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