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
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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?
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What is Drug Development?
Lab
Development
Discovery
Basic
PreResearch Clinical
Clinical Testing
I
IND
II
III
IIIb IV
NDA
Commercial Market
Marketing
Product
Launch
Sales
SNDAs
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The Purpose of Drug Development
P.I.
From Lab to Label: The Outcome of Drug Development
is the Negotiated Language of the Prescribing Information
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What Disciplines Are Involved in Drug
Development?

Drug Discovery Scientists

Project Management

Pharmacologists

Financial Management

Toxicologists
Executive Management


Microbiologists


Regulatory Agencies
Biopharmaceuticists

Volunteers

Patients

Advocacy Groups

Investors

The Media

Chemists (Process, Engineers,
Organic, Analytical)

Clinicians

Biostatisticians

Information Professionals

Regulatory Affairs
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Drug Development Begins with the End in Mind:
Product Labeling
Development
Labeling
Lit
Searches
New
Drug
Pharmacology
Toxicology
Pharmacokinetics
Drug Metabolism
Clinical Efficacy
Clinical Safety
VISION
Description
Indication
Precautions
Warnings
Contraindications
Dosage /
Administration
How Supplied
Role of Regulatory Affairs in the Drug
Development Universe
FDA
Senior
Management
Clinical
Project Management
Regulatory
Affairs
Pharmacology
Info
Toxicology Professionals
Biopharmaceutics
Biostatistics
Basic Research
Regulatory Affairs is the Company’s Ambassador to FDA
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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)
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Functions of Regulation
 To protect patients from harmful
medical products
 To facilitate the availability of
beneficial medical products to
patients
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The legal framework for drug regulation in the
United States
CONGRESS
LAWS
REGULATIONS
FDA
GUIDELINES
INDUSTRY
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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)
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NDA (NME) Approval Time Has Decreased
Since PDUFA 1992
60
50
40
30
NDAs Approved
Time (months)
20
10
19
83
19
86
19
89
19
92
19
95
19
98
20
01
20
04
0
Source: FDA
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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)
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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 AntiInflammatory Drugs
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The Difference
REGULATIONS
(Credit: Steve Wilson, FDA)
GUIDELINES
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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.)
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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.
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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
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“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
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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
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“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
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Doing Clinical Trials in the U.S.
The Role of the IND
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The Investigational New Drug (IND) Application
as the Platform for Drug Development
Lab
Development
Discovery
Basic
PreResearch Clinical
Clinical Testing
I
STRATEGY
IND
II
III
IIIb IV
NDA
Commercial Market
Marketing
Product
Launch
Sales
SNDAs
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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.)
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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
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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
IND
Submitted
Chem
&
Mfg
NDA
Submitted
Mfg Scaleup
Synthesis &
Purification
Formulation Development
Animal
Studies
Short term Animal
Long term Animal
Phase 1
Clinical
Studies
Phase 2
Phase 3
PK Studies
Time
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IND Principal
Goals
Clinical Protocol
Subject must not be
exposed to
unnecessary
risks
SAFETY
CMC
CMC procedures
ensure that the drug is
adequately
reproducible and
stable
Preclinical/Other Data
Adequate evidence that
the drug is “reasonably”
safe for administration
to humans
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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
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The Phases of Clinical Development
Phase 1
• 20-80 Subjects
• Patients or Normal Volunteers
• Metabolism/Pharmacologic
Actions
• Side Effects with Increasing Dose
• Early Efficacy Information
• ADME
Phase 3
• Hundreds to Thousands of
Subjects
• Patients with Disease Under
Study
• Well Controlled Studies
• Efficacy and Safety
Phase 2
• Several Hundred Subjects
• Patients with Disease Under
Study
• Well Controlled Studies
• Efficacy and Safety
Phase 4
• Post-NDA Approval
• Epidemiology Studies
• Marketing Studies
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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.
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The Common Technical Document Format for the
NDA
Module 1
Not Part of the CTD
Regional
Administrative
Information
1.1 Submission ToC
CTD Table of Contents
2.1
CTD Introduction
2.2
Module
2
Quality
Overall
Summary
2.3
Nonclinical
Overview
2.4
Nonclinical Written
and Tabulated
Summaries
2.6
Clinical
Overview
2.5
Clinical
Summary
2.7
Module 3
Module 4
Module 5
Quality
3
3.1 ToC
Nonclinical
Study Reports
4
4.1 ToC
Clinical Study Reports
5
5.1 ToC
CTD
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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)
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Interactions with FDA
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Meetings with FDA During Early Drug Development
Can Shorten NDA Review and Approval Time
NDA Review Time (mos)
35
30
25
20
No Meeting
Meeting
15
10
5
0
PreIND
Phase Phase End of Phase
1
2
Phase
3
2
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
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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
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Key Ingredients of Successful Meetings
Science/
Medicine
Information
Professionals
Regulatory
Good
Knowledge
Mtg
Meeting Process
Management
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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
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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
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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 !
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FDA Meetings During Drug Development
Pre-IND
EOPII
Pre-NDA
AdComm
Label
Lab
Development
Discovery
Basic
PreResearch Clinical
Clinical Testing
I
IND
II
III
IIIb IV
NDA
Commercial Market
Marketing
Product
Launch
Sales
SNDAs
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Types of FDA Meetings
TYPE
PURPOSE
Pre-IND
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
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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.
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Five Key Success Factors
FACTOR
1. Request Letter
2. Information Package
3. Preparation
4. Meeting Management
5. Negotiation Skills
DRIVERS OF SUCCESS

Clarity about the purpose of the meeting

Clarity about the sponsor’s position and questions


Sufficient detail to justify the meeting

Reader-friendly, well-organized


Necessary and sufficient background information

Anticipation of objections


Reasoned alternatives

The right experts in attendance
Concise, informative, logical
Thorough knowledge of the data
Sponsor Team Leader
 Listen, clarify, respond / propose
 Professionalism
 Know when to push back, when to concede
 Time out: stop, reflect, return another day
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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
Center Director
Office of Compliance
Inspectors
Office of New Products
Division of NO !
Division of
Endless Questions
(Dr. Elengold, CBER)
Division of YES
- 48 -
FDA View of Pharmaceutical Company
CEO
Marketing
R&D
(Dr. Elengold, CBER)
Manufacturing
Legal
QA
Regulatory
Affairs
- 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
Any Questions?
Thank you!