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Title: Clinical Trials/ An overview
Description: This is a lecture on Anti-arrhythmic agents/ some old, some new as part of the St. Georges University Biomedical Science course in the Human Cardiovascular and Respiratory Pharmacology module.
Description: This is a lecture on Anti-arrhythmic agents/ some old, some new as part of the St. Georges University Biomedical Science course in the Human Cardiovascular and Respiratory Pharmacology module.
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Cardiovascular disease is a major problem in developed countries
CVD is rising in developing countries
200 drugs for CVS in development
Evidence based medicine
The integration of best research evidence with clinical expertise and patient values
Needs latest scientific evidence to be applied to clinical practice
Involves assessment of research in terms of category and level of evidence
Category and level is used to define strength of recommendation
Developing new medicines
Takes an average of 10-15 years
1 in every 5000-10,000 is approved
Stages:
Pre-discovery (can take decades) - Identifying new novel drug target
Drug discovery - 5000 - 10,000 compounds
Pre-clinical - 250 drugs
Clinical trials - 5 drugs (phase 1-3)
FDA review - 1 drug
Lipitor - biggest drug blockbuster in history
Drug discovery and development
3 stages: (not all drugs follow these stages)
1 - Drug discovery
Candidate molecules chosen on pharmacological properties
Drug targets are functional proteins (receptors, enzymes, transport proteins)
100s - 1000s of potential drug targets (proteins that play disease roles) - but not all
are druggable - some are limited by adverse effects/complexity
Process:
Cloning of target protein
Assay to measure functional activity
Automated systems to allow for speed and economy
Screening of large compound libraries
Optimisation - alter chemical properties to increase potency, selectivity and
stability
2 - Preclinical Development
Non-human studies
Toxicity testing - testing for hazardous acute effects (main priority)
Pharmacokinetic analysis and formulation (ADME)
Assessment of feasibility of large scale synthesis and purification as well as
stability
3 - Clinical Developmental
Volunteers and patients
Efficacy testing
Side-effect profiles and potential dangers
Phases 1-4
Pharmacokinetics - What happens to the drug
Pharmacodynamics - What happens to the drug target
Clinical trial in its simplest form:
Application of experimental treatment and observation during or following treatment to
measure effect
Outcome measure may be death, occurrence/reoccurrence of morbid condition or
difference indicative of change
Types of clinical trials
Uncontrolled trial - everyone gets the treatment (rarely done presently)
Controlled trial - treated group is compared to a control group
Standard therapy is given to control group (2 or more active treatments may be
compared) or
Placebo is given to control group
Randomised (individuals/communities) are allocated randomly to each study group (e
...
treatment/placebo)
Problematic areas in clinical trials
Ethics (protection of human subjects)
Eligibility (sex, age, nationality)
Degree of masking (single blind/double blind)*
Randomisation
Intention to treat analysis (what if patient drops out of study)
Selection of groups (interventional and comparison)
Selection of end points
Interpretation of results
Trial duration
Selection of traditional vs equivalence testing (e
...
same effectiveness but cheaper)
Key experimental design issues
Bias and confounding
Internal and external validity
*Single blind - patient unaware of group, Double blind - patient and admin unaware
Bias in clinical studies
Bias - systematic error in a clinical study which is not reduced by increasing the study
sample size (as opposed to random variation)
Classification - (type) of bias is based on the source of bias
Types of bias
Selection bias
Systematic differences between baseline characteristics of the groups that are
compared
Performance bias
Systematic differences between care given to groups/exposure to factors other
than that being studied
Attrition bias
Systematic differences between groups in withdrawals from a study
Detection bias
Systematic differences between groups in how outcomes are measured
Reporting bias
Systematic differences between reported/unreported findings
Confounding bias
3rd variable exists which isn't accounted for
It is associated with the cause
It is also associated with the effect
It is not distributed the same between the
groups being studied
The supposed cause-effect relation will be
confounded by the third variable
e
...
Confounder
Risk factor
Association
Exposure
Disease
Relationship of interest
Validity of an investigation
Internal validity
Internally valid study if conclusions represent the truth for individuals studied
...
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Title: Clinical Trials/ An overview
Description: This is a lecture on Anti-arrhythmic agents/ some old, some new as part of the St. Georges University Biomedical Science course in the Human Cardiovascular and Respiratory Pharmacology module.
Description: This is a lecture on Anti-arrhythmic agents/ some old, some new as part of the St. Georges University Biomedical Science course in the Human Cardiovascular and Respiratory Pharmacology module.