CVD Drug development: an overview Flashcards
What is evidence based medicine?
‘integration of best research evidence w clinical expertise + patient values
What does evidence based medicine require?
Requires latest scientific evidence to be applied to clinical practice
Involves assessment of research in terms of category + level of evidence
Category + level is used to define strength of recommendation
How is EBM classified?
1a (best)
Systematic reviews of randomised clinical trials
1b
Individual randomised clinical trials
2a
Systemic reviews of cohort studies
2b
Individual cohort studies + low-quality RCTs
3a
Systematic reviews of case=controlled studies
3b
Individual case-controlled studies
4
Case series, poor quality cohort + case-control studies
5
Expert opinion based on clinical experience
What are the classes of drugs currently used to treat CVD?
Nitrates
Beta-blockers
Ca2+ channel blockers
Diuretics
ACE inhibitors
Angiotensin receptor blockers
Anti-arrhythmics
Example and effect of Nitrates:
Example:
Gylceryl trinitrate
Effect:
Stimulate NO release causing vasodilation
Example and effect of Beta-blockers:
Examples:
Carvedilol, bisoprolol, nebivolol, atenolol
Effects
Block B-adrenoreceptors, reducing effect of adrenalin
Example and effect of Ca2+ channel blockers:
ex:
Verapamil, diltiazam, amlodipine
eff:
Relaxes arterial SMCs, increases vasodilation
Example and effect of Diuretics:
Furosemide, bumetanide,
bendroflumethiazide
effects:
Act on kidney to increase salt + water loss
Example and effect of ACE inhibitors:
Captopril, ramipril, lisinopril
effects:
Inhibits ACE, salt, water loss + vasodilation
Example and effect of Angiotensin receptor blockers :
Valsartan, losartan, candesartan
Angiotensin receptor antagonists, increase vasodilation
Example and effect of Anti-arrythmics:
Amiodarone, digoxin, verapamil
Reduce electrical activity of the heart
Example and effect of Thrombolytics :
Alteplase, reteplase, tenecteplase
streptokinase
Activate plasmin system, fibrin
breakdown
Anti-platelet drugs
Example and effect of anti-platelet drugs :
Aspirin, clopidogrel
Inhibit platelet aggregation
Example and effect of anti-coagulants :
Wafarin, heparin, FIIa and FXa inhibitors
Inhibit clotting cascade
Example and effect of statins:
Simvastatin, pravastatin, atorvastatin,
lovastatin
Decrease cholesterol production,
increase LDL receptors
Example and effect of fibrates :
Bezafibrate, ciprofibrate
Shift from LDL to HDL profile
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 + formulation
Clinical development- volunteers + patients, efficacy testing, side-effects + potential dangers
Steps in DRUG DISCOVERY:
Target identification/selection
Lead finding + optimisation
Target identification/selection
Drug targets are functional proteins- e.g., receptors, enzymes, transport proteins e.g., ARBs
Limitations not biological by emerging adverse effects during clinical testing, cost + complexity of drug discovery + development (regulation)
Lead finding + optimisation
Cloning of target protein
Assay to measure functional activity
Automated systems to allow for speed + economy
High-throughput screening of large compound libraries
Natural products, fungal, plants, bacteria e.g., antibiotics + sirolimus
Lead optimisation, complex chemistry to increase potency, selectivity + stability
PRECLINICAL DEVELOPMENT
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
CLINICAL DEVELOPMENT
Phase 1, 2, 3 + 4
Clinical trial in its simplest form is ‘application of experimental variable (treatment to person or group of persons + observation during or following treatment to measure its effect’
Outcome measure may be death, occurrent or recurrence of morbid condition, or difference indicative of change e.g., BP measurement
What are the types of clinical trials?
Uncontrolled trial- everyone gets the treatment (rarely done nowadays)
Controlled group- a treated group is compared w a control group
- Standard therapy is given to control group
- Placebo is given to control group
2 or more active treatments may be compared
Randomised controlled trial- individuals or communities are allocated randomly to each study group e.g., treatment/placebo
List some clinical trial design issues:
Ethical issues- protection of human subjects
Implications of eligibility criteria- sampling
Degree of masking
Randomisation
Intention to treat analysis
Selection of interventional + comparison groups
Selection of end points
Interpretation of results
Trial duration
Selection of traditional vs equivalence testing
Analysis+evaluation of clinical trials
Key experimental design issues
Bias
Internal + external validity
Analysis + presentation of clinical trials results
Interpretation
Key design issues for human clinical trials?
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
What are the different types of bias?
Selection bias
Performance bias
Attrition bias
Detection bias
Reporting bias
Selection bias
Systematic differences between baseline characteristics of the groups that are compared
Performance bias
Systematic differences between groups in the care that is provided, or in exposure to factors other than the interventions of interest
Attrition bias
Systematic differences between groups in withdrawals from a study
Detection bias
Systematic differences between groups in how outcomes are determined or measured
Reporting bias
Systematic differences between reported + unreported findings
What validates an investigation?
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
Analysis and presentation of clinical trial results
Clinical trials contain 4 main types of figures = flow diagrams, Kaplan-Meier plots, forest plots + repeated measures plots
Interpretation- what factors can affect interpretation of clinical trials from conception to dissemination of the results
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
How can imaging of CVD help diagnosis/ drug development?
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
Why consider imaging for CVS drug development?
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
Surrogate endpoints
= “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”
What evidence is needed for imaging to be a surrogate for clinical endpoints
Measure changes in plaque volume/burden
Measure changes in plaque composition
Be reproducible + repeatable
Correlate w clinical outcome
Examples of drugs used
Proteins
Antibodies
Oligonucleotides
insulin/tPA
TARGETING 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 - PCSK9 timeline for drug
development - Incredibly short discovery phase
and development of PCSK9
inhibitors
Phase 1 of clinical trial:
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)
Phase 2 of CT:
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.
Phase 3 of CT
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.
Phase 4 of CT:
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.
