Phase_0_trials/Microdosing studies_by_DR_SURYA_K.pptx

This presentation, “Phase 0 Trials by Dr. Surya K,” is designed to offer a clear, structured, and professional overview of Phase 0 clinical trials—also known as Exploratory Investigational New Drug (eIND) studies or “humanized preclinical trials.” It is especially helpful for medical students, postgraduates, researchers, pharmacology educators, and professionals involved in clinical research, drug development, and regulatory affairs.

Why This Presentation?
Before any drug reaches the public, it must pass through years of rigorous testing. However, the earliest stage—Phase 0 trials—is often confusing or overlooked. This presentation explains why Phase 0 is important, how it differs from traditional Phase I–IV trials, and how it helps in making faster, safer, and more ethical decisions in drug development. As a part of my continuing research and academic work in pharmacovigility, clinical trials, and psychopharmacology, I wanted to simplify this concept for learners and young researchers. I am Dr. Surya K, actively involved in clinical research, pharmacology education, and ongoing studies on psychosis and pharmacovigilance at King George’s Medical University (KGMU), Lucknow. This presentation is part of my academic dedication to simplify complex clinical trial concepts for students, postgraduates, and healthcare professionals.

1. PHASE “0” TRIALS/MICRODOSING STUDIES Presenter: Dr. SURYA K (JR- 3) Peer Support: Dr. Pranav US (JR-3) Department of Pharmacology and Therapeutics King George’s Medical University, Lucknow, UP, India- 226003 Email: drsuryakgmu @gmail.com

2. Abbreviations IND: Investigational New Drug PK: Pharmacokinetics PD: Pharmacodynamics NOAEL: No Observed Adverse Effect Level NDA: New Drug Application FDA: Food and Drug Administration AMS: Automated Mass Spectrometry PET: Positron Emission Tomography 12-09-2025 Dr. SURYA K 2

3. Contents Introduction Goals & Objectives Features Types of phase 0 trials Designing a microdosing Advantages Limitations 12-09-2025 2 Dr. SURYA K

4. Specific learning objectives By the end of this teaching learning session, the co learners shall be able to Explain the concept and purpose of Phase 0 trials Discuss goals and objectives of Phase 0 trials What are the different types of phase 0 trials Discuss the advantages, and limitations Explain about ethical considerations in this trial 12-09-2025 4 Dr. SURYA K

5. Introduction Drug discovery is process, which aims at identifying a compound therapeutically useful in terms of preventing, treating and curing a disease Drug discovery & development is a long, complex, and expensive activity Requires 10-15 years of sustained effort & $1.5 billion dollars Nearly one-third of investigational new drugs (INDs) fail in phase 1 trials due to poor PK-PD, safety issues 12-09-2025 Dr. SURYA K 5

6. 12-09-2025 Dr. SURYA K 6 If phase 1 fails, human volunteers are exposed unnecessarily and large numbers of animals are used Phase 0 trials were introduced to address metabolism and PK-PD, safety issues early

7. DRUG DISCOVERY PRECLINICAL PHASE CLINICAL TRIAL PHASES PHASE I PHASE II PHASE III REGULATORY APPROVAL POST MARKETING SURVEILLANCE INDA NDA New drug development Time : 10-15 years PHASE 0

8. Phase 0 trials Phase 0 trials, originated in 2006, were introduced by the U.S. FDA guidance to assess the PK/PD profile First literature data appeared in 2003 Defined as less than 1/100 th of the active pharmacological doses, with maximum single dose of ≤100 micrograms Also called Microdosing studies or Exploratory Investigational New Drug studies It involves limited human exposure & has no therapeutic/diagnostic intent 12-09-2025 Dr. SURYA K 8

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10. Purpose Assist in GO versus NO-GO decision making earlier in drug development Uses relevant human models instead of inconsistent animal data It is a recent designation for exploratory first-in-human trials 12-09-2025 Dr. SURYA K 10

11. Goals Provides human PK-PD relationship data Evaluate human PK (e.g., bioavailability) for selecting promising compounds Early elimination of compounds with poor PK or PD properties such as lack of target effect or rapid clearance 12-09-2025 Dr. SURYA K 11

12. Objectives Evaluate and select best lead compound from multiple preclinical compounds Confirm whether mechanism of action defined in non-clinical models is achievable in humans Refine and validate biomarker assays Evaluate a novel imaging probe in humans by assessing its distribution, targets 12-09-2025 Dr. SURYA K 12

13. Features Conducted before phase 1 studies Conducted in limited number of subjects (10-15) Limited drug exposure (< 7 days) Involves very small doses Helps confirm endpoints like bioavailability, metabolism & PD assessments 12-09-2025 Dr. SURYA K 13

14. 12-09-2025 Dr. SURYA K 14 No therapeutic or diagnostic intent Reduce attrition at phase 1 Entire trial timeline: usually completed in ≤ 6 months Enable faster and cost-effective path to early clinical development

15. Types 1. Pharmacokinetics (pk) or imaging Aim: Evaluate human biodistribution and target binding using sensitive imaging & microdoses Preclinical requirement: Toxicology studies must show that a dose 100× the proposed human dose does not cause adverse effects 12-09-2025 Dr. SURYA K 15

