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Pharmacology > Clinical trials > Flashcards

Clinical trials Flashcards

1
Q

CTIMPS

A

clinical trials investigational medicinal product

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2
Q

what makes a study a CTIPM

A

a study that looks at safety or efficacy of a medicine, foodstuff, placebo in humans - as defined by the Medicines for Human Use (clinical trials) regulations 2004

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3
Q

Examining the safety and efficacy of an IMP includes

A

Intending to discover or confirm the clinical, pharmacological and/or other pharmacodynamic effects of one or more medicinal products,

identify any adverse reactions or

study the absorption, distribution, metabolism and excretion

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4
Q

adverse reaction

A

health complication resulting from taking a drug

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5
Q

what is an investigational medicinal product (IMP)?

A

new drug

established drug which you want to assemble in a different way from its licence/marketing authorisation

used for an indication not included in its authorisation.

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6
Q

How do we determine whether a study is a CTIMP?

A

Algorithm on MHRA

website (table which has questions/sections that it needs to be to be an IMP)

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7
Q

what won’t the Algorithm on MHRA website tell you

A

what clinical phase of study is

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8
Q

all clinical trials should be approved by

A

Sponsor (eg NHS Trust or Pharmaceutical company)

NHS Research Ethics Committee

If within the NHS, Health Research Authority

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9
Q

In UK, CTIMPs additional approved, overseen and monitored by:

A

Medicines and healthcare products Regulatory Agency (MHRA)

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10
Q

Who are clinical trials for?

Who needs to be convinced?

A 
Approval agencies (UK: European Medicines Agency /MHRA)
- Data used as evidence for licensing / authorising the drug

Prescribing doctors / NHS / National Institute of Clinical Excellence
- Especially opinion leaders

Patients

  • Some countries allow direct-to-patient marketing of prescription drugs
  • Patient groups may also be active and vocal

Insurance agencies

Pharmaceutical marketing teams will use information gathered in clinical trials

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11
Q

When planning a clinical trial you need to consider…

A

What condition do you want to licence / label it for?

Who are the patients?
Are there different groups or special populations (eg elderly or renal patients)?

What real benefit to patients do you want to show?
Lower event rates?
Do you need Patient Reported Outcome Measures (PROMs?)

But be flexible
Stuff happens
Sildenafil (Viagra) was originally developed for angina, but volunteers reported an interesting side effect!

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12
Q

Drug can be licenced for lots of indications – but you need to

A

be able to show it is effective in all of them

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13
Q

what was sidenafil originally developed for but what is it used for now

A

angina originally but now used erectile disfunction

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14
Q

What information must the clinical trials support?

A

Dosing regime
Including any special populations (e.g. elderly)
Clinical pharmacology/mechanism of action
Drug interactions
Contraindications
Warnings
Safety & side effects

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15
Q

what happens in the PRE-clinical trials

A

drug discovery and pharmaceutical development

Optimise scale-up for quality and cost

Develop analytical methods:
Assay methods

Develop formulation
Multiple forms (e.g. i.v., solid & liquid oral?)
Specialised forms? (e.g. slow release)
Stability (preferably at room temperature)

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16
Q

what 2 things would happen in the preclinical trial with understanding animals…..

A
  • Animal Pharmacokinetics
    Understand absorption, distribution, metabolism and excretion
    Active metabolites will need to be understood in detail
  • Animal safety assessment
    Safety pharmacology
    In vitro and in vivo toxicology
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17
Q

phase 1 clinical trial

A

First in human use
determine the lowest dose at which the treatment is effective and the highest dose at which it can be taken without causing harm.

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18
Q

phase 2 clinical trial

A

Tend to be first in patient use
Exploratory efficacy (Phase IIa)
Dose ranging and efficacy (Phase IIb)

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19
Q

phase 3 clinical trials

A

Multi-centre trials

Pivotal efficacy and safety

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20
Q

phase 4 clinical trial

A

post marketing surveillance

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21
Q

how many volunteers would you have in phase 1 studies

A

50-100

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22
Q

what is “first man” SAD - what is it for?

A

first man single ascending dose

- for safety and pharmacokinetics

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23
Q

how would you do single ascending dose

A

Dose is escalated in successive cohorts

ascending repeat dose - safety and pharmacokinetis

24
Q

what would you look at in phase 1

A
  • clinical pharmacology,
  • bioavailability and comparisons of alternate formulations
  • Absorption, distribution, metabolism, excretion
  • Including radiolabel studies
  • Safety pharmacology (e.g. cardiac and hepatic function)
  • Subgroup pharmacokinetics (e.g. elderly, ethnic)
  • Drug-drug interaction
25
Q

why is the aim of the SAD

A

Aim to find the maximum tolerated dose
Or the maximum dose that can be given
Or a maximum pre-specified limit (should be clearly above expected therapeutic dose)

26
Q

who is used to work out SAD

A

Usually men aged 18-45

Double-blind placebo-controlled

27
Q

what is assessed through SAD

A

Assess safety, tolerability & pharmacokinetics
PK: Cmax, Tmax, AUC, t1/2, VD, Cl
Assess more detailed pharmacokinetics (e.g. fasted vs. fed) at one dose (e.g. 25% of maximum tolerated dose)

