L23 Drug Design 2: Clinical trials Flashcards
How many drugs usually make it to the clinical trial?
5
How many phases are there in the clinical trial
4 + post marketing surveillance
Why are clinical trials (human trials) so important?
Species differences and human variability i.e. differences in pharmacodynamics and pharmacokinetics must be accounted for
TF: pre-clinical trial is the most expensive part of drug development
False, clinical trial is the most expensive
TF: most drugs get rejected in the clinical trial
True
What are the 3 fundamental questions answered during clinical trials
Does it work
Is it safe
How does it compare
Which entity regulates all clinical trials, drug approvals and post-marketing surveillance
Health Canada
TF: Drug must pass phase 4 before going onto market
False, it can be put on the market after passes phase 3
What is the goal of phase 1 of clinical trials
determine human safety, dosage, and fundamental pharmacokinetics
takes days or weeks
20-80 healthy volunteers take the drug to reveal potential side effects
TF: Drug development is most often halted at phase 1
False, preliminary work weeds out a lot of potential toxic effects so it isn’t very common
What is the goal of phase 2 of clinical trials
expanded state, to see if the drug works or not i.e. effectiveness and side effects. testing drug for pain and toxicity
also used to identify outliers (PM, URM)
takes weeks or months
100-300 patients suffering from the disease/conditions take the drug
TF: Documented side effects during phase 2 of clinical trials usually go up with time
False, they usually go down with time
What is the goal of phase 3 of clinical trials
Catch rare side effects by studying the drug in more people and for longer periods: efficacy, safety (side-effects, adverse reactions)
several years
1000-3000 patient volunteers
What is parallel design for
to test the drug compared to one already on the market
What is crossover experiment for
both groups are given market and test drug at different times + washing out to eliminate variability between 2 groups
(also to compare drug to market drug)
What are 2 things that are always required for clinical trial designs
randomization and double-blind
What are two things that can affect clinical trial designs
lifestyle and patient compliance
Why is it important to monitor people for a long time
- some beneficial effects only being to show after a long time
e.g. simvastatin showed effectiveness 5 years after consistent used patients suffering chronically
statins in general are more effective the longer you take them
- Some drugs can have long-term consequences after only using it for a short term.
e.g. a drug can help prevent relapses
TF: response to medication is much stronger in hidden application compared to open application
False, open application illicits a stronger response
open application: medication is administered by a doctor who talks to the patients (patient knows when its being administered and is being cared for)
What is behavioural conditioning
it is the ‘acquisition’ of a response after being exposed to it once
e.g. giving a pill without the drug after having taken the drug itself results in a response (although its weak) - this response is termed ‘evocation’
TF: placebo response is purely psychological
False, this is because the CNS controls physiological responses in the cardiovascular system, immune system, GIT, endocrine system and respiratory system. Thus placebo effect can be felt al throughout the body
TF: people who are worried about side effects are more likely to report them when getting a placebo
True
What are we hoping to achieve when applying pharmacogenomics in drug development
we want to be able to genotype people to know their metabolism (pharmacokinetics) ahead of time to know if how they will potentially respond to a drug
What are toxicogenomics
seeing who might have toxic reaction due to metabolic by-products based on genomics (e.g. distribution of p450 enzymes)
TF: you can get a yearly injection to prevent osteoporosis
True (recast, zoledronic acid)
what are the 4 things you need to review before applying for a new drug (after phase 3)
- characterize exposure database (design experiments, randomization and double-blind
- identify drug-related adverse effects
- estimate risk or rate of adverse effects
- identify risk factors for adverse effecs
Bringing a drug from lab to clinic takes _ years, _$ in investment with a _% rate of failure
14-17 years
4$ billion
95% rate of failure
Why have costs for R&D of new drugs started levelling off (after increasing in the recent years)
- we have better ways of targeting diseases
- big increase in development of orphan drugs
Why do so many drugs fail?
unclear pathogenesis, drug design is currently a guessing game (low efficacy)
this is evident when looking at drug design for AD
What must be done in preparation for the drug hitting the market?
