U.S. Regulation of Drug Development and the Role of The Information Professional

1. U.S. Regulation of Drug Development and the Role of The Information Professional Alberto Grignolo, Ph.D. Corporate VP and General Manager PAREXEL Consulting Alberto.Grignolo@PAREXEL.com

2. Think about it . . . If you had to sign a letter authorizing the availability of a new medicine to 250 million Americans -- What kind of information (and how much of it) would you want to have about the drug?

3. I II III IIIb IV What is Drug Development? Development Commercial Lab Discovery Market Basic Research Pre-Clinical Clinical Testing Marketing Product Launch Sales IND NDA SNDAs

4. The Purpose of Drug Development P.I. From Lab to Label: The Outcome of Drug Development is the Negotiated Language of the Prescribing Information

5. Drug Discovery Scientists Pharmacologists Toxicologists Microbiologists Biopharmaceuticists Chemists (Process, Engineers, Organic, Analytical) Clinicians Biostatisticians Information Professionals Regulatory Affairs Project Management Financial Management Executive Management Regulatory Agencies Volunteers Patients Advocacy Groups Investors The Media What Disciplines Are Involved in Drug Development?

6. Drug Development Begins with the End in Mind: Product Labeling Development Labeling Lit Searches Description Indication Precautions Warnings Contraindications Dosage / Administration How Supplied Pharmacology Toxicology Pharmacokinetics Drug Metabolism Clinical Efficacy Clinical Safety New Drug VISION

7. Role of Regulatory Affairs in the Drug Development Universe FDA Senior Management Project Management Regulatory Affairs Biopharmaceutics Clinical Biostatistics Pharmacology Info Professionals Toxicology Basic Research Regulatory Affairs is the Company’s Ambassador to FDA

8. The Regulation of Drug Development • In the United States, the entire process of drug development and commercialization is regulated • (except the price of the drug, but . . . just wait)

9. Functions of Regulation • To protect patients from harmful medical products • To facilitate the availability of beneficial medical products to patients

10. The legal framework for drug regulation in the United States CONGRESS LAWS REGULATIONS FDA GUIDELINES INDUSTRY

11. Definitions • Laws: legislation passed by the United States Congress and signed by the President • Examples: • FDCA (Food Drug and Cosmetic Act, 1938) • PDUFA (Prescription Drugs User Fee Act, 1992, 1997, 2002) • FDAMA (FDA Modernization Act, 1997)

12. NDA (NME) Approval Time Has Decreased Since PDUFA 1992 Source: FDA

13. Definitions • Regulations: rules issues by FDA consistently with Laws, published in the Federal Register and contained in Code of Federal Regulations (CFR) • Examples • INDs: 21 CFR 312 • NDAs: 21 CFR 314 • IRB and Informed Consent (21 CFR 50 and 56)

14. Definitions • Guidelines: “informal” documents issued by FDA to clarify requirements; often specific to therapeutic areas or technical disciplines • Examples: • Guidelines on Drug Stability Testing • Guideline on How to Develop Anti-Inflammatory Drugs

15. The Difference (Credit: Steve Wilson, FDA) GUIDELINES REGULATIONS

16. Proactive Information Needs • New regulations (Federal Register) • Proposed, draft and final guidances (Federal Register, What’s New in CDER and CBER) • Advisory Committee meeting announcements (Federal Register) • Industry news (journals, newspapers) • Drug development process research (Tufts CSDD, IoM, etc.)

17. Fundamental Principle • No drug can be marketed in the United States until “substantial evidence” of its quality, safety and effectiveness has been provided to FDA’s satisfaction.

