Cardiovascualr Drug Development Flashcards
Medicines in development for CVD by type and phase of development
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200+ in phases (phases 1-3) at a time
Why do we need clinical trials? (3)
Remedies and their effectiveness…in the 17th Century!
Biliary colic with jaundice (aka gallstones)
….bleeding,
….colonic of tobacco
…..draught of worm-wood, white wine, sheep’s trittle’s (pellets)
…powdered egg shells
…millipedes drowned in white wine
… fresh juice of horse dung
Scottish naval surgeon,
James Lind (1716-1794), is
generally credited with
being the first to discover
the cure for scurvy in 1747
He carried out a “controlled clinical trial” on 12 subjects with scurvy
The subjects were grouped in pairs and each pair given a different
“treatment”
Group 1 : Cider drink
Group 2 : Elixir of vitriol
Group 3 : Vinegar
Group 4 : Seawater
Group 5 : Oranges and lemon
Group 6 : Spicy paste
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 is used to define strength of recommendation
Levels of evidence (8)
1a: Systematic reviews of randomized clinical trials
1b: Individual randomized 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
Drugs used to treat cardiovascular disease (12)
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nitrates: stim. NO release = vasodil
beta-blockers: block beta adreno r’s = red. adren effect
ca2+ channel blockers: relaxes arterial smooth muscle cells = inc vasodil
Diuretics: act on kidney = incr. salt + water loss
ACE inhib: inhib. ACE, salt, water loss + vasodil
ANG r blocker: r’s antagonist inc vasodilation
Anti-arrhythmics: red. electrical activity of heart
anti-platelet : inhib platelet aggr.
anti-coags: inhib clotting cascade
statins: dec. chole produ. - inc. LDL r’s
Fibrates: shift LDL to HDL profile
on avg how long does a new drug take to be made? (6)
10-15yrs total
3-6yrs : drug discovery + preclin
6-7yrs : clinical trials
0.5-2yrs: FDA review
1 in 5000-10000 approved
1bill us dollars for one drug = risky
biggest success + failure of CVD drugs (2)
+ Lipitor/statins: Biggest drug blockbuster in history
with sales of $100 billion (before patent expiry…)
- 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 the drug development project? (6)
1) DRUG DISCOVERY: Candidate molecules
chosen on basis of
pharmacological properties
2) PRECLINICAL DEVELOPMENT:
Non-human studies
Toxicity testing
Pharmacokinetic analysis
and formulation
3) CLINICAL DEVELOPMENT: Volunteers and patients
Efficacy testing, side-
effects and potential
dangers
stage 1 target selection (4)
Drug targets are….
-Functional proteins
-Receptors, enzymes, transport proteins e.g. ARBs
~100s-1000 potential drug targets
i.e. proteins that play a role in disease but are they “druggable”?
Limitations not biological but emerging adverse effects during clinical testing, cost and complexity of drug discovery & development
(regulation)
Stage 1 lead finding + optimisation (5)
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 and
sirolimus (rapamycin)
Lead optimisation, complex chemistry to
increase potency,
selectivity & stability
stage 2: Non-human studies, Toxicity testing,
Pharmacokinetic analysis and formulation (4)
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
stage 3 : Volunteers and patients, Efficacy testing, side- effects and potential dangers (4)
4 phases :
Phase I
Phase II
Phase III
Phase IV
What kind of drugs does drug discovery include? (3)
Biopharmaceuticals: Proteins, antibodies &
oligonucleotides as therapeutic agents
e.g. Insulin and Tissue plasminogen activator (tpa)
Targeting cholesterol homeostasis: PCSK9 inhibitors (5)
PCSK9 targets LDL receptors for degradation
- Dec. 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 = short - Incredibly short discovery phase and development of PCSK9 inhibitors
Targeting cholesterol homeostasis: PCSK9 inhibitors (5)
PCSK9 targets LDL receptors for degradation
- Dec. 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 = short - Incredibly short discovery phase and development of PCSK9 inhibitors
A clinical trial in its simplest
form is… (2)
“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
Uncontrolled trial (2)
– Everyone gets the treatment
– Rarely done nowadays
Controlled trial (4)
– a treated group is compared with a control
group
i. Standard therapy is given to control group
ii.Placebo is given to control group
– 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)
Clinical trial design issues: at least 10 things to look for in clinical trials (10)
Problematic areas that may affect outcome include:
- Ethical issues (protection of human subjects)
- Implications of eligibility criteria (sampling)
- Degree of masking
- Randomisation
- Intention to treat analysis
- Selection of interventional and comparison groups
- Selection of end points
- Interpretation of results
- Trial duration
10 Selection of traditional versus equivalence testing
Analysis and evaluation of clinical trials (5)
- Key experimental design issues
- Bias
- Internal and external validity
- Analysis and presentation of clinical trials results
- Interpretation
Key design issues for human clinical trials (5)
- 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
Sources of bias (systematic error) in clinical studies (5)
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 and
unreported findings
Validity of an investigation - 2 types (2)
Internal Validity:
A study is internally valid if the study conclusions
represent the truth for the individuals studied
because the results were not likely due to the
effects of chance, bias, or confounding
External Validity (Generalisability):
A study is external valid if the study conclusions
represent the truth for the population to which the results will be applied because both the study population and the reader’s population are similar enough in important characteristic
Analysis and presentation of clinical trial results (4)
Clinical trials contain 4 main
type of figures:
Flow diagrams
Kaplan-Meier plots
Forest Plots
Repeated measures plots
Interpretation - factors affecting it (6)
rom conception to dissemination of the results
1) Investigator/author - tetsing errors, biases, CoI’s etc.
2) Reviewer - inadeq. expertise, bias, poor quality review
3) Editor - publication bias, impact + priority
4) Practitioner - bias, advertising
5) Media/public - institutional hype, media hype, limited expertise, competing interests
6) Other investigators - overinterpreted, meta/mega-analyses
Imaging of CVD: Diagnosis (3)
HEART: Cardiac function,
perfusion and contractility
Assessed non-invasively by ultrasound, SPECT, PET & MRI
ARTERIAL WALLS: Narrowing of arterial walls and calcium deposition
MOLECULAR LEVEL: Cellular and molecular level detection of pathways of relevance to disease
Why consider imaging for cardiovascular drug
development? (2)
Image, track and quantify
molecular biomarkers not amenable to biopsy e.g. heart and vasculature
Effectiveness of new
treatments can be
determined with smaller
patient populations and
shorter trials
What is a Surrogate endpoint of a trial? (2)
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? (4)
Measure changes in plaque volume/burden
Measure changes in plaque composition
Be reproducible and
repeatable
Correlate with clinical
outcome
Imaging techniques in cardiovascular drug
development (4)
Intravascular ultrasound (IVUS)
– invasive imaging of coronary artery wall,
atherosclerosis progression monitored
Carotid artery intima-media thickness (CIMT)
– Non-invasive, surrogate endpoint for effect of therapy on
atherosclerosis
Magnetic resonance imaging (MRI)
– Non-invasive, high spatial resolution, detect early CVD, help
select appropriate therapy, monitor progress & streamline
development of novel pharmaceuticals
Positron emission tomography (PET)
– Positron emitting radioisotope imaging provides functional
information, useful when combined with CT
Human Myocardial Angiotensin II receptor
PET/CT Imaging
using PET + CT = baselin image of brain
when you add ATR antagonist = blocks = angII binding prevention seen
