What are the different phases of drug development?
Phase 0= Predictions for humans
Phase 2= Effectiveness
Phase 3= safety
Phase 4= Post marketing
What are the two stages of drug treatment?
Disease modifying- changes the course of the disease eg makes the tumour smaller
Symptomatic- treats the symptoms, not the disease itself.
What is a biomarker?
Readily measurable marker of response to drug eg drop in blood pressure in hypetension
But isn't necessarily accepted by regulatory authorities as decrease in blood pressure doesn't necessarily predict outcome. Decreased BP doesn't mean decreased outcome of stroke in patients etc
What is a surrogate endpoint?
Surrogate endpoint is the terminology used by drug companies/government regulatory agencies to describe a biomarker that strongly predicts clinical outcome.
eg reduction in viral load, and increased CD4+ cell count accurately predicts that these individuals will have improved survival.
What is outcome defined by?
What the patient feels, functions/survives.
eg pain, surgery, hospital admission, death
What are the important characteristics of biomarkers?
Repeated measurements possible
Often high content information
Rapid indication of response
Can be prognostic or diagnostic value.
What are important characteristics of clinical outcome?
Subjective- eg pain- 1 patient might feel pain more than the other.
Often only happens once- eg death
Can take many years for differences to be evident.
What is the problem with biomarkers?
The Responder Paradox
Blood pressure rarely predicts individual beneficial clinical outcome- a small % of patients have death prevented but the large % will have adverse effects.
Is blood pressure as a biomarker a good surrogate endpoint? Why or why not?
No they are not
Example- 2 drugs given for high blood pressure
- Both reduce blood pressure in a similar manner.
-However one decreases incidence of stroke more than the other.
- Biomarker data predicts equal effectiveness of treatments
- Outcome assessment reveals marked differences between treatments.
- Disease processes are complex and outcomes are subject to many variables
What are the benefits of using surrogate end points?
Shorter clinical trials
Accepted to be strongly related to outcome- so beneficial to use them instead to having long and expensive trails for outcome.
What are the most widely used surrogate endpoint?
Drug concentration to design generic drugs. Drugs with same concentration so no clinical outcome required.
What phases of drug development do adverse drug effects monitoring correspond to?
Phases 3 and 4
How is adverse drug effects monitoring done?
Biomarker/ surrogate endpoints
- Liver-ALT (alanine aminotransferase)
- Kidney- Serum creatinine
- Heart-QT interval