18. Some Definitions • Quality: the characteristics of the drug, including its manufacturing • Safety: the relative risk of harm • Effectiveness: the benefit provided to the patient • Risk/Benefit Ratio: the degree to which risk is acceptable, given the amount of benefit provided to the patient

19. “Substantial Evidence”: What Is It ? • Quality: tight procedures, reproducibility of manufacturing, specifications, pass FDA inspection • Safety: low risk demonstrated in tests on animals and patients • Effectiveness: benefit demonstrated in tests in animals and patients

20. Substantial Evidence: How Do We Get It ? • Testthe product in animals and patients; see if it works and if it does any harm • Use “controlled conditions of testing” to eliminate the possibility that test results are wrong • Apply rigorous scientific, medical and regulatory standardsthroughout

21. “FDA’s Satisfaction”: How Do We Know What FDA Wants ? • Regulations state what must be done, in general • Guidelines provide advice on what is required for specific products • Meetings: very specific technical discussions and negotiations on individual products • Correspondence: technical negotiations on very fine points

22. Doing Clinical Trials in the U.S. The Role of the IND

23. I II III IIIb IV The Investigational New Drug (IND) Application as the Platform for Drug Development Development Commercial Lab Discovery Market Basic Research Pre-Clinical Clinical Testing Marketing Product Launch Sales IND NDA SNDAs STRATEGY

24. Information Needs for Regulatory Strategy • Identify similar drugs/treatments for specific indications • Obtain regulatory approval documents (EPARs, FDA Approval Packages/SBAs) • Identify all relevant guidance documents, both regulatory (EMEA, FDA) and medical (ASCO, etc.)

25. Information Needs for Clinical Development Strategy • Define market size for indication, including by class of drugs • Incidence & prevalence of indications in various countries to develop strategy for selection of patient groups and trial locations re: proof-of-concept studies • Identify competing products in development (pipeline) • Literature search to identify pivotal clinical trials re: standard trial protocol examples

26. Why do we need an IND? IND (Investigational New Drug Application) is an exemption from the law that prohibits interstate shipment of unapproved drugs An IND is required in order to conduct clinical trials in the United States

27. IND Submitted NDA Submitted Mfg Scaleup Phase 1 Synthesis & Purification Short term Animal Phase 2 Long term Animal PK Studies Formulation Development FDA Phase 3 FDA Chem & Mfg Animal Studies Clinical Studies Time

28. IND Principal Goals Clinical Protocol Subject must not be exposed to unnecessary risks SAFETY Preclinical/Other Data Adequate evidence that the drug is “reasonably” safe for administration to humans CMC CMC procedures ensure that the drug is adequately reproducible and stable

29. Information Needs for INDs • Safety, pharmacokinetics, and toxicity of study drug or drugs similar to study drug in animals and humans – to provide evidence that drug is “reasonably” safe for administration to humans • Safety and efficacy of a class of drugs via a specific administration (IV, oral, etc.) in specific indications to justify a protocol dose selection

30. The Phases of Clinical Development Phase 1 Phase 2 • 20-80 Subjects • Patients or Normal Volunteers • Metabolism/Pharmacologic Actions • Side Effects with Increasing Dose • Early Efficacy Information • ADME • Several Hundred Subjects • Patients with Disease Under Study • Well Controlled Studies • Efficacy and Safety Phase 3 Phase 4 • Hundreds to Thousands of Subjects • Patients with Disease Under Study • Well Controlled Studies • Efficacy and Safety • Post-NDA Approval • Epidemiology Studies • Marketing Studies

31. The New Drug Application (NDA) The vehicle through which sponsors formally request that the FDA approve a new pharmaceutical for marketing in the US, on the basis of demonstrated quality, safety and efficacy.

32. The Common Technical Document Format for the NDA Not Part of the CTD Module 1 Regional Administrative Information 1.1 Submission ToC CTD Table of Contents 2.1 CTD Introduction 2.2 Module 2 Nonclinical Overview 2.4 Clinical Overview 2.5 Quality Overall Summary 2.3 CTD Nonclinical Written and Tabulated Summaries 2.6 Clinical Summary 2.7 Module 5 Clinical Study Reports 5 5.1 ToC Module 4 Nonclinical Study Reports 4 4.1 ToC Module 3 Quality 3 3.1 ToC

33. Information Needs for NDA Submission and Beyond • Literature search for safety and efficacy in humans of study drug in comparable indications, administrations, or dosages – clinical trials, review articles, case studies, etc. • Literature search on all published studies for specific drug and indication for 505(b)(2) submissions (“paper” NDAs) • After NDA approval, the obligation to report drug safety information from patients and/or additional studies grows exponentially and is a significant information management challenge (pharmacovigilance)

