CVD Drug development: an overview Flashcards

Question

Analysis+evaluation of clinical trials

Answer 1

Key experimental design issues Bias Internal + external validity Analysis + presentation of clinical trials results Interpretation

Answer 2

Target population -What groups are being 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 summarise the results? -What statistical tests will be used for hypothesis testing? Interpretation + biological/clinical significance of the results obtained Sources of bias (systematic error) in clinical studie

Answer 3

Selection bias Performance bias Attrition bias Detection bias Reporting bias

Answer 4

Systematic differences between baseline characteristics of the groups that are compared

Answer 5

Systematic differences between groups in the care that is provided, or in exposure to factors other than the interventions of interest

Answer 6

Systematic differences between groups in withdrawals from a study

Answer 7

Systematic differences between groups in how outcomes are determined or measured

Answer 8

Systematic differences between reported + unreported findings

Answer 9

Internal Validity: study is internally valid if the study conclusions represent the truth for the individuals studied bc the results were not likely due to the effects of chance, bias or confounding External Validity: (generalizability) = study is externally valid if the study conclusions represent the truth for the population to which the results will be applied bc both the study populations + the reader’s populations are similar enough in important characteristics

Answer 10

Clinical trials contain 4 main types of figures = flow diagrams, Kaplan-Meier plots, forest plots + repeated measures plots

Answer 11

Investigator/author- inadequate power, multiple testing errors, biases, conflicts of interest, combined endpoints, noninferiority trials Reviewer- inadequate expertise, bias, poor quality review Editor- publication bias, impact + priority Practitioner- bias, advertising Media/public- institutional hype, media hype, limited expertise, competing interests Other investigators- over-intepreted meta/mega-analysis

Answer 12

Heart- cardiac function, perfusion + contractility Assess non-invasively by US, SPECT, PET + MRI Arterial walls- narrowing or arterial walls + Ca2+ deposition Molecular level- cellular + molecular level detection of pathways of relevance to disease

Answer 13

Image, track + quantify molecular biomarkers not amenable to biopsy e.g., heart + vasculature Effectiveness of new treatments can be determined w smaller patient populations + shorter trials

Answer 14

= “a surrogate endpoint of a clinical trial is a laboratory measurement or physical sign used to substitute for a clinically- meaningful endpoint that measures directly how a patient feels, functions or survives. Changes induced by a therapy on a surrogate endpoint are expected to reflect changes in a clinically-meaningful endpoint”

Answer 15

Measure changes in plaque volume/burden Measure changes in plaque composition Be reproducible + repeatable Correlate w clinical outcome

Answer 16

Proteins Antibodies Oligonucleotides insulin/tPA

Answer 17

* 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 * PCSK9 timeline for drug development * Incredibly short discovery phase and development of PCSK9 inhibitors

Answer 18

A small number of people, who may be healthy volunteers, are given the medicine. The drug is being trialled in human volunteers for the first time. Researchers test for side effects and calculate what the right dose might be to use in treatment. Researchers start with small doses and only increase the dose if the volunteers do not experience any side effects, or if they only experience minor side effects. (NOT RANDOMISED)

Answer 19

The new medicine is tested on a larger group of people who are ill. This is to get a better idea of its effects in the short term.

Answer 20

Carried out on medicines that have passed phases 1 and 2. The medicine is tested in larger groups of people who are ill, and compared against an existing treatment or a placebo to see if it's better in practice and if it has important side effects. Trials often last a year or more and involve several thousand patients.

Answer 21

The safety, side effects and effectiveness of the medicine continue to be studied while it's being used in practice. Not required for every medicine. Only carried out on medicines that have passed all the previous stages and have been given marketing licences – a licence means the medicine is available on prescription.