1. Phase 0/eIND Clinical Trial Nimita Dave, M.S. April 28, 2011

2. The Critical Path for Medical Product Development http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html

3. Three Dimensions on the Critical Path http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html

4. Industry-FDA Interactions During Drug Development http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html

5. Drug Development Timeline Eliopoulos, H., et al. (2008). Clin Cancer Res., 14(12): 3683-3688.

6. Where does the problem lie? Stagnation Have been using yesterday’s technology to design today’s drugs Reluctance to move on to new technology –Fear of falling behind by trying to move ahead

7. What can be done? Basic science Validate tools for drug development in the lab Overcome the apparent disconnect between basic science and applied science to modernize the industry

8. “A new product development toolkit….. is urgently needed to improve predictability and efficiency along the critical path.” http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html

9. Exploratory IND(eIND) Studies

10. Exploratory IND Study Exploratory IND study is a clinical trial that -  is conducted early in phase 1,  involves very limited human exposure, and  has no therapeutic or diagnostic intent (e.g., screening studies, microdose studies) Also known as phase 0 trial

11. Concept of Phase 0 Trial  Exploratory IND(eIND) Approach – Limited number of subjects Limited range of doses Limited period of time  Requires less preclinical data  Includes microdose/sub- pharmacologic/pharmacologic dose

12. Goals of eIND Approach  Determine whether a mechanism of action defined in experimental systems can also be observed in humans  Provide important information on pharmacokinetics (PK)  Select the most promising lead product from a group of candidates  Explore a product’s biodistribution characteristics using various imaging technologies

13. Phase 0 versus Traditional First-in-human Studies RequirementPhase 0 studies ‘Traditional’ first-in-human studies Benefits of human microdosing MaterialsGram quantitiesKilogram quantities Significantly lower quantities at a time when compound supply is often rate- limiting Preclinical toxicology package Reduced package StandardSignificant reduction in cost and time Number of patients 10-15Usually >20Relatively small number of patients Time to completion 4-6 months12-18 months8-12 months Wilding, I. R., & Bell, J. A. (2005). Drug Discovery Today, 10(13): 890-894.

14. 1. Pharmacokinetics or Imaging Studies  Microdose Studies – Administration of 1/100 th of the therapeutic dose or 100 μg, whichever is smaller Usually radiolabeled with 14 C PK - Blood samples collected and analyzed by Accelerator Mass Spectrometry (AMS) Imaging - PET Scan

15. 1. Pharmacokinetics or Imaging Studies Preclinical Package –  Extended single-dose toxicity studies Single mammalian species 14 days By the intended clinical route of administration  No genetic toxicity data  No safety pharmacology data

16. 2. Pharmacological Effect Studies  Pharmacologically relevant doses  Does not include defining a MTD  Single or repeat dose study

17. 2. Pharmacological Effect Studies  Preclinical Package 2-week repeat dose toxicology study in a sensitive species By the intended clinical route of administration No. of administrations = No. of intended clinical administrations Safety pharmacology data required Genetic toxicity data required

18. 2. Pharmacological Effect Studies  Dose selection Starting dose is 1/50 th of NOAEL from 2-week toxicology study Maximum clinical dose would be the lowest of the following – i. 1⁄4 of the 2-week rodent NOAEL on a mg/m2 basis ii.Up to 1⁄2 of the AUC at the NOAEL in the 2-week rodent study, or the AUC in the dog atthe rat NOAEL, whichever is lower iii. The dose that produces a pharmacologic and/or pharmacodynamic response or at which target modulation is observed in the clinical trial

20. Clinical Success Rate with Phase 0 Trial Early PK data can help fail problematic drugs faster –Provides a quick read to help with go or no- go decisions Can chose the best candidates from panels of drugs for further development

21. Overview microdosing literature ReferenceDrugSpeciesMethodOutcome Lappin & Garner (2003) Nat Drug Discov 2:233 Xceleron  1A- adrenoceptor antagonist oral HumanAMSLinear 5-50-500µg Sandhu et al (2004) Drug Metab Dispos 32:1254 Merck Research Labs USA AZT analogue oral+i.v. DogAMSLinear 0.02-1mg Balani et al (2006) Drug Metab Dispos 34:384 Millennium Pharmaceuticals Fluconazole Tolbutamide MLNX oral RatLC-MSLinear 0.001-5mg Linear 0.01-1mg, 10 mg Cmax, t1/2 linear, AUC non-linear

