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Corporate VP and General Manager

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Presentation on theme: "Corporate VP and General Manager"— Presentation transcript:

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

2 to 250 million Americans -- What kind of information
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 What is Drug Development?
Lab Discovery Commercial Market Basic Research Pre-Clinical Clinical Testing Marketing I II III IIIb IV 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 What Disciplines Are Involved in Drug Development?
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

6 Drug Development Begins with the End in Mind: Product 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

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) REGULATIONS GUIDELINES

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 ?
Test the 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 standards throughout

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

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

27 Formulation Development
IND Submitted NDA Submitted FDA FDA Chem & Mfg Synthesis & Purification Mfg Scaleup Formulation Development Short term Animal Animal Studies Long term Animal Phase 1 Clinical Studies Phase 2 This slide summarizes these steps in drug development in the context of a U.S. IND. Phase 3 PK Studies Time

28 SAFETY 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 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 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 3 Quality 3 3.1 ToC Module 4 Nonclinical Study Reports 4 4.1 ToC Module 5 Clinical Study Reports 5 5.1 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 Key Ingredients of Successful Meetings
Good Mtg Science/ Medicine Regulatory Knowledge Meeting Process Management 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 FDA Meetings During Drug Development
Pre-IND EOPII Pre-NDA AdComm Label Development Lab Discovery Commercial Market Basic Research Pre-Clinical Clinical Testing Marketing I II III IIIb IV Product Launch Sales IND NDA SNDAs

43 Types of FDA Meetings PURPOSE TYPE Pre-IND End of Phase I (rare)
Verify acceptability End of Phase I (rare) Confirm early safety End of Phase II Confirm early efficacy; agree Phase III Pre-NDA Outline NDA approach Ad-hoc Technical Meetings CMC, Tox, Clinical issues Advisory Committee Meetings Address medical establishment Teleconferences Ad hoc Labeling Meeting Negotiate final labeling

44 FDA Has Provided Guidance for Industry Meetings
Guidance for Industry: Formal Meetings With Sponsors and Applicants for PDUFA Products 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 ), (2) certain end of Phase 1meetings (21 CFR ), (3) end of Phase 2/pre-Phase 3 meetings (21 CFR ), and (4) pre-NDA/BLA meetings (21 CFR ). 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
DRIVERS OF SUCCESS 1. Request Letter Clarity about the purpose of the meeting Clarity about the sponsor’s position and questions Sufficient detail to justify the meeting 2. Information Package Concise, informative, logical Reader-friendly, well-organized Necessary and sufficient background information 3. Preparation Thorough knowledge of the data Anticipation of objections Reasoned alternatives 4. Meeting Management Sponsor Team Leader The right experts in attendance Listen, clarify, respond / propose 5. Negotiation Skills Professionalism Know when to push back, when to concede Time out: stop, reflect, return another day

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!

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