drug development 2

Question 1

why were we able to make Covid vaccines so quickly?

Answer 1

basic research before the clinical trials had been going on for 15 years before that

Question 2

Why are clinical trials so important?

Answer 2

• Because we never know what the drug effects will be on people until we test it in human trials.
• there are species differences, as well as human variability (even between members of the same family), that account for differences in drug pharmacokinetics and drug pharmacodynamics

Question 3

what questions do clinical trials answer?

Answer 3

1. Is it safe?
2. Does it work?
3. How does it compare to available drugs?

Question 4

who regulates all clinical trials and drug approval & monitors post-marketing surveillance ?

Answer 4

health canada

Question 5

who is in charge of clinical trials?

Answer 5

health canada

Question 6

what are the stages of clinical trials?

Answer 6

1, 2, 3, then put on market, then 4

Question 7

explain stage 1 of clinical trials.

Answer 7

• determines human safety and fundamental pharmacokinetic (Will determine safety, dosage, and pharmacokinetics.)
• 20 to 80 healthy volunteers (Volunteers are looked after and paid. They are monitored carefully.)
• Start with low doses, then work up to a therapeutic dose to see what’s safe and effective to administer.
• takes days or weeks

Question 8

Explain stage 2 of clinical trials.

Answer 8

• initial work on whether or not it works,
• takes weeks or months with hundreds of people with the disease
• evaluate for effectiveness, and look for side effects
• can also expand pharmacokinetic studies. You can predict drug toxicity (poor metabolizers), and poor responders (rapid metabolizers), so now you know the range of pharmacokinetic responses in humans.
• If everything works, and the side effects are reasonable for what the drug treats, then move to phase III.

Question 9

Explain stage 3 of clinical trials.

Answer 9

• efficacy and safety; looking at side effects and how it compares to currently available drugs
• It takes several years and thousands of people.
• Verify effectiveness, monitor adverse reactions from long-term use

Question 10

When designing clinical trials what must you always have? What are the two main types?

Answer 10

• double blind, so nobody knows who is getting what, and randomized so we get the same distribution of people in both groups.
• Parallel design: To test the drug compared to one already on the market. A drug that is already on the market is in one group and the drug currently being tested in the other, to see if the one being tested is better.
• Crossover: drug already on the market (washout) then drug tested for group 1, and drug tested (washout)
  then the one already on the market for group 2 (quite effective), and then we compare and see which drug is
  more effective. This can eliminate variability between the two groups; they both get both drugs.

Question 11

What must we control in a clinical trial?

Answer 11

• Lifestyle – is very important and can have effects on one’s condition, so one must make sure
  that people in different groups of a trial have similar lifestyles.
• Patient compliance – The placebo effect is very much affected by the psychology of the person. So, one must make sure that people take the drug as they should. Hospitalization rates are different whether people are fully, partially, or not at all compliant.

Question 12

Why is it important to monitor both short term and long term effects of a drug?

Answer 12

• monitoring a drug for a short
  period of time may not reveal the efficacy of the drug. (Statins increase in efficacy with time)
• need to monitor not only if drug is effective, but also, what happens after one stops taking the drug to see if the
  problem comes back.

Question 13

I’m what ways can side effects affect patient bias? What else can affect them? Give examples using benzodiazepines.

Answer 13

• can influence positively or negatively
• Lorazepam (benzodiazepine) is no longer effective after 2 weeks since side effects of sedation wears off BUT Amitriptyline, the side effects do not wear off, so relief of pain continues.
• Magic of belief: Very strong, we all respond positively to being cared for and feeling like we’re doing something to improve our situation.

Question 14

How does hidden application (given by machine) vs open application (given by person) affect the patient’s response to the drug?

Answer 14

Higher response with person

Question 15

What is conditioned response and why is it important to control for it?

Answer 15

• Some parts of brain that increase or decrease in response to a placebo vs. drug, we can see that some of the areas that light up are similar
• placebo can do some of the things the drug does

Question 16

How is placebo response affected by age?

Answer 16

Higher for children and decrease with age

Question 17

What is the nocebo response?

Answer 17

• negative effect in some people,
• occurs when people given the placebo are asked to monitor for side effects. Everyone has ups and downs, but when people are worried about side effects because of a drug they are taking, the “downs” may be intensified.

Question 18

Why do we need to look at toxicogenomics in clinical trials?

Answer 18

need to see who might have a toxic reaction due to a metabolic by-product. ( Ex: looking at different distributions of P450 enzymes may allow us to avoid adverse reactions)

Question 19

What happens after phase 3 clinical trials are done?

Answer 19

data needs to be sent for evaluation of safety and efficacy and includes
- Characterize exposure database – characterize that you really did do random assignments
- Identify drug-related adverse effects
- Estimate risk (or rate) of those adverse effects
- Identify risk factors for those adverse events

Question 20

Number of new drugs per $billion R&D decreased every year, until recently, they started to level off
for what 2 reasons?

Answer 20

• we have better ways of targeting cancer with monoclonal antibodies
• we have a big increase in development of orphan drugs

Question 21

What happens once the drug is approved?

