Dr. Kumud MoreICRI, Mumbai15/04/10

“enabling critical decisions in early drug development™

SynonymsMicrodosingMicrodose FFirst In Human( FIH) studiesPhase OProof of concept studies

PHASE O

Study of new drug in microdoses to derive PK information in human before undertaking phase I studies is called PHASE 0

The emerging and generally accepted definition of “microdose”: 21 CFR 361.1

“1/100th or lower of the expected therapeutic dose.”

A dose less than 100ug

(The test compound has no pharmacologic effect at microdose concentrations)

Microdosing & 21 CRF 361.1Microdosing approach in man could ‘accelerate’ drug

development without compromising clinical safety

Microdosing helps researchers select better drug candidates for clinical trials by providing early human PK and bioavailability data. Microdosing will not provide information on PD & dosage

Reduced development time Candidate selection to human PK data in as little as 3 months

Reduced cost of development Prepare 100g of test compound vs kilograms of test compound

IntroductionA technique whereby sub pharmacological

doses of prospective drug candidates are administered

It is relatively recent innovation and there remains a degree of uncertainty as to whether such a small dose will adequately predict the pharmacokinetics of the therapeutically active dose?

First-in-human testing of new investigational agents with sub- therapeutic dose

Involves very limited human exposure, and has no therapeutic intent

The test compound has no pharmacologic effect at microdose concentrations

Lasts for 7-14 days

MotivePhase O clinical trials, developed in response to

the United States Food and Drug Administration (FDA)'s recent exploratory Investigational New Drug (IND) guidance, January 2006

FDA notes further that, such studies precede "the traditional dose escalation, safety and tolerance studies that ordinarily initiate a clinical drug

development program."

Used primarily for in-house decision making not for regulatory submission

ObjectivesPrimary:

Determine the pharmacokinetics Determine a non -toxic dose range

Secondary : Determine the safety of an chemical entity

Selection of Agents for Phase 0 TrialsSuccessful clinical development depends

heavily on a Pharmacokinetic (PK) end pointThe target or biomarker is credentialed

A wide therapeutic window is expectedTarget or biomarker modulation is

anticipated at nontoxic doses and over short durations of exposure (e.g., 7 days)

Target modulation is likely to be determined with a relatively small sample size (10 to 15 patients)

Statistical limitationsLimit sample size to 6-15 patients, generallyDefine primary endpoint(s) prospectivelyIf possible, obtain a measure of intra -patient

variability for the pre-treatment endpoint valuesDefine thresholds for declaring treatment effect

on biomarker (efficacy) for an individual patientTarget a reasonable efficacy % threshold, across

patients at a dose level, for detection with high power (90%)

Maintain a reasonable false positive rate (10%) across dose level

Not widely adopted for key reasonsThere are no dedicated clinical trials

facilities designed for Phase O conduct

Sample collection

For some therapeutic purposes it wont apply

Types of Phase 0 Trial Designs

Phase O trial designs vary depending on the particular study objectives

Transition from preclinical to clinical development is critical to the design of phase O trials and requires close collaboration between laboratory, drug development, and clinical scientists.

Phase O trial Designs are designed To Primarily show that the drug affects the

target in human disease To evaluate clinically the properties of two or

more structurally similar analogues directed at the same molecular target

To develop novel imaging probes or technologies to evaluate the biodistribution, binding

characteristics, and target effects of an agent in humans

To determine a statistically significant, treatment-related change from baseline in a PK end point.

Enrollment of Patients in Phase 0 TrialsNon therapeutic nature of phase O trials Important to ensure that participation will not

adversely affect a patient's eligibility to participate in subsequent therapeutic trials or adversely delay other therapy

Shorter washout periods, such as 2 weeks or less, are probably sufficient

Ethical issuesQuestion- whether ethics itself has to formulate a

new critique to account for the novel aspects of phase O trials.

Urgency- because the expectation is that the number of phase O trials being conducted will only increase

The experiment has to be scientifically valid, based on a reasonable hypothesis and a research methodology that can be expected to reach its stated end points.

