Cardiovascular drug develoment Flashcards
How long can the development of medicine take?
10-15 years
What are the stages of drug development?
- Drug discovery: Candidate molecules chosen on basis of pharmacological properties
o Target Identification/Selection
o Lead Finding and Optimisation - Preclinical development:
o Non-human studies
o Toxicity testing
o Pharmacokinetic analysis and formulation - Clinical development:
o Volunteers and patients
o Efficacy testing, side-effects and potential dangers
What are drug targets for CVD drugs?
o Functional proteins
o Receptors, enzymes, transport proteins e.g. ARBs
Not all drug discovery is for small molecule inhibitors:
• Proteins, antibodies & oligonucleotides as therapeutic agents
o Insulin – protein drug
o Tissue plasminogen activator – protein drug
What happens in Lead Finding and Optimisation
- Cloning of target protein
- Assay to measure functional activity
- Automated systems to allow for speed & economy
- High-throughput screening of large compound libraries
- Lead optimisation, complex chemistry to increase potency, selectivity & stability
What happens in Preclinical Development?
Non-human studies/ Toxicity testing/ Pharmacokinetic analysis and formulation
- Pharmacological testing for hazardous acute effects
- Preliminary toxicology testing
- Pharmacokinetic testing for absorption, metabolism, distribution & elimination
- Chemical & pharmaceutical development to assess the feasibility of large-scale synthesis & purification as well as stability
What happens in clinical Development?
- Volunteers and patients/ Efficacy testing, side-effects and potential dangers
- There are 4 phases
What is a target protein for cholesterol homeostasis?
PCSK9 inhibitors
• PCSK9 targets LDL receptors for degradation
• Decreases the ability to uptake cholesterol in the liver and remove from the circulation
• PCSK9 mAbs prevent LDLR degradation, promote recycling and cholesterol uptake
What is a clinical trial?
- “Application of experimental variable (treatment to person or group of persons) and observation during or following treatment to measure its effect”
- Outcome measure may be death, occurrence or recurrence of morbid condition, or difference indicative of change e.g. blood pressure measurement
What are the 3 types of clinical trials?
• Uncontrolled trial
o Everyone gets the treatment
o Rarely done nowadays
• Controlled trial – a treated group is compared with a control group
o Standard therapy is given to control group
o Placebo is given to control group
o Two or more active treatments may be compared
• Randomised controlled trial (individuals (or communities) are allocated randomly to each study group (e.g. treatment/placebo)
What are 10 potential issues in clinical trials?
- Ethical issues (protection of human subjects)
- Implications of eligibility criteria (sampling)
- Degree of masking
- Randomisation
- Intention to treat analysis – must always consider data from even those that have dropped out
- Selection of interventional and comparison groups
- Selection of end points
- Interpretation of results
- Trial duration
- Selection of traditional versus equivalence testing – traditional only looks at if the drug is better than the current gold standard at treating whereas equivalence looks at if it has the same effectiveness as the current gold standard + other benefits ie low costs
What is considered during the analysis and evaluation of clinical trials?
- Key experimental design issues
- Bias
- Internal and external validity
- Analysis and presentation of clinical trials results
- Interpretation
What are key design issues for human clinical trials?
• Target population
o What groups are to be investigated?
o Can sufficient number of individuals be recruited?
o Ethical approval?
• How are endpoints to be defined/what data is to be collected?
• Specify study protocol o Will treatments be assigned at random? o Sample size calculations? o How will treatments be given? o Will subjects be followed over time?
• Analysis of data
o What statistics will be used to summarize the results?
o What statistical tests will be used for hypothesis testing?
• Interpretation and biological/clinical significance of the results obtained
What are the sources of bias (systematic error) in clinical studies?
- Selection bias
- Performance bias
- Attrition bias
- Detection bias
- Reporting bias
What is selection bias?
Systematic differences between baseline characteristics of the groups that are compared
What is performance bias?
Systematic differences between groups in the care that is provided, or in exposure to factors other than the interventions of interest