-name
-manufacturing requirements (drug delivery system, usually pills are favoured)
-economical (cheap)
-stable drug (long shelf-time)
-soluble
-quality control
What can be done to improve drugs that have short half-lives
design slow-release capsule that allows for slow absorption
then you only need to take it once a day
What is the goal of phase 4 of clinical trials
monitor the drug to detect very rare side effects or beneficial effects, post-marketing phase to study effectiveness in general population and optimize drug (dosage, frequency, administration)
e.g. side effect of aspirin in children detected in phase 4
For drugs with rare toxicity, more than _ patients must be exposed to generate a signal
100 000 patients
How is a drug monitored?
physician ask questions, pharmacists can notify government if patient reports something
TF: Drugs that do not explicitly say that pregnant women should not take it are safe to take when pregnant
FALSE!! drug must be approved for pregnant women
Why must we be cautious when administering approved drugs to young and old patients?
these groups are excluded from clinical trials (along with pregnant women) so special problems or side effects may arise
From which phase is patient compliance information taken from
phase 4
What kind of warning is used for medication that are valuable and important but associated with serious risk
black box warning
indicate that maximum precaution must be taken
most serious medication warning required by FDA
What are the 3 classes of trials for special cases
class 1: emergency, fast trial e.g. COVID-19 vaccines
class 2: for life threatening diseases
class 3: normal
TF: Orphan drugs may get shorter time frame from clinical testing to market
True
What is an example for orphan drug development
treatment for metastatic uveal melanoma, rare cancer of the eye
What are some major disease targets
oncology, infectious diseases, neurology
What are checkpoint inhibitor drugs. Explain using an example
drugs used in cancer treatment, receptor on T cell or ligand on cancer cell is inhibited using antibodies - blocking checkpoint
PD-1 is a negative costimulatory receptor expressed on activated T-cells. Binding of PD-L1 and PD-L2 to this receptor inhibits T cell function
> blocking receptor on T-cell so that it can no longer be activated by ligand on cancer cell (cancer cell ligand inhibits T-cell recognition of tumour as an invader)
What is Pembrolizumab
a checkpoint inhibitor effective for non-small cell lung cancer
What is another option for cancer treatment other than checkpoint inhibitors
target CTLA-4 receptors on T-cells by which T-cells bind to dendritic cells
Which drug is used to treat Chronic lymphocytic leukaemia? How does it work?
Ibrutinib, highly potent, oral once a day 24 hour target inhibition
Blocking the BTK enzyme responsible for B cell proliferation by forming a bond with Cys-481 (selective)
Promotes apoptosis in CLL cells and inhibits CLL cell migration (metastasis)
TF: Those who already had chemotherapy showed higher success rate wth Ibrutinib
False
What are the two strategies involving antibodies in cancer therapy?
- antibody delivers toxic compound to tumour cell (specific to tumour cells)
- targeting abnormality in tumour cell to inhibit its growth (MAB, different side effects to chemo but extends quality of life)
What is radioligand therapy
attach radioactive compound to the antibody to target and destroy cancer cell
What can be used to treat migraines? how does it work?
CGRP (calcitonin-gene related peptide) blocker (MAB)
CGRP levels are abnormally high in certain types of migraines
What is the difference between PCSK9 inhibitors and statins when treating CVD
statins block the synthesis of cholesterol while PCSK9 inhibitors block PCSK9 thus decreasing circulating levels of cholesterol
TF: Combining statins and PCSK9 inhibitors can help reduce the risk of atherosclerosis
True!
What is a drug that can help treat heart failure
Neprilysin blockers
Nepriysin break down naturietic and other vasoactive peptides that work to lower blood pressure and promote sodium excretion
What drug is used to cure Hepatitis C
Sofosbuvir (Sovaldi)
blocks RNA replication of the virus
What is a new vaccine in 2023 that helps babies survive from a certain respiratory virus
Respiratory Syncytial Virus (RSV) vaccine (Beyfortus)
TF: Intracellular targets are currently well understood and a main focus for future drug development
False! we still need to research and understand intracellular targets
What does the future hold for drug development (7)
-new routes of drug administration
-intracellular target studies
-CNS BBB drugs
-obesity
-AIDS, cancer, gene therapy, antiviral drugs, proteomics, personalized therapy, prevention of dementia (AD, pathogenesis)
TF: Drugs developed for humans are ineffective in other animals
False! they may be beneficial for pets