Its like breaking new ethical ground by challenging the long-standing principle that the interests of human subjects always take precedence over the interests of society(The National Bioethics Advisory Commission)

Regulatory Issues

First and foremost the regulations address the ethical demands for safety and efficacy.

For FIH studies safety is the key factor.

Is different safety information appropriate at different stages of drug development?

How much is an investigator expected to know for a single microdose study in man?

Changes to Regulations in the US?

EMEA has given reasonable guidance for the early characterization of human PK / ADME with ‘first-in-human’ (FIH) single sub-pharmacological (‘microdose’) of drug candidate(s)

Options

1. Change 21 CRF 361.1 to allow for FIH testing under RDRC and IRB approval.

1. Specify non-clinical safety studies required to support single microdose clinical studies

2. Develop a simplified process (Exploratory IND?) for FIH testing

Regulatory Issues-US FDA

US FDA guidelines have come in 2006 – (21CFR 361.1) under Radioactive Drug Research Committee (RDRC)

Current 21 CRF 361.1 regulations indicate that no radioactive drug may be studied “first in humans” because investigators must first provide pharmacological dose calculations based on published literature or other human data.

Guidance and Acceptance of Microdose Techniques in Europe

EMEA Position Paper

Came into operation in July 2003

Specifies non-clinical safety studies required to support single microdose clinical studies

Describes microdosing studies as exploratory in nature and conducted pre-Phase I with one or several closely-related compounds

Document provides ‘streamlined’ regulatory pathway for early drug candidate selection in humans

Microdosing: Prerequisites

Technical: Need for highly sensitive and specific methodsAMS (Accelerated Mass Spectrometry) - Need for

isotope labeling (14C) for compounds being testedPETAMS & PET are valuable tools for:

Microdosing Low radiation mass balance Metabolite profiling Absolute bioavailability

Regulatory: Toxicology data

AdvantagesReduced manufacturing requirements Reduced toxicologic requirementsDemonstration of drug-target effects Assessment of pharmacokinetic-pharmacodynamic

relationships in humans earlier in clinical development

To establish at the very earliest opportunity-before large numbers of patients have been exposed to potential drug-associated toxicity

To assess whether further clinical development is warranted.

To develop products faster and more efficiently

Microdosing: AdvantagesProvides sufficiently useful PK information to

decide on confirmatory development (human & animal toxicology)

Establish likely pharmacological dose and determine first dose for subsequent Phase I study

Helps in early de-selection: Cost saving related to manufacturing, scaling up & CTs

Impact on animal use and testing-reduced Helps improve attrition rate in late phase of

clinical trials by allowing sponsor to choose best candidates

Develop molecule with suitable PK faster/ improve existing PK profile

Microdosing: Limitations? Predictive accuracy of microdosing

PK at microdose vs. therapeutic dose False positive/ negatives Compound metabolism and solubility (limited

solubility at higher doses; ? Microdose too small) May not predict the behavior of clinical doses;

Non-linearity may be induced when binding, metabolizing, or eliminating systems become saturated

Study mainly based on PK parameters - not efficacy and safety based

Regulatory hurdles

Microdosing: Limitations? Scheduling of drug development: Scale up

of chemical synthesis on hold Expensive and large equipment Need to prove cost-effectiveness

Limitations in the Application of Phase 0 Trials Not all agents are appropriate for phase 0 testingRange of resources required for the preclinical and

clinical aspects of phase O studies, particularly those evaluating target or biomarker effects, is not available at most academic institutions

The non therapeutic nature of the trials makes recruitment difficult and third party payers are not likely to cover the associated clinical care costs

Well-organized system for biospecimen procurement and processing and an efficiently integrated and dedicated team of laboratory and clinical investigators with expertise

Concept is not widely accepted by industry because apparently only a handful of companies have acknowledged doing exploratory IND trials, and none had PD as a primary end point

Conclusion Can greatly improve the efficiency and success

of subsequent trials, particularly those for the development of molecular targeted agents

Excellent opportunity to establish feasibility

and further refine target or biomarker assay methodology

Phase 0 trials do not replace phase I trials conducted under a standard IND to establish dose-limiting toxicities and define a recommended phase II dose