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CP - 1 > 12 - Drug development and clinical trials > Flashcards

12 - Drug development and clinical trials Flashcards

1
Q

How long does a drug typically take to develop?

A

10 years from discovery through to market

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2
Q

Discovery vs development?

A

Discover = the molecule is synthesised
Involved test tubes, cell cultures
Development involves clinical trials and getting it ready for general use in the market

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3
Q

How much does it cost to develop a drug

A

3 billion per drug that is successfully developed

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4
Q

What portion of drugs that are tested in humans reach the market

A

Only 1/10

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5
Q

Why is patency important?

A

In order to make money to cover the costs of the drug, developers rely on the patency of 18 YEARS from DISCOVERY (is then open to generic competition

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6
Q

In which phases has there been an increase in cost during drug development?

A

Phases 2 and 3
Means these phases are becoming LESS EFFICIENT
Discovery and preclinical development is about the same cost

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7
Q

What are the 3 top revenue earning drugs?

A

IMMUNOLOGY (things that end in ab are antibodies)

also infectious disease and oncology

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8
Q

What is a blockbuster drug?

A

makes more than 1000 million/1 billion a year in revenue

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9
Q

What are the 4 phases of drug development?

A

0 (PREDICTION of what effective doses would be for humans using non-human species. Helps to determine reasonable starting doses for phase 1)

1 (tolerability - PK and how well the drug is tolerated)

2 (effectiveness - does the drug work)

3 (safety - looking at toxicity)

4 (post marketing - send out to market and see how people actually use them)

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10
Q

Biomarker?

A

Is a readily measurable indicator of response

is not a clinical outcome - is used to see if the drug seems to be having an effect that is related to the dose/conc

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11
Q

Surrogate?

A

A biomarker that is known to be associated with the outcome (is a good predictor of the outcome) can be used as a surrogate endpoint i.e. viral load in HIV > mortality

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12
Q

Outcome

A

How the patient feels/functions/survives

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13
Q

What are the 2 reasons that clinical trials are done?

A

Learn and confirm

  1. Learn - exploration of the unknown and development of hypothesis
  2. Confirm - develop confidence and TEST a hypothesis
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14
Q

Phase 0?

A
  • non-clinical phase
  • data from non-human animals gives indication of:
  • probable mechanism of action
  • what likely effective concentrations are
  • major routes of elimination
  • oral absorption properties
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15
Q

Phase 1?

A

Tolerability

  • start with very small doses as based on phase 0
  • slow increase and watch what happens
  • stop when adverse effects are noticed (max tolerable dose!)
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16
Q

Difference between tolerability and tolerance?

A

Tolerability - the max dose you can tolerate before experiencing adverse effects
Tolerance - describes when you take a medicine repeatedly and you get tolerance and you do not react with as big of an effect

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17
Q

What do you learn from phase 1?

A
  • single and multiple dose PK
  • adverse effect PD?

20-30 people

Phase 1 is about learning and tolerability

18
Q

Phase 2?

A 
Effectiveness (confirm the drug works)
- Phase 2A
> proof of concept 
> yes/no decision point 
- Phase 2B
> learn dose-response curve (most actually do conc-response curves)
> learn effective doses
> learn target concentration
  • 100 people
19
Q

Phase 3?

A

Safety
- learn the adverse effects in a target population
- confirm the effective dose (need to consider method effectiveness i.e. did they take their pills?)
- learn the pharmacodynamics of surrogate/outcome
- PK and PD of predictable vairables i.e. what are the things that are predictive of individual differences for improving dose i.e. sex, age, other drugs
- about 1000 patients
( only find out about the more common adverse effects)

20
Q

Phase 4?

A

Post-marketing
- confirm effective dose
- confirm common adverse effects
- LEARN UNcommon adverse effects
- learn use effectiveness
> use in real clinical practice i.e. don’t like taste
- learn pharmacoECONOMICS (is based on the use effectiveness)

Goes form being in well controlled conditions to 100 000 in first few months. Risky time.

21
Q

4 examples of herbal alternative medicines?

