PHAR 300 Lecture Notes - Lecture 7: Antigen, Ibrutinib, Rheumatoid Arthritis
7 Jun 2018
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PHAR300
Drug design 2 : clinical trials
Drug development process
-way drugs are clinically tested to prove they are or
not effective
-after clinical trials -> government review agency
-then post-marketing surveillance
-a lot of the compounds that would be toxic are
detected in animal models
-in terms of effectiveness to treat a particular
disease, animal models can never duplicate humans
-> we have to account for that, we may never be
able to perfectly predict what would happen in
humans
-huge variations in humans in pharmacodynamics
and pharmacokinetics => we have to test in
humans to see the range of responses we will get
-lot of the cost in the clinical trial phase, and lot of time (15% of the costs = discovery : target
identification, validation, lead identification and validation ; 13% costs = pre-clinical studies : in
vitro validation and in vivo validation)
-clinical trials = key to find effectiveness and safety
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Clinical trial
-well designed system where we ask fundamental questions -> should give yes / no answers
-is it safe in people
-does it work
-how does it compare to what is available already -> if not at least as good as what is
already on the market, not allowed to be sold
-regulations are determined by government agencies, FDA in the US, Health Canada (for what is
allowed to be sold in Canada, regulates clinical trials and drug approval, monitors the post-
marketing surveillance, recalls if something goes wrong)
-get permission to do clinical trials -> then phase 2 and 3
-safety starts with a few people, and then more in phase II and many more in phase III
•Phase I
-will determine basic safety and pharmacokinetics in humans
-very strict guidelines, protocols and places
-start with very low doses
-20 to 80 volunteers to determine safety, dose range and pharmacokinetics
-usually not too many surprises with regard to the safety
-goals :
-initial safety and tolerability (pharmacology)
-safe dosage range is determined
-side effects are identified
•Phase II
-more volunteers (100-300), usually with the problem we are
intending to use the drug for
-evaluate effectiveness
-look for side effects
-if it looks safe and effective -> ask the patient how he feels
-e.g. pain -> McGill pain questionnaire
-we have to compare to placebo (might be as good initially,
which is what we expect, but after a few days, the placebo
response starts to decrease as an analgesic => statistical
difference between the drug and the placebo)
2
-document the side effects very carefully, often pretty unpleasant at the beginning but tend to
shade
-pharmacokinetic data from phase I will be expanded in phase II with more people -> we can
see the distribution of metabolism ; able to see very rapid metabolisers, the poor metabolisers
(we can thus pick a cut off) => indication that we have a variation between people in drug
metabolising enzymes -> we might want to watch out for this because the drug might be
ineffective for some people / be careful with the dose for the rapid metabolisers
-goals :
-effectiveness (therapeutic exploratory)
-dose response
-further evaluation of safety
•Phase III
-much larger groups of volunteers (1500-3000), have the problem we are concerned about
-see effectiveness and monitor negative effects with long term use
-people involved are monitored all the time, they get excellent medical care
-double blind trial + randomised
-parallel design : placebo vs. drug ; crossover design : first drug, then washout and then placebo
vs first placebo, then washout and then drug ; we can have more than one drug and many groups
of people
-things to control :
-lifestyle -> if we test a drug and we want to see people at risk of developing diabetes -> test
placebo and our drug -> monitor for lifestyle modification BECAUSE if they joined the
study, they may be adapting their lifestyle without realising it (eating more healthy,
exercising…) => we have to show that our drug is better than placebo and than modified
lifestyle
-compliance (how often people take the drug) has to be monitored as well (people more
compliant are more motivated -> same for placebo and drug)
-chronic diseases -> monitor the drug for a long time -> very important (if we just look at the
placebo vs people with the drug, with time, statistical difference appears later and the
difference gets bigger with time)
-e.g. for Simvastatin and placebo -> same proportion without heart failure during the
first year, but then proportion with placebo decreased way more than with Simvastatin
-if we test a drug that has a short term action (e.g. relief of pain for ulcers) and we see that
there seems to be about the same effect -> mistake, if we look 6 months after they started
taking the drug, big difference between the people (relapses in some of them -> with A most
is back but not with B) => look at what goes on with time
-side effects can bias patient’s reaction
-e.g. pain intensity, with placebo,
amitriptyline and lorazepam -> both of
the drugs have CNS side effects where
people feel more sedated
-pain intensity decreases with the 3 of
them, but at one point of time, we
develop some type of resistance to some
of the side effects of benzodiazepine ->
pain intensity increases again with
lorazepam (sedation wears off)
-psychology of the user and social factors can
have a very powerful effect in addition to what the
drug may or may not be doing
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Document Summary
Way drugs are clinically tested to prove they are or not effective. After clinical trials -> government review agency. A lot of the compounds that would be toxic are detected in animal models. In terms of effectiveness to treat a particular disease, animal models can never duplicate humans. > we have to account for that, we may never be able to perfectly predict what would happen in humans. Huge variations in humans in pharmacodynamics and pharmacokinetics => we have to test in humans to see the range of responses we will get. Clinical trials = key to nd effectiveness and safety. Well designed system where we ask fundamental questions -> should give yes / no answers. How does it compare to what is available already -> if not at least as good as what is already on the market, not allowed to be sold.
