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Phase 0/eIND Clinical Trial
Nimita Dave, M.S.
April 28, 2011
The Critical Path for Medical Product Development
http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html
Three Dimensions on the Critical Path
http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html
Industry-FDA Interactions During Drug Development
http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html
Drug Development Timeline
Eliopoulos, H., et al. (2008). Clin Cancer Res., 14(12): 3683-3688.
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
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
“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
Exploratory IND(eIND) Studies
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
Concept of Phase 0 Trial
Exploratory IND(eIND) Approach – Limited number of subjectsLimited range of dosesLimited period of time Requires less preclinical data Includes
microdose/sub-pharmacologic/pharmacologic dose
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
Phase 0 versus Traditional First-in-human Studies
Requirement Phase 0 studies
‘Traditional’ first-in-human studies
Benefits of human microdosing
Materials Gram quantities Kilogram quantities
Significantly lower quantities at a time when compound supply is often rate-limiting
Preclinical toxicology package
Reduced package
Standard Significant reduction in cost and time
Number of patients
10-15 Usually >20 Relatively small number of patients
Time to completion
4-6 months 12-18 months 8-12 months
Wilding, I. R., & Bell, J. A. (2005). Drug Discovery Today, 10(13): 890-894.
1. Pharmacokinetics or Imaging StudiesMicrodose Studies –
• Administration of 1/100th of the therapeutic dose or 100 μg, whichever is smaller
• Usually radiolabeled with 14C
• PK - Blood samples collected and analyzed by Accelerator Mass Spectrometry (AMS)
• Imaging - PET Scan
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 dataNo safety pharmacology data
2. Pharmacological Effect Studies
Pharmacologically relevant doses
Does not include defining a MTD
Single or repeat dose study
2. Pharmacological Effect StudiesPreclinical 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
2. Pharmacological Effect Studies Dose selection • Starting dose is 1/50th 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
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
Overview microdosing literature
Reference Drug Species
Method
Outcome
Lappin & Garner (2003) Nat Drug Discov 2:233 Xceleron
1A-adrenoceptor antagonist oral
Human AMS Linear 5-50-500µg
Sandhu et al (2004) Drug Metab Dispos 32:1254 Merck Research Labs USA
AZT analogue
oral+i.v.
Dog AMS Linear 0.02-1mg
Balani et al (2006) Drug Metab Dispos 34:384Millennium Pharmaceuticals
FluconazoleTolbutamideMLNX
oral
Rat LC-MS Linear 0.001-5mgLinear 0.001-5mgLinear 0.01-1mg, 10 mg Cmax, t1/2 linear, AUC non-linear
Overview microdosing literature
Reference Drug Species
Method
Outcome
Yamane et al (2007) J Chromatogr B 858:118
Fexofenadine
oral
Human LC-MS Linear 0.1-60mg
Vuong et al (2007)J Pharm Sci Vitalea Science
Zidovudine Human AMS Linear 520ng- 60mg
O’Brien, Z et al Poster presented at AAPS San Diego, Nov 2007 Neurocrine
DiphenhydramineOral+i.v. NBI-1oral
Human AMS Linear 0.1-50mg
Linear 0.1-10mg
www.speedel.com Renin inhibitorSPP635oral+i.v.
Human AMS Linear 0.1-50mg
Trial by Consortium for Resourcing and Evaluating AMSMicrodosing (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
CREAM trial: overall results
CREAM trial: overall results
Drug Was microdose predictive of therapeutic dose?
Warfarinoral; 0.1 vs 5 mg
CL/F predicted but volume of distribution not predictive
ZK253 Scheringoral+i.v.; 0.1 vs 50 mg
Low oral BA in human predicted i.v. PK predictive within factor of 2
Diazepami.v.; 0.1 vs 10 mg
i.v. PK predictive
Midazolamoral+i.v.; 0.1 vs 7.5 mg
BA due to 1st pass predictivePK predictive
Erythromycinoral(+i.v.) 0.1 vs 250 mg
No test (but lessons with acid-labile drugs)
EU Microdose AMS Partnership Program
Published on 20 January 2006
MEDICINE, RESEARCHMajor injection of EU funds for a microdose projectA 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 ... . . .
EU Microdose AMS Partnership Program
Published on 20 January 2006
MEDICINE, RESEARCHMajor injection of EU funds for a microdose projectA 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 ... . . .
EU Microdose AMS Partnership Program
Drug Reason for Selection
Fexofenadine PgP and OATP substrate
Paracetamol Extensive phase II metabolism
Phenobarbital Metabolic stability, Long t½
Propafenone CYP 2D6 substrate;Saturable first-pass metabolism
Sumatriptan Cytosolic monamine oxidase metabolism
S-19812 Formation of non-selective metabolite
Clarithromycin CYP-3A4 and PgP substrate
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)
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).
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).
Issues underlying low rate approval of oncological drugs
Lack of preclinical systems to predict efficacy and toxicity
Prolonged timeline for drug developmentHigh costs involvedIncreasing complexity of clinical trials
Phase 0 Trial in Cancer Drug Development
33Murgo, A. J. et al. Clin Cancer Res 2008;14:3675-3682
Timeline of the Phase 0 Trial of ABT-888
Kummar, S., et al. (2009). J. of Clin. Onco., 27(16): 2705-2711.
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.
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