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Sita CP > Lecture 14: Drug development and Clinical Trials > Flashcards

Lecture 14: Drug development and Clinical Trials Flashcards

1
Q

3x steps to clinical drug development

A
  1. Discovery (physical discovery, newly sythesized or traditional)
  2. Development
  3. General use
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2
Q

Long and costly process of clinical drug development

A

Discovery –> Market = 10 years
$3 billion NZ per drug
9/10 tested dont reach market
Patent protection is very important to drug developers

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3
Q

Increased cost in certain phased of clinical drug development

A
  1. Discovery (cost hasnt changed much)
  2. Development increased
  3. General use increased
    - as all easy drugs have been discovered and all the hard drugs are left to be developed
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4
Q

Which clinical drugs have the greatest sales worldwide?

A

Medications for chronic diseases

  • people take them for their lifetime
  • this is where all the money is going
    e. g. Chrons disease, Psychosis, Depression, Rheumatoid arthritis
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5
Q

What are the 5 phases of drug development?

A 
Phase 0: Predictions for Humans
Phase 1: Tolerability
Phase 2: Effectiveness
Phase 3: Safety
Phase 4: Post marketing
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6
Q

BSO

A

Biomarker
Surrogate
Outcome

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7
Q

Biomarker

A

readily measurable marker of response

e.g. w. ThiopentoneL EEg is an objective measure of the response to the anaesthetic induction agent

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8
Q

Surrogate

A

Biomarker used for regulatory approval
e.g. Reduction in HIV viral load (evaluate treatment according to the extent of the decrease in the amount of virus in blood)
Note: BP no longer used as a surrogate biomarler to assess reduction in CVD (Heart attack and stroke risk)

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9
Q

Outcome

A

evaluate HOW the patient:
- functions(sex)
- feels (pain)
- survives (death. stroke - risk of multiple)
Overall: does the drug do something useful and how does the patient f.f.s.

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10
Q

Difference b/w Learn and Confirm

A
  1. Learn(observe)
    - explore unknown (e.g. tolerated dose) and develop hypothesis/model
  2. Confirm (test hypothesis)
    - develop confidence (tolerable dose but is it effective?)
    - test hypothesis/model
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11
Q

Phase 0 of Clinical drug development

A

Non clinical. PREDICTIONS FOR HUMANS

  • collect data from non-humans
  • probable mechanisms of action (mammals tend to have conserved physiological processes across species)
  • likely effective concs (rat and human enzymes tend to require same concentrations to be effectively inhibited)
  • major routes of elimination (kidney or liver)
  • yes or no to oral absorption properties
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12
Q

Phase 1 of Clinical drug development

A

TOLERABILITY (10-50 patients)
- start with very small doses and slowly increase until adverse effects are noted
Learn:
a) single and multiple dose PK
b) adverse effect PD (concentration related to nause/headaches)
Phase 1 usually done on:
1. young and healthy patients as they should be more able to tolerate it if things go wrong
2. Advanced cancer patients, who arent responding to treatment. Have new cancer therapies tested on them

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13
Q

Phase 2 of Clinical drug development

A

EFFECTIVENESS (100-500 patients)

  1. 2A phase: proof of concept –> Yes/No decision point (confirmation of whether or not drug has an effect)
  2. 2B phase: learn:
  3. dose response curve
  4. effective doses(relieve symptoms and improve function)
  5. target concentration (PK and PD)
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14
Q

Phase 3 of Clinical drug development

A

SAFETY (1000+ patients)
- Safety: learn adverse effects in target popn (freq)
Note: wont know if ADR occurs less than 1/1000 as isnt a large enough study
- Confirm effective doses: “method effectiveness”
- Learn PD of surrogate/outcome
- Learn PK and PD of covariates (age, sex and other drugs)

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15
Q

Method effectiveness

A

Do you have an effect if you take the medication WHEN you’re supposed to take it
Part of safety Phase 3
Note: method effectiveness/compliance to methods of drug consumption tend to be good

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16
Q

Phase 4 of Clinical drug development

A

POST-Marketing (100,000 patients) (in market)
(is now available for market use, appears to be safe enough in a large number of patients and appears to be reasonably effective. Note: Cannot insure that it is 100% safe)
1. Confirm effective doses
2. Confirm common adverse effects
3. Learn uncommon adverse effects
- stressful time for companies as is impossible to know of rare, adverse effects from small studies
e.g. rabdomyalisis from statin
4. Learn “use effectiveness”
5. Lean pharmacokinetics

