Regulatory Framework for Phase I & Clinical Pharmacology Studies

1. Regulatory Framework for Phase I & Clinical Pharmacology Studies Funmilayo O. Ajayi, PhD, FCP, FIST Procter & Gamble Cincinnati, Ohio

2. Talk Overview • Background Information: • history of drug approval regulation • drug development paradigm • Pre-clinical Studies & Required Data for IND • IND Filing and Clinical Hold Issues • Regulatory Importance of PK and PK/PD Data • Sponsor-Agency Communication

3. Regulation of New Drug Development • < 1906 - No effective regulation of human drugs • 1906 - Drug removed from market only if adulterated or misbranded • 1938 - Requirement of evidence of safety of new drugs • 1962 - Requirement of evidence of safety & effectiveness • 1997 - FDA Modernization Act: enabled PDUFA • 2002 - Medical Device User Fee & Modernization Act • 2007 - FDA Amendments Act

4. Substantial Evidence of Effectiveness • “....Evidence consisting of adequate and well-controlled investigations, including clinical investigations, by qualified scientific experts, that proves the drug will have the effect claimed in its labeling....” Section 505 (d) Fed. Food, Drug & Cosmetic Act, 1962

5. The Drug & Cosmetic Act • Federal Food, Drug and Cosmetic Act: • Defines what new drugs are • States that a new drug must be the subject of an approved new drug application (NDA) • Food and Drug Administration (FDA): • Interprets and enforces the laws provided in the Act

6. Regulations & Guidance Documents • Code of Federal Regulations (21 CFR): • Written by the FDA to instruct and direct the public in how this law is to be applied • Outlines the general procedures and requirements that are binding on the FDA • Guidance Documents / Guidelines: • Less than regulations but provide detailed guidance for specific situations

8. Types of Preclinical Testing • Short Term Animal Studies (Acute): • Determine pharmacological action and toxicity • Long Term Animal Studies (Chronic): • Look for potential side effects that may result from long term use such as carcinogenicity • Look for reproductive effects

9. Species Selection • Data in two (2) Species is required • Why 2 Species? • Species differences in response • Rodent – almost always rat • Mouse has poorest clinical concordance • Non-rodent – dog, non-human primate • Considerations • Compound supply • Route of administration – e.g. mini-pig for dermal

10. Overview of Study Types • Safety Pharmacology - functional assessment of major systems • General Toxicology - target organs, “chronicity of the toxicity” • Developmental and Reproductive Toxicology - fertility and reproductive performance (Seg I) - embryo/fetal development (Seg II) - neonatal development (Seg III) • Genetic Toxicology - potential for cancer and heritable mutations • Carcinogenicity • Specialty Toxicology

11. Why Preclinical Testing? • Detect overt toxicity • Identify, describe and characterize hazards - reversible? - clinically monitorable? • Establish dose-response estimation of pharmacology & toxic effects • Assess drug distribution to organ systems • Identify metabolic, kinetic and elimination pathways • Assess carcinogenicity, reproductive toxicity and teratogenic potential

12. Dose Range Provide data for dose selection for definitive study Identify major target organs Lead selection Species selection Definitive Provide data for dose selection for FIH Establish NOEL and MTD Define toxicity over duration of study Provide TK data General Toxicology Data – How Used

13. NOEL and NOAEL

14. Required Duration of Repeated Dose Toxicity Studies to Support Phase I & II Trials

15. What is an IND? A submission through which a drug sponsor alerts the FDA of its intention to conduct clinical trials with an investigational drug Application seeking permission to do clinical trials in humans A request for exemption from the Federal laws that prohibits unapproved drugs from being shipped in interstate commerce

16. Types of INDs

17. IND Regulations/Guidances 21 Code of Federal Regulations, Section 312 1987 IND Rewrite 1995 Content and Format of Investigational New Drug Applications for Phase I Studies, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products 1997 ICH M3 Non-clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals

18. When to File an IND An IND is filed prior to initiation of clinical trials in humans if it is to evaluate a: New chemical entity New indication for marketed agent New route of administration New dosage level

