Lecture 14: Drug development and Clinical Trials Flashcards
3x steps to clinical drug development
- Discovery (physical discovery, newly sythesized or traditional)
- Development
- General use
Long and costly process of clinical drug development
Discovery –> Market = 10 years
$3 billion NZ per drug
9/10 tested dont reach market
Patent protection is very important to drug developers
Increased cost in certain phased of clinical drug development
- Discovery (cost hasnt changed much)
- Development increased
- General use increased
- as all easy drugs have been discovered and all the hard drugs are left to be developed
Which clinical drugs have the greatest sales worldwide?
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
What are the 5 phases of drug development?
Phase 0: Predictions for Humans Phase 1: Tolerability Phase 2: Effectiveness Phase 3: Safety Phase 4: Post marketing
BSO
Biomarker
Surrogate
Outcome
Biomarker
readily measurable marker of response
e.g. w. ThiopentoneL EEg is an objective measure of the response to the anaesthetic induction agent
Surrogate
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)
Outcome
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.
Difference b/w Learn and Confirm
- Learn(observe)
- explore unknown (e.g. tolerated dose) and develop hypothesis/model - Confirm (test hypothesis)
- develop confidence (tolerable dose but is it effective?)
- test hypothesis/model
Phase 0 of Clinical drug development
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
Phase 1 of Clinical drug development
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
Phase 2 of Clinical drug development
EFFECTIVENESS (100-500 patients)
- 2A phase: proof of concept –> Yes/No decision point (confirmation of whether or not drug has an effect)
- 2B phase: learn:
- dose response curve
- effective doses(relieve symptoms and improve function)
- target concentration (PK and PD)
Phase 3 of Clinical drug development
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)
Method effectiveness
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
Phase 4 of Clinical drug development
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
Use effectiveness
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
Alternative medicines
Alternative medicines arent known to be Safe or Effective
- Herbal/Traditional medicines
- Patent protection unlikely
- Health foods/Nutraceuticals
Herbal/ Traditional medicine component of alternative medicines
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)
Unlikely to get patent protection medicine component of alternative medicines
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
Health foods/Nutraceuticals component of alternative medicines
No claims, no testing, no good?
- St Johns Wart
- Black Cohosh
- Bracken Fern
- Natural Treatment **
4x major elements of Clinical trial design
ABCS
- Assessment
- Blinding
- Comparison
- Sequence
Assignment components of Clinical trial design
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))
Blinding components of Clinical trial design
Blinding is used to reduce bias
- Open (marketing use but w/o much scientific merit)
- Single blind (investigator knows but subject doesn’t)
- Double blind (neither investigator nor subject knows)
- -> Double dummy (comparison of two physically different treatments) - Triple blind (if sequence is loss or misinterpreted. = no one ever knows what treatment was given)
- fraudulence can occur (make up own codes) - Unblinded
