Drug Development Process Flashcards
agencies that regulate and conduct research
NIH, NCI, cooperative groups (CALGB, ECOG, COG, alliance group)
accelerated development review
unmet medical need (ie. rare type of sarcoma), start early phase I
parallel track
Access to life-saving treatment to patients who for various reasons were unable to participate in clinical trials - with IND
treatment IND
Expanded access to a drug during phase 2 or 3 trials if it potentially represented a safer or better alternative to treatments currently available for terminal or serious illness
IND approval time
FDA approves in 6-9 months, may offer advice on how to develop the drug
IND definition
#investigational new drug application #submitted prior to starting clinical trials post pre-clinical #waiting period of 30 days (FDA may signal that review will be longer than 30 days) #contents, chemistry, pre-clin data, proposed clinical protocol, investigators brochure
when are sponsor /FDA meetings encouraged in drug development process?
prior to IND submission, mid phase II or phase I/II, when NDA submitted, when review submitted
which applications go to the FDA advisory committee?
NDA and review (NOT IND)
What is FDA ODAC?
oncology drug advisory committee - decisions are not binding ->advice goes to full advisory committee
preclinical
#obtain lethal dose in 10% of animals (usually a small animal (mouse, rat) and a larger animal (rabbit, monkey)->determines LD10, initial dose in humans #define quantitative and qualitative organ tox (single and long term dosing, post mortem's performed) #same scheduled and route planned for humans
LD10
lethal dose in 10% of animals -dose used to start phase I testing is 1/10th of this dose in mg/m2 in the MOST sensitive species (could be mouse of monkey) (this # is controversial, some think it should be higher, new designs bump this dose up quicker)
FDA 1572 form
#preclinical #statement of investigator who places conduct of all in pursuing the study on investigator #signed by all investigators #basically a CV of investigators
FDA 1571 form
#preclinical #this is the IND application
IND exempt studies (3pts)
#study not intended to support FDA approval of a new indication or a significant change in pdt labeling #study not intended to support a significant change in advertising #study does not involve a ROA or dosage level or use in a pt population or other factor that significantly increases the risks associated with use of the pdt
phase I objectives (6pts)
#SAFETY #determine PK and PD (pharmacology) #determine MTD #describe drug related toxicity #determination of tx activity is a secondary objective #historically in cancer pts with no other options (in panc CA this may be 2nd line but in breast CA this may be 6th, 7th, 8th line) #15-30pts
phase I limitations (4pts)
#potential for subtherapeutic dose #extended period for completion #limited info regarding pt variability and cumulative tox #pts seen are NOT the patients of interest (heavily pretreated, advanced dz)
cohort determination (5pts)
#standard 3+3 #continual reassessment method (CRM) #modified CRM #PK or PD guided design (using preclinical info) #patient choice method (rare, pt selects dose based on expected ae's)
standard cohort (3+3)
3pts per a level, usually 4-8 escalations, if no DLT the whole cohort advances one level, if at 2nd level 1/3 pts has DLT enroll new set of 3 pts at same level, if no new DLT (so 1/6 has DLT) then can move to 3rd level but if one did have a DLT (so 2/6 have DLT) would drop back down to 2nd level with 3 more pts; also if 2/3 have DLT at a particular level you would go back a level and add 3 pts to ensure this is the MTD (ie. level below where 2/3 pts have DLT)
continual reassessment method (CRM)
#estimates probability of MTD at each dose level based on a priori estimates (previously known info) #uses real time information as trial progresses
modified CRM
#start with standard cohort (3+3), then escalate with a single pt per dose level until toxicity, then begin the 33% rule, so if 1/3 pts DLT add 2pts to that dosing level, if then 1/3 move up, if 2/3 that determines DLT #much more efficient as fewer pts but limitation is less pk,pd data collected
dose escalation types (3pts)
#fixed-conditional scheme #modified fibonacci method #dose-limiting toxicity rate
dose escalation - fixed-conditional scheme
#start 100% increase until minimal tox (often grade II) #THEN 50% increase until unacceptable tox (grade II-IV depending on lots of factors) #THEN 25% increase until MTD #good for honing in on correct MTD
dose escalation - modified fibonacci method
#1st dose increase 100%, then 67%, 50%, 45%, 33% (2x, 3.3x, 5x, 9x, 12x, 16x) #lots of problems with honing in on correct MTD #fibonacci=1+1=2, 2+1=3, 3+2=5, etc
dose escalation - dose-limiting toxicity rate
estimate before trial begins what the tox is expected to be, usually only have 2-3 dose escalations, can change dose escalations based on real-time information