MP4 Clinical trials

Question 1

what do phase II clinical trials test?

Answer 1

• efficacy
• side effects

Question 1

what do phase I clinical trials test?

Answer 1

• ADME / pharmacokinetics
• safety and side effects

Question 2

what do phase III clinical trials test?

Answer 2

• long-term efficacy / safety
• comparison with current treatment

Question 3

what do phase IV clinical trials test?

Answer 3

• post-marketing safety and effectiveness

Question 4

who are phase I clinical trials tested on?

Answer 4

healthy volunteers

Question 5

who are phase II clinical trials tested on?

Answer 5

a small number of patients

Question 6

who are phase III clinical trials tested on?

Answer 6

in a large number of patients

Question 7

who are phase IV clinical trials tested on?

Answer 7

in general patients’ population

Question 8

overview of phase I clinical trials

Answer 8

• sometimes called ‘First in Humans’ trials
• in 50-200 healthy volunteers
• in a clinical setting (‘Clinical Research Unit’, managed by healthcare professionals)
• IND by injection or orally as a liquid or capsules
• strict monitoring (during and after time in CRU)

Question 9

why may a phase I clinical trial not occur in healthy volunteers? give examples

Answer 9

• if it is unethical to administer a drug to healthy people (eg. cancer drugs have a high rate of side effects and must be tested on cancer patients only)
• there are debates around whether it is ethical because usually low income people that need money are the ones volunteering to take part

Question 10

what strict monitoring is there in phase I clinical trials?

Answer 10

blood / urine samples
- pharmacokinetic profile and biochemical profile
- liver / kidney functions, blood count, inflammation etc. (need to be sure that liver function and blood count do not change)

physical examination
- blood pressure, heart rate etc.

record of side effects experiences by volunteers

Question 11

describe phase I clinical trial volunteer recruitment requirements (not exclusion criteria)

Answer 11

• must be able to give informed consent
• must meet strict pre-defined inclusion criteria (free from the disease and ‘healthy’)

Question 12

typical exclusion criteria for phase I clinical trials

Answer 12

• under 18 or over 55-60
• pregnant women or women of child-bearing age
• recent participation in another trial
• smoking, taking OTC or herbal medicines

there may be more criteria specific to the drug

Question 13

explain why under 18 and over 55-60 year olds are typically excluded from phase I clinical trials

Answer 13

• older people tend to experience more side effects because their pharmacokinetic profile changes
• eg. reduced kidney function so excretion of drug is reduced

Question 14

what is the NHS Over-volunteering Prevention Scheme?

Answer 14

• excludes people from taking part in too many clinical trials too close together
• NHS keeps a list of those that have taken part
• taking too much blood over a prolonged period of time (2 trials too close together) can cause anaemia

Question 15

explain why those who smoke or take OTC or herbal medicines are typically excluded from phase I clinical trials

Answer 15

• smoking increases the rate of metabolising enzymes in the liver so data would be interfered with
• OTC or herbal medicines may interact with the drug that is being tested in the trial

Question 16

describe the typical protocol of phase I clinical trials

Answer 16

• computer generated randomisation of volunteers into groups of 3 (need groups of at least 3 so an average can be taken)
• blinded administration and placebo-controlled

1. single ascending doses
2. multiple ascending doses
3. optional: effect of food on pharmacokinetics

Question 17

explain what is meant by the first stage of phase I clinical trials: single ascending doses

Answer 17

• initial dose lower than predicted minimum effective dose
• dose escalation if no serious adverse effects and pharmacokinetics is as expected
• trial is stopped when maximum pre-determined dose is reached or serious adverse effects occurred

Question 18

explain what is meant by the second stage of phase I clinical trials: multiple ascending doses

Answer 18

• several doses given at predetermined time intervals
• can be in the same group of volunteers or a different group
• ‘cross-over’ is needed if the same group is used (those that got the placebo in the first stage must get the drug this time, those that got the low dose the first time must get the high dose next time)

Question 19

explain what is meant by the third stage of phase I clinical trials: effect of food on pharmacokinetics

Answer 19

‘safe doses’ taken with high fat content meal

Question 20

what is the typical duration of phase I trials?

Answer 20

12-18 months

Question 21

who are phase II clinical trials performed in?

Answer 21

• 100-300 patients with the disease
• high homogeneity in patients recruited (same gender, same age range, same stage and severity of disease)

Question 22

what is tested and monitored in phase II clinical trials?

Answer 22

• different doses and dosing regimens
• pre-determined efficacy measure (eg. for asthma, decreased frequency of symptoms related to asthma; coughing, wheezing etc.)
• monitoring of side effects

Question 23

what is the aim of phase II clinical trials?

Answer 23

to determine effective dosing regimens for phase III trials

Question 24

describe the duration and success rate of phase II clinical trials

Answer 24

- typical duration is 2 years - success rate is less than 50% if those that passed phase I trials

Question 25

why may a company terminate a trial even if the drug is successful?

Answer 25

- usually for financial reasons - another company may be also testing a similar drug and have started the phase III trials and they know they can't compete with them

Question 26

how many hospitals are involved in phase III clinical trials?

Answer 26

- several - 2 studies are required by regulatory bodies - usually 3 are performed because there is a risk that if you only do 2, one will give negative data and one will give positive so they would have to launch a 3rd study anyway

Question 27

how much money do phase III clinical trials cost?

Answer 27

- they are very expensive - 90% of development costs go towards phase III trials

Question 28

what is the aim of phase III clinical trials?

Answer 28

prove IND is 'better' than current treatment or placebo

Question 29

describe the typical protocols of phase III clinical trials

Answer 29

cross-over - half the population does the placebo first and then they swap and do the drug and the other way round for the other half - everyone must try the drug and placebo to avoid bias double blinded

Question 30

describe the typical duration and success rate of phase III trials

Answer 30

- typical duration is 3-5 years - success rate is 60% of those that passed the phase II trials

Question 31

what is an NDA? how does the process of one work?

Answer 31

- New Drug Application - if phase III trials show significant statistical improvement on placebo or current treatment - submission of long dossier (set of papers) to government agencies (in every single country) - when satisfied, the government agency will issue a Marketing Authorisation

Question 32

what is included in the dossier of an NDA?

Answer 32

- detailed info about the drug and medicine - pre-clinical and clinical data - packaging, labelling, information leaflets (for patients and prescribers) etc. - post-marketing surveillance plans (phase IV trials)

Question 33

describe phase IV trials

Answer 33

- also called post-marketing surveillance or 'pharmacovigilance' - take place after the product has been approved

Question 34

what is the aim of phase IV trials?

Answer 34

monitoring of the new medicine in practice - is it effective in all patients? - does it cause adverse effects in some patients? - does it improve patient's quality of life? - is it better value than other treatments?

Question 35

what is the 'yellow card' scheme in the UK?

Answer 35

- used to report side effects after new drugs are being sold on the market - medicine can be withdrawn from the market if not effective or causes serious adverse effects

Question 36

describe marketing and promotion of newly approved drugs. also give the aim of their promotion

Answer 36

- essential to recover the development costs and make profits - very different strategy from other industries (POM can't be advertised to the general public in the EU or UK) aims - make the medical and scientific communities aware of the new drug - convince healthcare systems to adopt the new drug

Question 37

pharmacists' roles in clinical trials

Answer 37

- preparing and dispensing medicines for trials - discarding medicines at the end of the trials - safeguarding trial volunteers / patients - ensuring medicine is used as per protocol and following guidelines / regulations - ensuring adequate storage of medicines for trials - ensuring proper storage and management of study files - data analysis