Dr. Kumud More ICRI, Mumbai 15/04/10 Micro dosing “enabling critical decisions in early drug development™ Dr. Kumud More ICRI, Mumbai 15/04/10

Synonyms Microdosing Microdose F First In Human( FIH) studies Phase O Proof 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 361.1 Microdosing 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

Introduction A 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

Motive Phase 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

Objectives Primary: Secondary : Determine the pharmacokinetics Determine a non -toxic dose range Secondary : Determine the safety of an chemical entity

Selection of Agents for Phase 0 Trials Successful clinical development depends heavily on a Pharmacokinetic (PK) end point The target or biomarker is credentialed A wide therapeutic window is expected Target 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 limitations Limit sample size to 6-15 patients, generally Define primary endpoint(s) prospectively If possible, obtain a measure of intra -patient variability for the pre-treatment endpoint values Define thresholds for declaring treatment effect on biomarker (efficacy) for an individual patient Target 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 reasons There are no dedicated clinical trials facilities designed for Phase O conduct Sample collection For some therapeutic purposes it wont apply 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

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 Trials Non 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 issues Question- 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) "But in oncology, we just don't have that for many of our targets now." And because validation of these assays in patients is often difficult, phase 0 trials are at serious risk of failure. The same commentator notes that they run the risk of concluding that a drug is inactive when in fact it is active. Under such circumstances of futility, it would be unethical to involve human subjects, especially seriously ill human subjects, because there is no possibility of any benefit, direct, indirect, or even to others. Thus, an essential requirement for the validity of phase 0 trials would be the availability of assays reasonably validated in earlier animal and in vitro studies for the purposes of subsequent clinical studies

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 Change 21 CRF 361.1 to allow for FIH testing under RDRC and IRB approval. Specify non-clinical safety studies required to support single microdose clinical studies 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 methods AMS (Accelerated Mass Spectrometry) - Need for isotope labeling (14C) for compounds being tested PET AMS & PET are valuable tools for: Microdosing Low radiation mass balance Metabolite profiling Absolute bioavailability Regulatory: Toxicology data

Advantages Reduced manufacturing requirements Reduced toxicologic requirements Demonstration 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: Advantages Provides 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 testing Range 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