17
Q

Use effectiveness

A

Prescription given, will you DISPENSE and/or USE the drug
PArt of Post marketing Phase 4
- is the medicine worth it?
- provides cost effectiveness in a realistic setting (allows to learn pharmacoeconomics) as Pharmac is essentially paying for drugs that no one is taking if there is low use effectiveness

18
Q

Alternative medicines

A

Alternative medicines arent known to be Safe or Effective

  1. Herbal/Traditional medicines
  2. Patent protection unlikely
  3. Health foods/Nutraceuticals
19
Q

Herbal/ Traditional medicine component of alternative medicines

A

Digoxin (fox glove plant)
Morphine (opium poppy)
Aspirin (weeping willow)
Quinine (malaria treatment from synchona tree)
Gossipol (chinese antifertility treatement. good method effectiveness but low use effectiveness)
Artemesin (marlaria treatment form wormwood)
Taxol (anticancer agent from bark of Pacific ewe tree)

20
Q

Unlikely to get patent protection medicine component of alternative medicines

A

Uneconomic for full drug development
- molecule is known to exist and cannot be patented
- therefore drug companies wound fund
Now up to WHO and Bill&Linda Gates Foundation: develop usefull medicines w/o patent protection

21
Q

Health foods/Nutraceuticals component of alternative medicines

A

No claims, no testing, no good?

  • St Johns Wart
  • Black Cohosh
  • Bracken Fern
  • Natural Treatment **
22
Q

4x major elements of Clinical trial design

A

ABCS

  1. Assessment
  2. Blinding
  3. Comparison
  4. Sequence
23
Q

Assignment components of Clinical trial design

A

Biased: first come, first served
- loss of blinding. Investigator is able to guess which subjects are getting different treatments even if he/she is blinded to the actual assignment
Good assignment method: RCT (list is randomly permuted from which subjects are drawn) –> ensures a desired balance of 50% in each of the 2 treatment groups. Groups aren’t effected by the randomisation process
1. Balanced (e.g. equal men and woman)
2. Stratified (e.g. sex, previous stoke/disease)
- occurs if different subgroups have different responses
- stratify the randomisation process (different sequences are down up for each subgroup (e.g. one list for males and females individually))

24
Q

Blinding components of Clinical trial design

A

Blinding is used to reduce bias

  1. Open (marketing use but w/o much scientific merit)
  2. Single blind (investigator knows but subject doesn’t)
  3. Double blind (neither investigator nor subject knows)
    - -> Double dummy (comparison of two physically different treatments)
  4. Triple blind (if sequence is loss or misinterpreted. = no one ever knows what treatment was given)
    - fraudulence can occur (make up own codes)
  5. Unblinded
25
Q

When are blinded trials unblinded?

A

When the treatment has prominent beneficial effects of adverse effects
Very hard to prevent of adjust for in analysis

26
Q

Comparison component of Clinical Trial Design

A
  1. Active
    - dose control
    - concentration control
    - biomarker control
  2. Placebo
  3. Standard treatment
    - non-inferiority
    - add on
27
Q

Sequence component of Clinical Trial design

A
  1. Parallel
  2. Crossover
  3. Titration
    a) forced
    b) flexible
28
Q

Titration sequences in Clinical trial designs

A

titrations are a type of cross over design
Forced Titrations: fixed sequence of disease
Flexible Titrations: start at low dose.
a) keep dose constant if patient responds
b) increase dose if desired response isnt reached

29
Q

Parallel sequences in Clinical trial designs

A

**

30
Q

Crossover sequences in Clinical trial designs

A
31
Q

From results, how do you know which results are from an active drug of placebo?

A

e.g. cannabis treatment for multiple sclerosis/muscle pains
Results: placebo group was already lower than the 2x active treatment groups –> and the same difference persisted during the trial
Dependant on how BALANCED the RCT is (if patients have similar pre-trial scores)
Note: placebo controlled trials Dont solve all the problems

32
Q

Analysis Perspective on Clinical trial designs

A
  1. Intention/Want to treat
    - “use effectiveness –> pharmacoeconomic perspective
    - often contains biased/underestimate effect (due to poor patient compliance) + did patients swith b/w active and placebo treatments
  2. As treated
    - “method effectiveness” –> development science perspective (are the prescribed pills good)
    - have to consider ways of measuring what people take (via drug conc/ number of times bottle opened) = what the patient actually took from the treatment
    - takes into consideration what the subject actually took for their treatment –> therefore is more suitable for making scientific decisions
33
Q

What is the relationship b/w Chinese gossipel anti-fertility treatment for men?

A

Good Method effectiveness (works well scientifically)

Poor Use effectiveness (males dont take it as dont think it is their responsibility)

Sita CP (9 decks)

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