Micro dosing

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

2. Synonyms • Microdosing • Microdose F • First In Human( FIH) studies • Phase O • Proof of concept studies

3. 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)

4. 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

5. 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?

6. 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

7. 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, safetyand tolerance studies that ordinarily initiate a clinical drugdevelopment program." • Used primarily for in-house decision making not for regulatory submission

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

9. 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 widetherapeutic window is expected • Target or biomarker modulationis anticipated at nontoxic doses and over short durations ofexposure (e.g., 7 days) • Target modulation is likelyto be determined with a relatively small sample size (10 to15 patients)

10. 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

11. 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

12. Types of Phase 0 Trial Designs • Phase O trial designs vary depending on the particular studyobjectives • Transition from preclinicalto clinical development is critical to the design of phase Otrials and requires close collaboration between laboratory,drug development, and clinical scientists.

13. Phase O trial Designs are designed • To Primarily show thatthe drug affects the target in human disease • To evaluate clinically the properties of two or more structurally similar analoguesdirected at the same molecular target • To develop novel imagingprobes or technologies to evaluate the biodistribution, bindingcharacteristics, and target effects of an agent in humans • To determine a statisticallysignificant, treatment-related change from baseline in a PKend point.

14. Enrollment of Patients in Phase 0 Trials • Non therapeutic nature of phase O trials • Important to ensure thatparticipation will not adversely affect a patient's eligibilityto participate in subsequent therapeutic trials or adverselydelay other therapy • Shorter washout periods, such as 2 weeks or less, areprobably sufficient

15. Ethical issues • Question- whether ethics itself has to formulatea new critique to account for the novel aspects of phase O trials. • Urgency-because the expectation is that the number of phase O trialsbeing conducted will only increase • The experiment has tobe scientifically valid, based on a reasonable hypothesis anda research methodology that can be expected to reach its statedend points. • Its like breaking new ethical ground by challenging the long-standingprinciple that the interests of human subjects always take precedenceover the interests of society(The National Bioethics AdvisoryCommission)

16. 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?

17. 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

18. 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.

19. Guidance and Acceptance of Microdose Techniques in Europe

20. 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

21. 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

22. 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 fasterand more efficiently

23. 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

24. 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

25. Microdosing: Limitations • ? Scheduling of drug development: Scale up of chemical synthesis on hold • Expensive and large equipment • Need to prove cost-effectiveness

26. Limitations in the Application of Phase 0 Trials • Not all agents are appropriatefor phase 0 testing • Range of resources requiredfor the preclinical and clinical aspects of phase O studies,particularly those evaluating target or biomarker effects, isnot available at most academic institutions • The non therapeuticnature of the trials makes recruitment difficult and third partypayers are not likely to cover the associated clinical carecosts • Well-organized system for biospecimen procurement and processingand an efficiently integrated and dedicated team of laboratoryand clinical investigators with expertise • Concept is notwidely accepted by industry because apparentlyonly a handful of companies have acknowledged doing exploratoryIND trials, and none had PD as a primary end point

27. Conclusion • Can greatlyimprove the efficiency and success of subsequent trials, particularlythose for the development of molecular targeted agents • Excellent opportunity to establish feasibilityand further refine target or biomarker assay methodology • Phase 0 trials do not replace phase I trials conductedunder a standard IND to establish dose-limiting toxicities anddefine a recommended phase II dose