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
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)
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!