cardiovascular drug development Flashcards
why do we need clinical trial?
- In the past, a patient suffering from gallstones would undergo inappropriate treatments. Clinical trials allow a more scientific, evidence-based medicine approach.
- Scurvy –>characterised by swollen and bleeding gums with loosened teeth, soreness and stiffness of the joints and lower extremities, bleeding under the skin and in deep tissues, slow wound healing and anaemia.
what is evidence based medicine?
“The integration of best research evidence with clinical expertise and patient values.”
- Requires latest scientific evidence to be applied to clinical practice
- Involves assessment of research in terms of
- category and level of evidence
- Category and level are used to define strength of recommendation
what are the levels of evidence/type of study
1a–> systematic reviews of randomised clinical trials
1b–> individual randomised clinical trials
2a–> systematic reviews of cohort studies
2b–> individual cohort studies and low quality RCTs
3a–> systematic reviews of case controlled studies
3b–> individual case-controlled studies
4–> case series, poor-quality cohort and case-control studies
5–> expert opinion based on clinical experience
how long does it take to develop a new medicine?
Developing a new medicine takes an average of 10-15 years. 1 in every 5,000-10,000 is approved
drug discovery–> preclinical–> clinical trials–> FDA review
what is post-marketing?
the phase where a drug has been approved by the FDA but it is still subject to monitoring & need to know the long-term side effects
describe lipitor
blockbuster drug for CVD diseases- sales of $11 billion. Statin drug treating cholesterol levels
describe torcetrapib
raised good cholesterol, strong scientific basis and rationale but failed clinical testing in 2006 after Pfizer spent $1 billion. Increased mortality rates as compared with placebo.
what are the 3 stages of a project?
- drug discovery: candidate molecules chosen on basis of pharmacological properties.
- Preclinical development: non-human studies, toxicity testing, pharmacokinetic analysis and formulation
- Clinical development: volunteers and patients, efficacy testing, side-effects and potential dangers
describe how drug discovery occurs
Target identification/selection:
drug targets are functional and specific proteins
- receptors
- enzymes
- transport proteins e.g. ARBs
- transcription factors (historically very difficult to target but now have finally been druggable).
o around 100-1000 potential drug targets i.e. proteins that play a role in disease but are they “druggable”?
- druggable target: whether it can be easily inhibited e.g. can the binding site of a ligand (e.g. receptor) be inhibited?
- Post translational modification of protein is a common target e.g. targeting phosphorylation sites/ protein kinases, so protein doesn’t get phosphorylated= no protein activation
Limitations are not biological but emerging adverse effects during clinical testing, cost and complexity of drug discovery and development (regulation).
what happens after you find the target?
Cloning of target protein–> develop assay to measure the functional activity–> automated systems to allow for speed and economy–> high throughput screening of large compound libraries–> find an effective compound e.g. natural products, fungal, plants, bacteria e.g. antibiotics and sirolimus (rapamycin).
what does pre-clinical development investigate?
- Pharmacological testing for hazardous acute effects
- Preliminary toxicology testing
- Pharmacokinetic testing for absorption, metabolism, distribution & elimination
- Chemical & pharmaceutical development to assess feasibility of large-scale synthesis & purification as well as stability (can they be stored at room temperature?)
what are the types of clinical trials?
A clinical trial may be:
- An uncontrolled trial – everyone gets the treatment
o Rarely done nowadays
- A 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
- Randomized (individuals (or communities) are allocated randomly to each study group (e.g. treatment/placebo)
what are the problematic areas that may affect outcome?
- ethical issues (protection of human subjects)
- Implications of eligibility criteria
- degree of masking (single blinded, double blinded)
- randomisation
- intention to treat analysis
- selection of interventional and comparison groups
- selection of end points
- interpretation of results
- trial duration
- selection of traditional versus equivalence testing
what are the key design issues for human clinical trials?
Target population:
- What groups are to be investigated?
- Can sufficient number of individuals be recruited?
- Ethical approval?
How are endpoints to be defined/what data is to be collected?
Specify study protocol:
- Will treatments be assigned at random?
- Sample size calculations?
- How will treatments be given?
- Will subjects be followed over time?
Analysis of data
- What statistics will be used to summarize the results?
- What statistical tests will be used for hypothesis testing?
Interpretation and biological/clinical significance of the results obtained
define bias
- Bias is a 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