A 
digoxin (fox glove)
morphine
aspirin 
quinine
> all come from plant sources
22
Q

Why aren’t herbal medicines medcines?

A

Not approved by Medsafe to be safe and effective.
Cannot make claims.
They may be effective but there are no real testing to show they are safe and effective

There is no money in it - patent protection is unlikely

23
Q

Example of St Johns Wort drug interaction

A

St Johns Wort + cyclosporin > cardiac transplant rejection

24
Q

What alternative medicines commonly interact with HF medications?

A
  • ST Johns
  • grapefruit juice
  • green tea
25
Q

What are the ABCS of clinical trial design?

A

A - Assignment
B - Blinding
C - Comparison
S - Sequence

26
Q

2 ways to Assign in clinical trials?

A
  1. First come first served
  2. Randomized
    > used to determine which subjects get which treatment
27
Q

First come first served assignment?

A

Often introduce bias or confounding. I.e. first group given treatment during one season. There is a loss of blinding.

28
Q

Randomized?

A

Needs to be balanced to ensure similar people in each group.
If different subgroups might have different responses i.e. have had a previous stroke then it is common to stratify the randomization sequence.

29
Q

Types of blinding?

A

Open - unblinded
Single blind - investigator knows subject doesn’t i.e. dr giving surgery
Double blind - both are not aware (most common)
> double dummy: can tell what they get from formulation i.e. pill and inhaler
Triple blind - no one knows. Error. i.e. randomisation sequence is lost or misinterpretated. No one knows what treatment was given

30
Q

Why is blinding used?

A

To reduce bias due to expectation of treatment

31
Q

3 kinds of comparisons as the control group

A
  1. Active treatment comparison
  2. Placebo
  3. Standard treatment
32
Q

Active treatment comparison

A
  1. Dose control (dif doses)
  2. Concentration control (helps to reduce the influence of random between individuals in PKs)
  3. Biomarker control (reflects the effect of the drug and so can be used and altered to control the intensity of treatment)
33
Q

Why use a control group?

A

To account for factors that might influence the outcome that are NOT experimentally assigned

34
Q

Placebo

A

Inactive substance. Best. If there is genuine uncertainty about the effect of the active treatment then it is considered ethical to randomise the placebo.

35
Q

Standard treatment?

A

i. e. known to be effective and is normally always used (most common in clinical trials)
- non-inferiority
- add-on

36
Q

Sequence?

A

The sequence of treatments can influence what is learnt from a trial and the kind of bias that can arise

  • parallel
  • cross over
  • titration
    > forced or flexible
37
Q

Parallel sequence?

A

Most robust with the least amount of assumptions needed to be made for analysis. There are different treatments assigned to different groups of subjects. Good design to answer ‘does the drug work?’ BUT gives unclear answers to learning questions that ask about the shape of the dose-response relationship of what dose is needed for a particular effect to be achieved

38
Q

Crossover?

A

Uses 2 or more treatments for each individual. Compare a person to themselves. More efficient. Allows individual dose response curves to be observed
> CONS
- carryover treatment effects (if long half life)

39
Q

Titration?

A

Special kind of crossover design.
Forced:
Giving a fixed sequence of doses to each subject to learn about dose response relationship (10mL > 20mL)
Flexible:
Start with a low dose and if subject responds then the dose is kept constant. Dose is only increased if the desired response isn’t reached

40
Q

Analysis perspective?

A

There are perspectives to be considered when analysing a clinical trial.

Intention to treat analysis
As treated

41
Q

Intention to treat?

A
  • only considers the treatment assignment
  • does NOT take into consideration whether or not the patient ACTUALLY took the treatment
  • means that the size of the treatment effect will be UNDER estimated if some subjects DONT take the active treatment or vv.
  • useful in making pharmacoECONOMIC decisions where the cost of the drug has to be paid whether or not the drug was actually taken

i.e. assumes use effectiveness (BIAS)

42
Q

As treated analysis?

A

Method effectiveness

  • takes into account info about what the subject actually took
  • less likely to have underestimation bias
  • more suited to making scientific decisions

CP - 1 (11 decks)

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