22. Overview microdosing literature ReferenceDrugSpeciesMethodOutcome Yamane et al (2007) J Chromatogr B 858:118 Fexofenadine oral HumanLC-MSLinear 0.1-60mg Vuong et al (2007) J Pharm Sci Vitalea Science ZidovudineHumanAMSLinear 520ng- 60mg O’Brien, Z et al Poster presented at AAPS San Diego, Nov 2007 Neurocrine Diphenhydramine Oral+i.v. NBI-1 oral HumanAMSLinear 0.1-50mg Linear 0.1-10mg www.speedel.comRenin inhibitor SPP635 oral+i.v. HumanAMSLinear 0.1-50mg

23. Trial by Consortium for Resourcing and Evaluating AMS Microdosing (CREAM trial) Pharmaceutical Companies –Eli Lilly –Hoffmann LaRoche –Servier –Schering AG Xceleron (AMS) Pharma Bio-Research (now: PRA International EDS) Scientific Advisory Board (Prof. Malcolm Rowland, chairman) First eIND Trial

24. CREAM trial: overall results

25. DrugWas microdose predictive of therapeutic dose? Warfarin oral; 0.1 vs 5 mg CL/F predicted but volume of distribution not predictive ZK253 Schering oral+i.v.; 0.1 vs 50 mg Low oral BA in human predicted i.v. PK predictive within factor of 2 Diazepam i.v.; 0.1 vs 10 mg i.v. PK predictive Midazolam oral+i.v.; 0.1 vs 7.5 mg BA due to 1 st pass predictive PK predictive Erythromycin oral(+i.v.) 0.1 vs 250 mg No test (but lessons with acid-labile drugs)

26. EU Microdose AMS Partnership Program Published on 20 January 2006 MEDICINE, RESEARCH Major injection of EU funds for a microdose project A new EU-funded project kicked off this month which aims to bridge the gap between the laboratory and the clinic. The EU Microdose AMS Partnership Programme (EUMAPP) aims to boost Europe’s expertise in micodosing and its application of AMS, or accelerator mass spectrometry, to developing new candidate drugs......

27. EU Microdose AMS Partnership Program Published on 20 January 2006 MEDICINE, RESEARCH Major injection of EU funds for a microdose project A new EU-funded project kicked off this month which aims to bridge the gap between the laboratory and the clinic. The EU Microdose AMS Partnership Programme (EUMAPP) aims to boost Europe’s expertise in micodosing and its application of AMS, or accelerator mass spectrometry, to developing new candidate drugs......

28. EU Microdose AMS Partnership Program DrugReason for Selection FexofenadinePgP and OATP substrate ParacetamolExtensive phase II metabolism PhenobarbitalMetabolic stability, Long t ½ PropafenoneCYP 2D6 substrate; Saturable first-pass metabolism SumatriptanCytosolic monamine oxidase metabolism S-19812Formation of non-selective metabolite ClarithromycinCYP-3A4 and PgP substrate

29. Challenges of eIND Studies Safety –Radiolabeled drugs Doesn’t work with every drug –European Union Microdose AMS Partnership Program (EUMAPP) Data not scaling –n is small –Scaling to a high dose Expense –Specialized equipment (AMS)

30. What does the industry think? An independent survey carried out across the entire pharmaceutical industry showed: –40% plan to adopt microdosing by 2008 –90% plan to adopt microdosing by 2010 Wilkinson M. Xceleron to accelerate growth further. DrugResearcher.com. www.drugresearcher.com, May 3 (2007).

31. What does the industry think? “By 2010 we believe that microdosing will already have gained a secure foothold at the interface between the preclinical and early clinical stages of drug development” “By 2015, microdosing can be expected to be a firm element in early-stage drug development, and at some point it might even be mandated by regulatory authorities” Mucke H. Microdosing in translational medicine: Pros and cons. CHA Advances Report. www.advancesreport.com, May (2006).

32. Issues underlying low rate approval of oncological drugs  Lack of preclinical systems to predict efficacy and toxicity  Prolonged timeline for drug development  High costs involved  Increasing complexity of clinical trials

33. Phase 0 Trial in Cancer Drug Development 33 Murgo, A. J. et al. Clin Cancer Res 2008;14:3675-3682

34. Timeline of the Phase 0 Trial of ABT-888 Kummar, S., et al. (2009). J. of Clin. Onco., 27(16): 2705-2711.

35. PBPK Model to Predict PK Profile using Phase 0 Clinical Study Sugiyama et al. Adv. Drug Deliv. Rev. 2011, doi:10.1016/j.addr.2010.09.010.

36. Questions/Comments? “New drug development is a very complicated and difficult undertaking, but one that makes an enormous difference to the health of people across the globe. It is a noble pursuit.” – J.R. Turner