34. Interactions with FDA

35. Meetings with FDA During Early Drug Development Can Shorten NDA Review and Approval Time NDA Review Time (mos) Source: DiMasi and Manocchia, DIA Journal 1997

36. Meeting Regularly with FDA is a Success Factor in Drug Development • Maintain ongoing relationship • Avoid misunderstandings • Communicate new data • Highlight and jointly resolve problems before they become too large • Anticipate difficulties • Monitor changes in FDA attitude or expectations of data • Avoid surprising each other • Accelerate development process • FDA Center for Drugs holds >1000 industry meetings every year

37. Regulatory Approval is Earned Gradually, Not in a “Final and Glorious Battle” with FDA • Planning for the Target Labeling early in development • Thorough development vision and plans • Ongoing communication with FDA: Build Trust • Data-driven development plan revisions • Strong project management on both sides • Learn from mistakes and take timely corrective actions in agreement with FDA

38. Good Mtg Regulatory Knowledge Science/ Medicine Meeting Process Management Key Ingredients of Successful Meetings Information Professionals

39. Success Factor No. 1: Science and Medicine • FDA decision-making is driven by data • FDA relies on internal reviewers and external experts to review data and make decisions • FDA decisions can change based on changes in science, medical knowledge and medical practice • If no data, then no positive FDA decision • Good science, good medicine and good study designs are keys to success

40. Success Factor No. 2: Regulatory Knowledge • Company representatives must know the rules (regulations, guidelines) • Regulatory precedents (previous FDA decisions on similar issues) are important • It is sometimes possible to “push” the FDA into a dialogue (e.g. post-approval commitments; generic biologics) • Being well-prepared is key

41. Success Factor No. 3: Meeting Process Management • FDA meetings must be planned and managed in a very specific way • There is a defined process for FDA meetings • Preparation and documentation are essential • Rehearsals are important for the theater … and they are important for FDA meetings too !

42. I II III IIIb IV FDA Meetings During Drug Development Pre-IND EOPII Pre-NDA AdComm Label Development Commercial Lab Discovery Market Basic Research Pre-Clinical Clinical Testing Marketing Product Launch Sales IND NDA SNDAs

43. Types of FDA Meetings

44. FDA Has Provided Guidance for Industry Meetings • Guidance for Industry: Formal Meetings With Sponsors and Applicants for PDUFA Products http://www.fda.gov/cder/guidance/2125fnl.pdf • Type A Meeting:immediately necessary for an otherwise stalled drug development program to proceed (i.e., a critical path meeting). Type A meetings generally will be reserved for dispute resolution meetings, meetings to discuss clinical holds, and special protocol assessment meetings that are requested by sponsors after FDA's evaluation of protocols in assessment letters.Scheduled within 30 days of sponsor’s request. • Type B Meeting: (1) pre-IND meetings (21 CFR 312.82), (2) certain end of Phase 1meetings (21 CFR 312.82), (3) end of Phase 2/pre-Phase 3 meetings (21 CFR 312.47), and (4) pre-NDA/BLA meetings (21 CFR 312.47). Scheduled within 60 days of sponsor’s request. • Type C Meeting: any meeting other than a Type A or Type B meeting. Scheduled within 75 days of sponsor’s request.

45. Five Key Success Factors

46. Examples of Information Needs re: Meetings with FDA (pre- and post-submission) • Background on FDA Reviewers • Literature search on specific drug combinations, incidence of adverse events, etc. re: safety concerns • Literature search on drug metabolism and toxicity to respond to concerns over dosing studies

47. Industry View of FDA (Dr. Elengold, CBER)

48. FDA View of Pharmaceutical Company (Dr. Elengold, CBER)

49. Conclusions • The FDA’s regulation of drug development is structured, logical, science-based, data-driven and “workable” • In practice, every drug is developed “to the beat of its own drum”, with a skillful mix of science, information and diplomatic art • Information Professionals play a key role in the drug development process and post-approval pharmacovigilance obligations by providing access to background, data, precedents and adverse event tracking to help meet today’s regulatory and patient care challenges

50. Any Questions? Thank you!