28
Q

multiple ascending dose

phase 1

A
  • Healthy volunteers
  • Escalate dose over days
  • Typical duration 7-10 days for drugs to be given chronically
  • Monitor safety, tolerability and PK as with Single Ascending Dose study
29
Q

phase 1 - pharmacodynamic studies

A

drugs under investigation may have a pharmacological effect in healthy volunteers that relates to target clinical effect in patients (e.g. heart rate, gastric acid secretion)
- may give confidence that drug will work - use with caution

may sometimes put mild disease in patients - phase 1 - patient volunteers - blurring boundaries w phase 2

30
Q

phase 1 -other

A

drug- drug interactions - (steady state of drug then single dose of interacting drug - monitor pharmokinetics)
focus on drugs used for the same condition

formula comparisons

radiojlabel studies - detailed ADME

specific safety pharmacology - ECG - monitor QT prolongation (risk of ventricular arrhythmia

31
Q

example of where phase 1 has gone wrong

A

BIA 10-2474 caused one death and five severe brain injuries.

32
Q

what is phase 2a and how many patients would you use

A

exploratory efficacy - 20-50 patients

33
Q

Phase 2a

A

first studies in patients (selected to maximise chance of seeing clinical effect)

proof of concept - marker of effect

give confidence to continue

design - double blind place or add on to current treatment (when unethical to withhold treatment)

34
Q

what may be necessary in IIa

A

flexibility as it is exploratory

35
Q

what is phase 2b? and number of patients?

A

dosing range

50-200 patients

36
Q

Phase IIb is bridge between

A
  • Phase IIa and Phase III

- Phase IIb is last chance to be flexible

37
Q

what is the primary aim of phase 2b

A

to determine the dose to be used in Phase III multi-centre studies and to determine the expected efficacy measure
Phase IIb will be the basis for statistically powering Phase IIIb
Phase IIb is critical: a mistake here could mean that the Phase III trial is inconclusive

38
Q

what is the design for phase 2b

A

Randomised double blind* placebo controlled often preferred
*Neither patient nor trial docs know which has been given, until all results decoded at end of trial
Comparator arm may also be performed at this stage

39
Q

when is the last chance to have any flexibility in the clinical trial

A

phase 2b

40
Q

phase 3

A

Phase III – confirmatory efficacy and safety

41
Q

what happens in phase 3

A
  • multi trial centres (one trial in each major market/country)
  • design criteria are locked down before trial (end point clinically meaningful)
  • Selection of patients must match planned prescribing label
42
Q

what are the designs of phase 3 trial

A

Randomised double-blind placebo-controlled
Comparator trial
Essential for European approval unless no comparator exists
Need to decide whether to test for superiority or equivalence (with advantage elsewhere, e.g. better safety or preferable dosing regime)

43
Q

what is compared in phase 3

A

Non-inferiority vs. Superiority vs. Equivalence

44
Q

Non-inferiority:

A

The new drug is at least as good as the old drug.

45
Q

Superiority

A

The new drug is better than the old drug.

46
Q

Equivalence

A

The new drug is equivalent to the old drug.

47
Q

statistical significance (alpha)

A

the probability of false positive (type 1 error) and is reported after a trial

eg. p<0.05 means there is a less than 5% chance of the declared effect being mistaken

48
Q

statistical power (beta)

A

the probability of detecting a positive response (at a given level) if one exists.

1-beta is the probability of a false negative is a positive effect exists

49
Q

when is statistical power normally calculated

A

before a trial to help set sample size - frequently not reported

50
Q

what is phase 3b

A

label and licence extensions
eg Studies in children, additional dosage forms, related clinical conditions

Doctors are free to use drugs off-label without these studies, but no marketing can take place.

51
Q

what is phase 4

A

post marketing pharmacovigilance

Drug companies conduct post-marketing / licencing pharmacovigilance to monitor long term safety of a drug after its launch.
Findings are published in Periodic Safety Update Reports

52
Q

where would you be unlikely to pick up rare but serious side effects

A

phase 3 trials

a fatal reactions may occur in fewer than 1 in 10,000 patients
eg thalidomide - picked up post marketing

53
Q

What happens after authorisation and post-marketing pharmacovigilance?

A

Unexpected adverse events and reactions of all licenced drugs are reported to MHRA by healthcare professionals or patients using the ‘yellow card’ system.

54
Q

Practicalities of setting-up and running a CTIMP

A

Is the study a CTIMP?
Are you testing the drug or using it as a tool?

Time needed to get approval from all relevant organisations.

Fees

Feasibility of identifying and recruiting participants.

Sufficient sample size and relevant outcome measures.

What is your source / original reference data

Are the participants fully informed about the study including risks.

55
Q

Does all equipment fulfil IQ OQ PQ

A

IQ: Installation quality installed correctly?
OQ: Operational quality working correctly?
PQ: Performance quality performing as expected?

Pharmacology (18 decks)

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