Lecture 10 (Drug Development - clinical trials)

Question 1

What are the 3 phases of drug testing? (clinical research) (3)
How many volunteers are needed for each one? (3)

Answer 1

Phase 1 – Healthy volunteers
(20-50 healthy volunteers)

Phase 2 – First time drugs work on patients
(100-500 volunteers including ill patients)

Phase 3 - Need proof to regulatory authorities
(1000-5000 volunteers)

Question 2

What are the main drug targets? (3)

Answer 2

-Receptors
-Enzymes
-Transport proteins

Question 3

What happens in lead selection? (2)

Answer 3

-Predict toxic/safety concerns
-Select a candidate

Question 4

What happens in preclinical/clinical development? (3)

Answer 4

-Define the dose/concentration to start human trials
-Target organs / rescue treatments
-Obtain regulatory approval of clinical

Question 5

What are the 3 dose groups of standard toxicology? (3)

Answer 5

-Low (no toxicology)
-Intermediate
-High (toxicology expected in target organ)

Question 6

What are the goals of non-clinical safety evaluations? (5)

Answer 6

-Toxicity
-(On / off target)
-(Reversibility)
-Toxicokinetics
-(Relate toxicity to exposure)
-Max non-toxic dose / Min affective dose
-Dose selection for first in Human
-Identification of specific monitoring requirements

Question 7

Which areas are undesirable effects on physiological functions tested? (3)

Answer 7

-Cardiovascular system (in vitro and in vivo)
-Central nervous system (Irwin observation, rat)
-Respiratory system (rat)

Question 8

What is the aim of each of these phases of testing? (4)
Phase 1
Phase 2
Phase 3
Phase 4

Answer 8

Phase 1 - To see if drug is in safe in humans / check for potentiality
(Basic research/Target selection)

Phase 2 – Proof of concept / how effective is drug / how much needed to be effective
(Pre-clinical research)

Phase 3 – Drug heavily tested on patients / approved by authorities
(Clinical research)

Phase 4 - Post marketing surveillance / detect rare or long-term adverse effects
(Regulatory review)

Question 9

What is lead finding? (3)

Answer 9

When the biochemical target acquired next you find the lead compounds

-Cloning of the target protein-normally (human form)
-Robotically controlled assay facilities capable of testing tens of thousands of compounds per day
-Large compound libraries kept by companies, routinely screened for new assays

Question 10

What is LD50?

Answer 10

Median lethal dose
(no longer used)

Question 11

What is the rodent and non-rodent animal used to test small molecules in animal toxicology?

Answer 11

Default rodent: rat
Default non-rodent: beagle

Question 12

What is Histopathology?

Answer 12

Histopathology is studying the structural manifestation of disease under a microscope where these results are one of the most important parts on non-clinical safety measurements.

Question 13

What does clinical pathology look at? (3)

Answer 13

-Haematology/Clinical chemistry
-Kidney and liver function
-Coagulation

Question 14

What does pathology look at? (2)

Answer 14

-Large organ toxicity
-Determining which organs are affected

Question 15

What are the goals of non-clinical safety evaluations? (4)

Answer 15

-Preliminary toxicology determines the non-toxic dose of the drug

-Animals are examined postmortem at the end of the experiment to identify histological and biochemical evidence of tissue damage

-Pharmacokinetic testing includes studies of absorption, metabolism, distribution and elimination in lab animals

-Asses feasibility of large-scale synthesis and purification

Question 16

What is done in Phase 1 of clinical trials? (5)

Answer 16

-Checks for any potential problems in physiological systems

-To see if the drug produces any unpleasant symptoms and the pharmacokinetic properties of the drug (ADME)

-Drug does/tolerance tested on smaller groups (cohorts)

-Also test the pharmacodynamic effects in volunteers

-Looks at how drug will interact with other drugs/foods

Question 17

What is done in Phase 2 of clinical trials? (5)

Answer 17

(part A)
-Exploratory study that has clinical efficacy
-Tests pharmacodynamics or biological activity
-Exploring the dose range
(part b)
-More definite dose range study in patients
-Efficacy as the main focus

Question 18

What is done in Phase 3 of clinical trials? (4)

Answer 18

(part a)
-Includes post marketing study commitments
-Trial that presents data to the regulatory agencies to decide if the drug is approved.
(part b)
-Study prior to approval with the intended support of publications rather than registration
-Results not included in the submission dossier.