16. 12-09-2025 Dr. SURYA K 16 2. Pharmacologically relevant doses Aim: Evaluate human PK of 2 or more analogues to help select the lead agent Preclinical requirement: Must establish NOAEL in a 2-week toxicology study 3. Pharmacodynamic (PD) end-point studies Aim: Evaluate the new molecular entity modulates the intended target in humans Preclinical requirement : Generally short-term, modified toxicity/safety studies in 2 species

17. Designing a microdosing Suitable compounds must fulfill prerequisites like: Primarily PD endpoint important for development Detectable, measurable and validated biomarker/target present Wide therapeutic window Target/biomarker modulation occurs in microdose within 7 days 12-09-2025 Dr. SURYA K 17

18. Procedure 1. Drug Compound Selection 2. Regulatory Toxicology – 14 days single dose study 3. Regulatory Submission 4. Decide dosing schedule & Volunteer Selection 5. Bioanalytical Methods – to define biomarkers 12-09-2025 Dr. SURYA K 18

19. 12-09-2025 Dr. SURYA K 19 6. Drug Manufacturing & Labelling Prepare microdose formulation with GMP standards 7. Dosing & Monitoring 8. Collect & Analyze Samples by bioanalytical Methods 9. Data Analysis & Reporting 10. Decision making

20. Advantages Early selection of promising compounds Avoid unnecessary participants & animals exposure to unattractive compounds Can be done in vulnerable patients  Drug-drug interaction assessment Saves costs and time by eliminating poor candidates earlier Overall acceleration of drug development process 12-09-2025 Dr. SURYA K 20

21. Limitations Risk of false negative results lead to discontinuation of promising candidates Caution needed with drugs having nonlinear kinetics Developing radioisotopes for AMS/PET is costly No therapeutic or diagnostic benefit to participants Difficulty in motivating volunteers for non-beneficial trials Limited microdosing study database 12-09-2025 Dr. SURYA K 21

22. Regulatory guidelines Position paper from European Medicines Agency (EMA) in 2004 Guidelines from FDA in 2006 ICH M3 International Guideline in 2009 India has no formal Phase 0/microdosing guidelines; therefore, researchers follow ICH/FDA/EMA guidance 12-09-2025 Dr. SURYA K 22

23. Summary Introduction Goals & Objectives Types of phase 0 trials Designing a microdosing Advantages Limitations 12-09-2025 Dr. SURYA K 23

24. Further reading Phases of Clinical Trials New Drug and Clinical Trials Rules,2019 High-Throughput Screening (HTS) 12-09-2025 Dr. SURYA K 24

25. Specific learning objectives achieved By the end of this teaching learning session, co-learners are now able to Explain the concept and purpose of Phase 0 trials Identify goals and features of Phase 0 trials What are the different types of phase 0 trials Discuss the advantages, and limitations Explain about ethical considerations in this trial 12-09-2025 25 Dr. SURYA K

26. Questions 1. What is the primary purpose of Phase 0 clinical trials? A) To test therapeutic dosage B) To evaluate pharmacokinetics and pharmacodynamics early C) To assess long-term safety D) To monitor post-marketing effects 12-09-2025 Dr. SURYA K 26

27. 12-09-2025 Dr. SURYA K 27 2. The maximum single dose used in Phase 0 trials is: A) ≤ 100 mg B) ≤ 100 micrograms C) ≤ 1 gram D) ≤ 10 milligrams

28. 12-09-2025 Dr. SURYA K 28 3. How many subjects are usually enrolled in Phase 0 trials? A) 50-100 B) 100-200 C) 10-15 D) More than 200

29. 12-09-2025 Dr. SURYA K 29 4. Which of the following is NOT a feature of Phase 0 trials? A) Limited drug exposure B) Therapeutic & diagnostic intent C) Short duration (less than 7 days) D) Human PK/PD evaluation early

30. 12-09-2025 Dr. SURYA K 30 5.Phase 0 clinical trials are typically completed within: A) 1 month B) 3 months C) 6 months D) 12 months

31. 12-09-2025 Dr. SURYA K 31 6. One advantage of Phase 0 trials is: A) Extensive therapeutic benefit to participants B) Saves costs, time & speeds up drug development C) Large scale safety evaluation D) Replace Phase 1 trials

32. References Sougata Sarkar, Vartika Srivastava, Manjushree Mohanty, Postgraduate Pharmacology, 1st edition, phase 0 trials/Microdosing, page no: 204 to 208 SK Gupta, New Drug Development, Drug Discovery and Clinical Research, 1st edition, page no: 27 to 34 Vishal Bansal, Clinical Research Fundamentals & Practices, 1st edition, phases of clinical trials, chapter 3, page no: 34 to 37 Rituparna Maiti, Postgraduate Topics in Pharmacology, 3rd Edition, clinical trial: phases, chapter 1, page no- 3 to 5 12-09-2025 Dr. SURYA K 32

33. 12-09-2025 Dr. SURYA K 33 AUDIENCE QUESTIONS

34. THANK YOU 12-09-2025 Dr. SURYA K 34