Answer 21

Need to prepare drug for the market:
- find trade name
- Work out manufacturing requirements based on pharmacokinetics and
pharmacodynamics (ideally a pill)
- pill must be Economical (cheap), Stable (don’t want it disintegrating on the shelf in a short time), Soluble

Question 22

How is a drug manufactured if it has a short half life?

Answer 22

Using slow release capsule

Question 23

How can drugs be approved to be OTC?

Answer 23

If a drug is available for prescription and has proven very safe with few side effects, it can be approved to be moved to over-the-counter (OTC) access.

Question 24

Explain phase 4 clinical trial.

Answer 24

• Drugs are monitored forever.
• Now given to millions of people, now can detect the very RARE side effects (or beneficial effects)
• Post-marketing phase (therapeutic use) – study effectiveness in the general population and optimizing drug
  use (may decrease dose, or frequency of administration).
• If something dangerous does come up in a significant number of people, the drug will be taken off the market
  (this is something that was not detected before)

Question 25

When are Uncommon adverse drug interactions usually caught? Why?

Answer 25

In phase 4 since for an adverse drug interaction that occurs in 1/1,000 cases one would have to study 3,000 cases to have a 95% chance of observing the event

Question 26

When are rare toxicity profiles caught? Why?

Answer 26

After the drug has been on the market for a while since more than 100,000 patients must be exposed to generate a signal

Question 27

How are drugs monitored when it is in the market?

Answer 27

• Done by the physician who will ask the patient questions about how they are doing; the patient is obliged to report anything going on with it.
• Patients are advised to speak to the pharmacist if they think there is any effect related to the drug. The pharmacist is supposed to notify the government.

Question 28

If the drug has been cleared for teratogenic effects in animal models, should pregnant women take it?

Answer 28

No unless they are approved for it or if it is a life or death situation

Question 29

What is a black box warning?

Answer 29

medication is still valuable and important to use but there is a serious risk associated

Question 30

What are the 3 classes of trials?

Answer 30

• Class 3: normal
• Class 2: faster, for certain life-threatening diseases for example
• Class 1: even faster, for emergencies. Most recent example has been the COVID-19 vaccines!

Question 31

What are the major disease targets?

Answer 31

oncology, infectious diseases, neurology (ex. pain, migraines, anxiety, depression, etc.)

Question 32

what is the interaction between immune system and tumor? what strategy was used to stop this?

Answer 32

• PD-1 is a negative co-stimulatory receptor expressed primarily on activated T cells.
• Binding of PD-1 to its ligands, the checkpoint proteins PD-L1 and PD-L2, inhibits effector T cell function.
• Expression of PD-L1 on tumor cells and macrophages can suppress immune surveillance and permit neoplastic growth.
• Strategy: block the receptors on the T-cell so they can no longer be activated by the ligands on the tumor cell. Now, the T-cell recognizes the tumor cell as an invader.

Question 33

what increased the survival rate of people with melanoma?

Answer 33

combination of monoclonal antibodies (Mabs)

Question 34

what does the drug Ibrutinib do? how often does it need to be taken? how selective is it?

Answer 34

• Forms a specific bond with Cys-481 in BTK, which in leukemia facilitates out of control reproduction of b cells
• this promotes apoptosis in CLL cells and inhibits CLL cell migration and adhesion
• taken once a day orally
• Selective for B cells (doesn’t wipe out immune system, so no cytotoxic effect on T cells,
  NK cells)

Question 35

what are the 2 strategies to make and antibody?

Answer 35

1. Making an antibody that could deliver a toxic compound to the tumor cell in order to kill it.
   - Identify something unique about this type of tumor cell that is absent on
   other kinds of cells.
   - Attach something toxic or radioactive onto the antibody and have it attack that specific component of the tumor cell.
   - Hopefully this delivers the toxic element to the cell and kills it with little toxicity to the other cells
2. Knowing an abnormality in a tumor cell and targeting it with an antibody so it is unable to grow.
   - A monoclonal antibody that is designed to bind to the receptor

Question 36

prostate cancer usually kills people how?

Answer 36

from the cells that escape from primary tumor and
travel to bone, liver, lung, brain (metastasis).

Question 37

what is a way to detect tumor metastasis of prostate cancer?

Answer 37

label tumor cells & detect metastasis by linking a radioactive compound to an antibody that recognizes a particular antigen that is only on prostate cells

Question 38

what is the idea behind cancer vaccines?

Answer 38

draw blood, link a tumor antigen to a cytokine, and then you infuse it back into the patient to stimulate the T-cells to attack cancer cells

Question 39

how can migraines be treated using Mabs?

Answer 39

Can block CGRP (calcitonin-gene related peptide), which is abnormally high in certain types of migraines

Question 40

what is the new target for treating heart failure?

Answer 40

• Natriuretic and other vasoactive peptides lower blood pressure and promote sodium excretion.
• Normally, they help to diminish effects of cardiac failure, but they are broken down quickly by an enzyme called Neprilysin.
• New drug developed which blocks Neprilysin and makes these good peptides last longer in circulation.