment
According to the protocol approved by MHRA
Volunteers got paid

Question 21

What does phase 2 clinical trials involve

Answer 21

About 500 PATIENTS

Clinical investigation to confirm kinetics and dynamics in patients
Provides some evidence of efficacy and identifies a likely dosage range

Question 22

What are phase 3 clinical trials

Answer 22

Formal therapeutic trials where efficacy will be established and evidence of safety obtained (so does it work for the condition we are testing)
Involves 1000-3000 patients

Question 23

What happens at the end of phase 3 clinical trials

Answer 23

All data (pre-clinical, pharmaceutical and clinical data) is submitted as an application to the regulatory authority for a license to sell the drug

Question 24

What occurs in a phase 4 clinical trial

Answer 24

Post-marketing surveillance to produce evidence of long term safety (can involve tens or hundreds of thousands of patients)

Question 25

What are pilot studies for

Answer 25

To test study design not estimate outcome

Question 26

What can trials be

Answer 26

Double blind Single blind Prospective Retrospective

Question 27

What does a placebo controlled study compare

Answer 27

Compare the outcome in two groups (one given active drug and other given placebo)

Question 28

What does an other therapy study compare

Answer 28

Compare the end points with the use of two different drugs

Question 29

What is a cross over design

Answer 29

When one group of patients start of with the study drug and the other with the compared therapy for a certain amount of time then they have a wash out period and swap drugs

Question 30

What is a randomised control clinical trial (RCCT)

Answer 30

When patients are assigned at random to either treatment(s) or control This is the gold standard

Question 31

What are the disadvantages of randomised control clinical trials

Answer 31

Results may not be generalisable Recruitment of patients Acceptability of randomisation process Administrative complexity (randomisation methods)

Question 32

Why is the fact that results may not be generalisable a disadvantage in RCCT

Answer 32

The subjects may not represent general patient population | Tend to be better at complying

Question 33

Why is recruitment a disadvantage of RCCT

Answer 33

Twice as many new patients needed for the study

Question 34

Why is the acceptability of the randomization process in RCCT a disadvantage

Answer 34

Some physicians will refuse (PFO closure) | Some patients will refuse (want treatment)

Question 35

What are commonly used phase 3 designs

Answer 35

``` Parallel Withdrawal Group/Cluster Randomized Consent Cross Over Factorial Large Simple Equivalence/Non-inferiority Sequential ```

Question 36

What is a superiority design

Answer 36

To show that new treatment is better than the control or standard (maybe a placebo)

Question 37

What is a non-inferiority design

Answer 37

To show that the new treatment: - Is not worse that the standard by more than some margin - Would have beaten placebo if a placebo arm had been included (regulatory)

Question 38

When designing a study what should the end points be

Answer 38

``` Simple as possible: Death No of hospital admissions Lowering of blood pressure Compare with pain control or change in mood ```

Question 39

What needs to be considered when designing a study

Answer 39

Hypothesis Endpoints Number of subjects Safety endpoints

Question 40

What needs to be thought of when choosing subjects

Answer 40

Need enough to be able to detect or reject a difference between the groups Statistical design is very important

Question 41

What does the number of patients depend on

Answer 41

Frequency of outcome measurement e.g. Smarties vs atenolol in mild hypertensives BP reduction: 200 patients over 12 weeks Stroke reduction: thousands of patients over five years

Question 42

How should a control drug be chosen

Answer 42

Placebo (50% effective in anxiety) | Drug of known efficacy (e.g. atenolol)

Question 43

What should be considered when choosing patients

Answer 43

Age and sex matched Race Other diseases and drugs Are they going to comply?

Question 44

What should be part of the exclusion/selection criteria

Answer 44

``` Exclude pregnant women Children Seriously ill patients Elderly patients Patients at risk of side effects ```

Question 45

Why should elderly people be excluded

Answer 45

Declining renal function

Question 46

How is analysis and interpretation done

Answer 46

Choice a statistical test | Are differences due to chance?

Question 47

What is normally taken as significance

Answer 47

p<0.05

Question 48

How can an insignificant finding be interpretated

Answer 48

No difference or just that the study hasn’t found one? | Two treatments may be clinically equivalent

Question 49

What needs to be considered in regards to ethics

Answer 49

``` Consent Ethics committee Placebos Children Study design ‘Policing’ studies MHRA/CSM/EU Insurance The Law ```

Question 50

How long does pharmaceutical produce development tend to take

Answer 50

About 10 years | Goes through reasearch, decision for development and development

Question 51

How many trials tend to drop out in phase 1

Answer 51

70%

Question 52

How many trials tend to drop out in phase 2

Answer 52

20%

Question 53

How many trials tend to drop out in phase 3

Answer 53

5-8%

Question 54

Where must all pre-clinical and clinical trial evidence be submitted

Answer 54

To the regulatory authority

Question 55

Who is the MHRA

Answer 55

Medicines and Healthcare devices Regulatory Authority - A committee on safety of medicines

Question 56

Where can the yellow card system be found

Answer 56

GPs Hospital doctors Pharmacists

Question 57

Name some important clinical trials

Answer 57

4S Scandinavian Simvastatin Survival Trial | Cholesterol and Recurrent Events Trial (CARE)

Question 58

What were the results of the 4S and CARE trial

Answer 58

4S - 37% reduction in revascularisation | CARE - stroke reduced by 31% (p=0.03)

Question 59

Why are good clinical trials necessary

Answer 59

Protect the public | Provide evidence to help rational prescribing

Question 60

Who regulates clinical trials in the UK

Answer 60

MHRA | Medicines and Healthcare products Regulatory Agency

Question 61

What is the best type of clinical trial

Answer 61

Prospective randomized double blind