Clinical Trials and Post Marketing Surveillance

Question 1

as defined by HPRA, a clinical trial is

Answer 1

a systematic investigation for the purpose of determining the effects of administration of a drug on a person where such administration may have pharmacological or harmful effect

Question 2

what is the primary concern of clinical trial legislation

Answer 2

• to protect subject safety rights and well being

Question 3

how are subject rights, safety and well being protected

Answer 3

through legislation which has requirements for

• recruitment
• ethics committees roles and responsibilities
• overview of inducement or payments to trial participants,
• insurance provisiions
• trial authorization through positive benefit:risk

Question 4

Phase I studies (first in man) are designed to do this

Answer 4

• establish safety, tolerability and pk
• single or multiple ascending dose
• normal healthy volunteers
• small size 12-80 subjects

Question 5

Phase II studies

Answer 5

• establish safety and efficacy in the intended population
• comparison with other drugs ir okacebi
• study interactions
• larger 100-200

Question 6

Phase III

Answer 6

• target population
• adverse effect, safety profile
• comparator product to establish superiority
• 1000-4000 subjects

Question 7

Phase IV

Answer 7

• post marketing in patients
• observational, PMC or new indications
• study specific safety parameter

Question 8

trial design should take into consideration the following

Answer 8

1. objectives
2. patient population
3. treatment
4. Removal of bias
   
   • controlled vs. uncontrolled
   • randomisation
   • crossover
   • blinding
5. Trial size
6. Attrition rates

Question 9

bias is controlle in a trial by

Answer 9

• using control groups
  
  • placebo, or competitor
• randomization
• blinding
• crossover

Question 10

when is the use of placebo not ethical, and what is an alternate means of still having a control group

Answer 10

• if the removal of available treatment could put the subject at risk
• use comparitor product

Question 11

randomization is performed to

Answer 11

• try to ensure that the comparitor groups (placebo or comparitor product) are as evenly matched as possible
• based upon similarity subjects are randomized to one treatment or the other

Question 12

blinding can involve

Answer 12

• single or double blind
• single blind = patient is blind
• double blind = patient and investigator and sponsor are blind

Question 13

what are some challenges in double blind studies

Answer 13

• not being able to blind the placebo or comparator
• the two should be as similar as possible such that study subjects or study staff are not unblinded

Question 14

Cross over studies involve

Answer 14

• the exposure of subjects to both treatments in a crossover design
• subject is allocated to treatment A for X amount of time then after a washout period crosses over to the second treatment, treatment B

Question 15

what are some challenges with crossover designs

Answer 15

• only allows for short treatment periods
• washout required between treatments which may not be appropriate in target population

Question 16

what is essential to achieving statistically sound results

Answer 16

• having enough subjects
• precalculation of sample size requried

Question 17

what is the difference between sequential design and classical hypothesis testing

Answer 17

• in sequential designs trial size is not fixed in advance
• data are evaluated as they are collected
• sampling is stopped in accordance with stopping rules as soon as significant results are observed
• conclusions reached earlier than with classical hypothesis testing

Question 18

what is the primary purose of Post Marketing surveillance

Answer 18

• assess ongoing benefit:risk through the safety profile of the product

Question 19

why is post marketing surveillance required

Answer 19

• clinical trials are relatively small in size
• can’t detect rare adverse events
• inclusion/exclusion often exclude patients with comorbid conditions; conmeds etc

Question 20

what is an intolerance

Answer 20

a small dose that produces and effect

Question 21

hypersensitivity

Answer 21

allergenic in nature

Question 22

idiosyncratic

Answer 22

uncharacteristic or unexpected

Question 23

what is an adverse drug reaction

Answer 23

A response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for modification of physiological function.

Question 24

what is an adverse event

Answer 24

Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment

Question 25

what is an unexpected adverse drug reaction

Answer 25

An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator's Brochure for an unapproved investigational medicinal product).

Question 26

a serious unexpected adverse event is

Answer 26

A serious adverse event (experience) or reaction is any untoward medical occurrence that at any dose: \* results in death, \* is life-threatening, NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe. \* requires inpatient hospitalisation or prolongation of existing hospitalisation, \* results in persistent or significant disability/incapacity, or \* is a congenital anomaly/birth defect.

Question 27

how can causality be assessed

Answer 27

* dechallegne * event goes away * rechallegne * event recurs

Question 28

what are some ways in which ADRs are collected

Answer 28

* spontaneous reporting * Phase IV studies * case reports * yellow card scheme * post marketing surveillance (active surveillance * prescription event monitoring * record linkage