NMF 3/6/03

Susan Galbraith, MB BChir PhDVice PresidentClinical DiscoveryOncology & Immunology

Phase 0 Trials

Why aren’t they more widely used by industry?

NMF 3/6/03

Questions which Phase 0 trials could answerQuestions which Phase 0 trials could answer

• Tissue distribution after microdosing Useful for PET imaging agent development Preparation for receptor occupancy studies

Comment

Clear utility to such studies

They form relatively small proportion of pharmaceutical industry studies

• Tissue distribution after microdosing Useful for PET imaging agent development Preparation for receptor occupancy studies

Comment

Clear utility to such studies

They form relatively small proportion of pharmaceutical industry studies

NMF 3/6/03

Questions which Phase 0 trials could answerQuestions which Phase 0 trials could answer• Mechanism of Action determination Enzyme or receptor binding or inhibition

CommentNeed to be in pharmacologically active dose range

This question is routinely asked / answered in studies in NHVs - SAD or MAD 7 to 14 day Phase I trials together with PK and safety assessments using traditional IND Safety margin required in exploratory IND for cancer patients would

generally permit dosing in NHVs with exception if compound is clastogenic

NHV SAD trials can accrue a cohort of 8 subjects per week – whole study completed across wide dose range in 8 weeks

• Mechanism of Action determination Enzyme or receptor binding or inhibition

CommentNeed to be in pharmacologically active dose range

This question is routinely asked / answered in studies in NHVs - SAD or MAD 7 to 14 day Phase I trials together with PK and safety assessments using traditional IND Safety margin required in exploratory IND for cancer patients would

generally permit dosing in NHVs with exception if compound is clastogenic

NHV SAD trials can accrue a cohort of 8 subjects per week – whole study completed across wide dose range in 8 weeks

NMF 3/6/03

Questions which Phase 0 trials could answerQuestions which Phase 0 trials could answer• Mechanism of Action determination (contd) Enzyme or receptor binding or inhibition

CommentDoing such studies in cancer patients raises ethical and accrual issues but could have advantage if PD effects only likely to be seen in tumor tissue

For oncology targeted agents TI may frequently not permit dose escalation into pharmacologically active range if exploratory IND dose range guidance applied

– Maximum dose - to achieve up to ½ of the AUC at the NOAEL in the 2-week rodent study, or the AUC in the dog at the rat NOAEL, whichever is lower

• Mechanism of Action determination (contd) Enzyme or receptor binding or inhibition

CommentDoing such studies in cancer patients raises ethical and accrual issues but could have advantage if PD effects only likely to be seen in tumor tissue

For oncology targeted agents TI may frequently not permit dose escalation into pharmacologically active range if exploratory IND dose range guidance applied

– Maximum dose - to achieve up to ½ of the AUC at the NOAEL in the 2-week rodent study, or the AUC in the dog at the rat NOAEL, whichever is lower

NMF 3/6/03

Questions which Phase 0 trials could answerQuestions which Phase 0 trials could answer• Selection of most promising lead from a group of compounds By testing for more desirable PK/PD characteristics

CommentAssumes lack of predictability for such characteristics in preclinical models

Infrequently have more than one compound as potential clinical candidates which can’t be prioritized based on preclinical screening tests

Comments about dose range and population (NHVs vs cancer patients) still apply

• Selection of most promising lead from a group of compounds By testing for more desirable PK/PD characteristics

CommentAssumes lack of predictability for such characteristics in preclinical models

Infrequently have more than one compound as potential clinical candidates which can’t be prioritized based on preclinical screening tests

Comments about dose range and population (NHVs vs cancer patients) still apply

NMF 3/6/03

Additional PointsAdditional Points

•Would use of Phase 0 trials speed drug development? Time to FIH could be faster with Phase 0 plan -but is

not major metric of interest – time to PoC is more relevant

Traditional toxicology package and traditional IND filing still required for subsequent trials

Could be used for early No Go, but in event of Go decision doing Phase 0 will add time and cost

•Would use of Phase 0 trials speed drug development? Time to FIH could be faster with Phase 0 plan -but is

not major metric of interest – time to PoC is more relevant

Traditional toxicology package and traditional IND filing still required for subsequent trials

Could be used for early No Go, but in event of Go decision doing Phase 0 will add time and cost

NMF 3/6/03

SummarySummary•Definite utility to microdosing trials for imaging agent development•Use of NHVs for SAD studies under traditional IND gains most of advantage that a Phase 0 PD/MoA trial in cancer patients could provide in a shorter time Exception is ability to obtain tumor PD

•Some circumstances where Phase 0 trials could be used in oncology for PD/MoA but TI often limits this•Ability to transition to traditional IND would increase incentive to use this tool

•Definite utility to microdosing trials for imaging agent development•Use of NHVs for SAD studies under traditional IND gains most of advantage that a Phase 0 PD/MoA trial in cancer patients could provide in a shorter time Exception is ability to obtain tumor PD

•Some circumstances where Phase 0 trials could be used in oncology for PD/MoA but TI often limits this•Ability to transition to traditional IND would increase incentive to use this tool