Clinical Trial Design Flashcards
Why are clinical trials important
They provide evidence and most medical practice is evidence based
Name some drug treatments which are based on clinical trial evidence
Treatment of: Myocardial infarction Stroke Many cancers Rheumatoid arthritis
What type of questions should be asked when developing a new drug/clinical trial
Does it work? What dose is therapeutic? What dose is toxic? Is it safe? Is it necessary?
Name some drugs used today that were developed before clinical trials
Digoxin
Warfarin
Name some false positives which have occurred with observational studies
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
What are observational studies difficult to replicate
Due to bias/different criteria
Why should robust clinical trials be conducted
What works in theory may not be best in practice
Give some examples of treatments which have changed due to robust clinical trials
Intermittent positive pressure ventilation (IPPV) - reduced use as no benefit
Tonsillectomy -
unnecessary in most cases
What acts and regulations are in place for clinical trials
UK Medicines Act 1968
The Medicines for Human Use (Clinical Trials) Regulations 2004
What should clinical trials test
Efficacy
Saftey
What should the drug efficacy be compared with in clinical trials
Placebo
Another drug
What are the stages in development
Drug discovery
Pre-clinical development
Clinical development
Name some drugs and how they were discovered
Fox gloves and digoxin
Poppies and morphine
Dogs and insulin
What is done in pre-clinical development
Animal pharmacology
Animal toxicology
Tissue culture
What does animal pharmacology test
Dose
Adverse effects
What does animal toxicology test
Teratogenicity
Fertility
Mutagenicity
How many phases are there in clinical trials
4
What does phase 1 (volunteer studies) in clinical development involve
Clinical pharmacology in normal volunteers generating pharmacokinetic, metabolic and pharmacodynamic data.
Usually involves around 100 subjects
What type of drugs can bypass phase 1
Cytotoxics
Give an example of a phase 1 trial
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
What does phase 2 clinical trials involve
About 500 PATIENTS
Clinical investigation to confirm kinetics and dynamics in patients
Provides some evidence of efficacy and identifies a likely dosage range
What are phase 3 clinical trials
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
What happens at the end of phase 3 clinical trials
All data (pre-clinical, pharmaceutical and clinical data) is submitted as an application to the regulatory authority for a license to sell the drug
What occurs in a phase 4 clinical trial
Post-marketing surveillance to produce evidence of long term safety (can involve tens or hundreds of thousands of patients)
What are pilot studies for
To test study design not estimate outcome
What can trials be
Double blind
Single blind
Prospective
Retrospective
What does a placebo controlled study compare
Compare the outcome in two groups (one given active drug and other given placebo)
What does an other therapy study compare
Compare the end points with the use of two different drugs
What is a cross over design
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
What is a randomised control clinical trial (RCCT)
When patients are assigned at random to either treatment(s) or control
This is the gold standard
What are the disadvantages of randomised control clinical trials
Results may not be generalisable
Recruitment of patients
Acceptability of randomisation process
Administrative complexity (randomisation methods)
Why is the fact that results may not be generalisable a disadvantage in RCCT
The subjects may not represent general patient population
Tend to be better at complying
Why is recruitment a disadvantage of RCCT
Twice as many new patients needed for the study
Why is the acceptability of the randomization process in RCCT a disadvantage
Some physicians will refuse (PFO closure)
Some patients will refuse (want treatment)
What are commonly used phase 3 designs
Parallel Withdrawal Group/Cluster Randomized Consent Cross Over Factorial Large Simple Equivalence/Non-inferiority Sequential
What is a superiority design
To show that new treatment is better than the control or standard (maybe a placebo)
What is a non-inferiority design
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)
When designing a study what should the end points be
Simple as possible: Death No of hospital admissions Lowering of blood pressure Compare with pain control or change in mood
What needs to be considered when designing a study
Hypothesis
Endpoints
Number of subjects
Safety endpoints
What needs to be thought of when choosing subjects
Need enough to be able to detect or reject a difference between the groups
Statistical design is very important
What does the number of patients depend on
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
How should a control drug be chosen
Placebo (50% effective in anxiety)
Drug of known efficacy (e.g. atenolol)
What should be considered when choosing patients
Age and sex matched
Race
Other diseases and drugs
Are they going to comply?
What should be part of the exclusion/selection criteria
Exclude pregnant women Children Seriously ill patients Elderly patients Patients at risk of side effects
Why should elderly people be excluded
Declining renal function
How is analysis and interpretation done
Choice a statistical test
Are differences due to chance?
What is normally taken as significance
p<0.05
How can an insignificant finding be interpretated
No difference or just that the study hasn’t found one?
Two treatments may be clinically equivalent
What needs to be considered in regards to ethics
Consent Ethics committee Placebos Children Study design ‘Policing’ studies MHRA/CSM/EU Insurance The Law
How long does pharmaceutical produce development tend to take
About 10 years
Goes through reasearch, decision for development and development
How many trials tend to drop out in phase 1
70%
How many trials tend to drop out in phase 2
20%
How many trials tend to drop out in phase 3
5-8%
Where must all pre-clinical and clinical trial evidence be submitted
To the regulatory authority
Who is the MHRA
Medicines and Healthcare devices Regulatory Authority - A committee on safety of medicines
Where can the yellow card system be found
GPs
Hospital doctors
Pharmacists
Name some important clinical trials
4S Scandinavian Simvastatin Survival Trial
Cholesterol and Recurrent Events Trial (CARE)
What were the results of the 4S and CARE trial
4S - 37% reduction in revascularisation
CARE - stroke reduced by 31% (p=0.03)
Why are good clinical trials necessary
Protect the public
Provide evidence to help rational prescribing
Who regulates clinical trials in the UK
MHRA
Medicines and Healthcare products Regulatory Agency
What is the best type of clinical trial
Prospective randomized double blind
