Could an EOP2A Meeting Shorten Drug Development Time?

1. Could an EOP2A Meeting Shorten Drug Development Time? Joga Gobburu Team Leader, Pharmacometrics, OCPB/CDER/FDA Based on the work jointly performed with Drs. Nguyen and Marroum

2. Background • Drug with symptomatic benefit • Proposed dosing - QD • Sustained effect desired • Drug exhibits short half-life, 2 hrs • Very large pivotal trials conducted • Typically pivotal trials are not large in this setting • Conventional and ER analyses conducted

3. Drug Development Diary Pre-Clinical Early PK, Safety, Form.Dev., POC, PKPD in Target pop. Pivotal Trials Rev 0 years 10 years Form.Dev. = Formulation Development POC = Proof-of-concept Rev = Regulatory Review (10 mo)

4. Conventional Analysis • Tx is statistically superior to placebo • change in response at trough • Drug is proposed to be given QD, but • Modest effect at trough • Short half-life • Is this a once-a-day drug? Modeling, probably, not needed to raise this question

5. ER Analysis • M&S needed to gain insights into the PKPD characteristics • Is the effect concentration-dependent at all? • Is the concentration-effect relationship linear? • Is there a delay between PK and PD? • Does tolerance develop? • Is the toxicity concentration dependent? • If qd is ‘really’ inadequate, alternatives? 

6. Clear concentration-effect relationship No delay between PK and PD Nonlinear concentration-effect relationship FDA performed the analysis during NDA review All ER data used, not just trough Cp (ug/L) 1 mg daily EC50 Time, h ER Analysis • Modeling demonstrated inadequacy of once a day regimen, for this formulation

7. ER Analysis Cp (ug/L) 1 mg daily 1 mg bid 1 mg tid • Simulations suggested bid, tid or more practically a modified release formulation might be considered EC50 Time, h

8. Drug Development Diary Submission is approvable Pre-Clinical Regulatory review indicated lack of sustained effect as a major deficiency. More rational dosing regimen proposed Early PK, Safety,Form.Dev, POC, PKPD in Target pop. Pivotal Trials Rev 0 years 10 years Form.Dev. = Formulation Development POC = Proof-of-concept Rev = Regulatory Review (10 mo)

9. Pre-Clinical Early PK, Safety,Form.Dev, POC, PKPD in Target pop. Pivotal Trials Rev 10 years Drug Development Diary Pivotal Trials Form.Dev. Rev 0 years 3-5 years Form.Dev. = Formulation Development POC = Proof-of-concept Rev = Regulatory Review (10 mo)

10. Summary of ER Analysis • Supported evidence for effectiveness • Aided in judging that QD dosing is sub-optimal • Eliminated the need for testing higher doses • Concentration dependent toxicity • Nonlinear effectiveness relationship • Provided alternatives for future development

11. Drug Development Diary Pre-Clinical Early PK, Safety, Form.Dev., POC, PKPD in Target pop. EOP2 Meeting Pivotal Trials Rev 0 years 10 years Form.Dev. = Formulation Development POC = Proof-of-concept Rev = Regulatory Review (10 mo)

12. EOP2A Meeting • Early studies in the target population were available with PKPD data • Given ER analysis performed, EOP2A would have been useful • Optimal dosing is expected, not just a p<0.05 • More rational dosing regimen needed • Considerable decrease in sample size • Improving efficiency of drug development

13. Acknowledgements • Division of Pharmaceutical Evaluation -1 (DPE-1) Pharmacometrics Team • Dr. Mehul Mehta • Director, DPE-1 • Dr. Sahajwalla • Deputy Director, DPE-1