19. Common Reasons for Clinical Holds The IND does not contain sufficient information for the FDA to assess risks to subjects Additional toxicology data is required - unexpected animal death or toxicity, or positive geno-toxicity Maximum human dose planned is not supported by toxicology data - e.g. low margin of safety CMC data is not sufficient or convincing Investigator is not qualified or ineligible Clinical Investigator’s Brochure is misleading, erroneous, or incomplete

20. Second Stage in New Drug Development • Involves three phases of clinical trials of the drug in humans: • Phase I, II & III

21. Clinical Trial - Phase I • Initial testing in humans • Normal volunteers or patients with or at risk for the target disease • Open-label, dose escalating, safety and tolerance PK studies • Healthy volunteers and patients • Intense level of monitoring • Flexibility in making dosage adjustments

22. Phase I & Clinical PharmacologyStudies R&D cost 800M -1.5B/drug NDA Discovery Phase I Market Preclinical Approval Phase III Phase II IND • Human Volunteer PK Profiles • Patient PK Profiles • PK/PD Models and Simulation • PopPK Studies • IVIVC Models In the 21st Century • Microsomes • CACO2 • Permeability • Solubility • Drug Interactions • Disease States • Special Pops • BE Studies

23. Regulations & A Few Guidance Documents • 21 CFR 320 • ICH Guidance Documents (15+) • EMEA Guidance Documents (30+) • General BA/BE Guidance • Population PK Guidance • Exposure/Response Guidance • USDA (Animal Welfare Act) • Good Laboratory Practices • BCS Guidance • IVIVC Guidance • SUPAC Guidance documents (IR, MR and SS) http://www.fda.gov/cder/guidance

24. General BA/BE Guidance • Intended to provide recommendations to sponsors planning to include BA and BE information for orally administered drug products in INDs, NDAs, ANDAs and supplements. • Also generally applicable to non-orally administered drug products when one relies on systemic exposure measures for BA/BE. * FDA Guidance: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations

25. PK/PD: Implication in New Formulations and/or New Doses of Approved Drugs* • Where blood levels ... are not very different, it may be possible to conclude ... is effective on the basis of pharmacokinetic data alone. • Even if blood levels are quite different, if there is a well-understood relationship between blood concentration and response (PK/PD), ..., it may be possible to conclude ... is effective on the basis of pharmacokinetic data without an additional clinical efficacy trial. *Guidance for Industry “Providing Clinical Evidence of Effectiveness for Human Drugs and Biological Products”, May 1998

26. Regulatory Support for Pharmacokinetics / Pharmacodynamic Data • FDAMA Sec. 115. Clinical investigations: • Support of one adequate and well-controlled clinical investigation by “confirmatory evidence” comprising PK or PK/PD

27. PK/PD - Why Bother? FDAMA, Sec. 115 Clinical Investigations CONGRESSIONAL COMMITTEE REPORTS* “confirmatory evidence” = “scientifically sound data from any investigation in the NDA that provides substantiation as to the safety and effectiveness of the new drug” • Confirmatory evidence =“consisting of earlier clinical trials, pharmacokinetic data, or other appropriate scientific studies” *House Commerce Committee, 10/7/97, and Committee on Disagreeing votes of the two Houses, 11/9/97

28. Regulatory Support for Pharmacokinetics FDA Modernization Act of 1997 (“FDAMA)” • Sec. 111. Pediatric studies of drugs • PK bridging studies to support use in pediatric population

29. Pharmacokinetics - Why Bother? Pediatric Labeling Regulations (21 CFR 201.56) “FDA may approve a drug for pediatric use based on …studies in adults, with other information supporting pediatric use …. Additional information supporting pediatric use must ordinarily include data on the pharmacokinetics of the drug in the pediatric population ….Other information, such as data on pharmacodynamic studies …..”

