Lec. 23 - Drug Design 2: Clinical Trials Flashcards
Why do we need to do human trials even after animal models?
Due to
- Human differences
- Species variability
- Differences in pharmacokinetics and pharmacodynamics
What part of drug development is most expensive?
Clinical trials
What are the 3 questions clinical trials aim to answer?
Is it safe?
Does it work?
Is there a better alternative already on the market?
What are the 3 phases to clinical trials?
Phase 1: Human safety/Pharmacokinetics:
20-80 healthy volunteers
Phase 2: Evaluate effectiveness/Side Effects:
100-300 patient volunteers (who have illness)
Phase 3: Verify effectiveness/Long time use:
1000-3000 patient volunteers
Describe clinical trials - phase 1
- Goal
- Population
- Duration
- Process
Goal:
Test human safety
Population:
20-80 healthy people, monitored carefully
Duration:
Days or weeks
Process:
-Starts with pharmacokinetics monitoring.
-If safe, expands to safety testing
(starting at low doses until therapeutic dose reached)
Describe clinical trials - phase 2
- Goal
- Population
- Duration
- Process
Goal:
- Test if drug works
- Evaluate side effects
Population:
100-300 patients with disorder
Duration:
Weeks or months
Process:
- Check for pain in patients
- Expand pharmacokinetics knowledge to range (poor metabolizers, poor responders)
Describe clinical trials - phase 3
- Goal
- Population
- Duration
- Process
Goal:
- Verify efficacy
- Study long term effects
Population:
1000-3000 patients
Duration:
Several years
Process:
- Verify adverse effects in long term use
- Find even rarer side effects (larger pool of participants)
Explain 2 methods of clinical trial
Parallel design:
- To test vs drug on the market
- Have two concurrent groups testing new drug vs one on market
Crossover design:
- 2 concurrent groups testing both market and new drug
- Market (washout) then new
- New (washout) then market
Name and explain 2 things to control for
Lifestyle:
- Important effect on patient well being
- Ex. have 4 groups for diabetes experiment (placebo vs. new drug vs. market drug vs. intense lifestyle change)
Patient Compliance:
-Mortality hin people will less than 80% complicance
Why do short term drugs still need to be monitored in long term?
See if the treatment is consistent (ex. is there an ulcer relapse)
ex. lorezepam (benzodiazepine) ‘pain relief’ effects wear off after a few weeks (as what was being felt was sedation)
What good study demonstrated the placebo response?
Doctor coming in with treatment vs machine administering hidden treatment.
Doctor yielded higher pharmacological response due to expectancy related effect
Describe an example of behavioural conditioning
Pill on its own -> brain activity
Pill + neutral stimulus -> brain activity (acquisition) Neutral stimulus (after conditioning) -> brain activity (evocation)
Conditioned response to neutral stimulus
Give an example of drug resistance being something to watch for in clinical trials
If your drug for a tumor were only somewhat effective, you could end up with a drug that whittles a tumour down to a few, drug-resistant cells that could then come back stronger.
It is important to monitor long term to ensure tumor resistance doesn’t occur
What needs to be done after phase III of a clinical trial?
Data needs to be evaluated for efficacy and safety (NDA, health Canada, etc.)
Name 4 ways NDA reviews information from clinical trials
- Characterize exposure database (check that random assignments occurred)
- Identify adverse effects
- Estimate risk of side effects
- Identify risk factors (ie patient characteristics)
What are orphan drugs? How are they funded?
Orphan drugs are made for specific diseases affecting a small number of people, so not much profit to be made.
Usually funded by governments
What is main reason for drug failure in clinical trials?
Pathogenesis of treatment clearly was incorrect! Drugs did not really target problem
What are 3 important factors for a drug going into market
Needs to be:
- cheap
- stable (no disintegrating on shelf)
- Soluble (ideally absorbed in pill. If not, injection)
What’s a possible solution to short half-life of drug?
Design a slow-release pill to take everyday
What is clinical phase 4?
Released to public, but continuously monitored for safety and efficacy.
INCREDIBLY uncommon side-effects can be found (since drug is being put out to millions of people)
Uncommon adverse drug reactions (ADR) can be observed (since 1/1000 reaction would need 3000 cases to have a 95% chance of observing it
What demographic is particularly observed during phase IV?
Elderly and young (as they are usually omitted from clinical trials)
What happens to a drug if there are serious risks, but still has therapeutic benefits?
Black box warning -> UTMOST caution must be used when taking drugs
What are the 3 classes of clinical trials?
Class3:
Normal
Class2:
Faster (ex. life-threatening diseases)
Class1: Even faster (emergencies)
Describe a success of MAB therapy in 2018.
Pembrolizumab won the nobel prize for immunotherapy against cancer.
Tumor cells can often utilize checkpoint proteins to inhibit T-cells (ex. PDL1 binds at PD1 receptor)
Pembrolizumab targets PD1, allowing T-cells to kill cancer.
Give an example of a drug successfully treating cancer
Ibrutinib treats chronic lymphocytic leukemia
Targets btk enzyme, which allows malignant B-cells to overly express.
Thus, ibrutinib blocks B-cell proliferation
What other functions can MAbs have to combat cancer?
- Deliver radioisotope to tumor cells
- Block Growth Factor receptors on tumor cells
- Used to identify tumor cells and give a more accurate prognosis
MAB implications for migraines?
Calcitonin-gene related peptide (CGRP) often implicated in migraines.
Mabs can be injected once a month to block CGRP and prevent migraines.
What treats Hep. C
Sofosbuvir
What drugs can help heart failure?
Heart is too weak and can’t pump blood
Natriurietic and vasoactive peptides usually lower BP, but they are broken down too fast by neprilysin
New drug targets neprilysin