30. Attrition On The R&D Process ~100 Discovery Approaches 7,000,000 Compounds Screened Preclinical Pharmacology Preclinical Safety 1 - 2 Products Clinical Pharmacology & Safety Discovery Exploratory Development Full Development Phase I Phase II Phase III 0 15 10 5 Idea Drug 11 - 15 Years

31. CHANGING THE INDUSTRY/FDA INTERPHASE:A CRITICAL PATH OPPORTUNITY Target Validation Screening Lead Development Pre-Lead Lead First in Human-FDA dialogue Proof of Concept-FDA dialogue Full Development-FDA dialogue Molecular Sciences And Technologies Expanded Scope: • Exploratory IND • Microdosing • PK/PD • Biomarkers • Desired Human Exposure • Proof of Non-viability • Proof of Concept Pharmacology Experimental Medicine Clinical Development

32. Critical Path Agenda and Opportunities • Need for a paradigm shift to improve the efficiency of clinical drug development • Model-based drug development approaches are powerful tools to improve clinical drug development, regulatory guidance and the quality of NDA submissions • Model-based drug development such as: • drug and disease modeling • exposure-response modeling • Importance of FDA and academia to lead the widespread adoption of the tools and concepts in the pharmaceutical industry

33. Drug Model Trial Design Strategies Results Graphics Structure Schedule Endpoints • Drug • Disease • Patients Replications Statistical Analysis Subject Selection Compliance Dropout Interface to SAS, Etc. Modify Trial Design Modify Drug Model Drug/Disease Modeling and Clinical Trial Simulation: A Well-Established Strategy

34. Extensive PK Sparse PK Mixed Effects Modeling 0.20 0.15 Drug Concentration 0.10 0.05 Safety Efficacy 0.0 0 1 2 3 4 5 6 Time (h) Exposure Exposure Population Pharmacokinetic & Dynamic Modeling:A Fundamental Tool to Characterize E-R Relationships Choice of Dosage Regimen

35. Advanced Quantitative Modeling: Implication in Drug Development & Approval Process • Exposure vs. response (efficacy & safety) relationship in dose selection • Computer-assisted simulation of clinical trials to address study  design and data analysis issues • Population PK/PD data analysis to understand variability and to provide evidence for label claims • Dose adjustment in special populations (hepatic, renal, gender, age and drug interactions) • based on inter-subject variability and risk assessment

36. Sponsor-Regulatory Agency Communication Communication brings added value or benefits to the drug development process The goal has always been to find ways to achieve more frequent and more direct communication with reviewers. Also to understand the….1. What?2. When?3. How? 4. Why?

37. Communication: On What? • Questions during the drafting of study protocols • more likely to arise earlier than later in clinical development when input can be of high value (e.g., specific study) • Review of finalized, individual study protocols or reports • often occurs right before or after next study begins • it is important to know when this will add value during IND phase • Comments on overall clinical development program • could be of value & provide context for role of study in overall program

38. Communication: When? • Pre-IND • enables discussion of issues related to specific study design before protocol is finalized – e.g. dosing strategy, proposed clinical pharmacology program • EoP2A • focus on questions or issues related to key E/R parameters of interest, data analysis, dose-ranging and proposed study designs for phase 2B and 3 • discuss special more complex issues in overall clinical development strategy (e.g., QT studies, pharmacogenetic studies, drug interactions with transporters)

39. Communication: How? Formal meetings: desired feedback may be more urgent given the time to set up meetings

40. Communication: How? • Informal Meetings – e.g. teleconferences • policies regarding direct communication between reviewers and sponsors varies with medical division • most medical divisions want sponsor to go through project managers for specific review questions • rationale is that medical divisions are better able to keep track of decisions made - especially those that impact or influence efficacy/safety or CMC issues

41. Communication: Why? • Open, timely, exchange of ideas between Sponsor and regulatory agencies • Obtain Agency’s views on questions / issues • Opportunity for specific questions to be addressed - e.g., # of special population or interaction studies • Minimize regulatory decision surprises • Facilitates good review management principles

42. Effective Communication Strategy • Submit IND protocols for review at least 90 days before anticipated start of study • State in cover letter that review of protocol &/or study report is requested • Provide adequate information / data • facilitates review & response to Questions • Describe role of study in overall development program and/or potential regulatory outcomes (e.g., label claim)

43. Questions?