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 -

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?

Think about it . . .

- 3 -

What is Drug Development?

Discovery Development Commercial

ProductLaunch

SalesI II III IIIb IV

Basic Research

Pre-Clinical

Clinical Testing Marketing

IND NDA

Lab Market

SNDAs

- 4 -

The Purpose of Drug Development

From Lab to Label: The Outcome of Drug Development is the Negotiated Language of the Prescribing Information

P.I.

- 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

New Drug

Labeling

DescriptionIndicationPrecautionsWarningsContraindicationsDosage / AdministrationHow Supplied

Development

PharmacologyToxicologyPharmacokineticsDrug MetabolismClinical EfficacyClinical Safety

VISION

Lit Searches

- 7 -

Role of Regulatory Affairs in the Drug Development Universe

FDA

Clinical

Pharmacology

Toxicology Basic Research

Biostatistics

Biopharmaceutics

SeniorManagement

Project Management

RegulatoryAffairs

Regulatory Affairs is the Company’s Ambassador to FDA

InfoProfessionals

- 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

LAWS

REGULATIONS

GUIDELINES

CONGRESS

FDA

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

0

10

20

30

40

50

60

NDAs Approved

Time (months)

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 -

REGULATIONS GUIDELINES

The Difference(Credit: Steve Wilson, FDA)

- 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 -

The Role of the IND

Doing Clinical Trials in the U.S.

- 23 -

The Investigational New Drug (IND) Application as the Platform for Drug Development

Discovery Development Commercial

ProductLaunch

SalesI II III IIIb IV

Basic Research

Pre-Clinical

Clinical Testing Marketing

IND NDA

Lab Market

SNDAsSTRATEGY

- 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 -INDSubmitted

NDASubmitted

Time

Synthesis & Purification

Formulation Development

Short term Animal

Long term Animal

Phase 1

Phase 2

Phase 3

Mfg Scaleup

ClinicalStudies

AnimalStudies

Chem&

Mfg

PK Studies

- 28 -

Clinical ProtocolSubject must not be

exposed to unnecessary

risks

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

IND Principal Goals

SAFETY

- 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

CTD

Module 1Regional

AdministrativeInformation

1.1 Submission ToC

Module 3Quality

33.1 ToC

Module 4Nonclinical

Study Reports4

4.1 ToC

Module 5Clinical Study

Reports5

5.1 ToC

QualityOverall

Summary2.3

Nonclinical Overview

2.4

Nonclinical Written and Tabulated

Summaries2.6

Clinical Summary

2.7

ClinicalOverview

2.5

Module 2

Not Part of the CTD

CTD Table of Contents

2.1

CTD Introduction

2.2

- 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

0

5

10

15

20

25

30

35

Pre-IND

Phase1

Phase2

End ofPhase

2

Phase3

No Meeting

Meeting

Source: DiMasi and Manocchia, DIA Journal 1997

ND

A R

evie

w T

ime

(mo

s)

- 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 -

GoodMtg

Science/Medicine

RegulatoryKnowledge

Meeting ProcessManagement

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 -

FDA Meetings During Drug Development

Discovery Development Commercial

ProductLaunch

SalesI II III IIIb IV

Basic Research

Pre-Clinical

Clinical Testing Marketing

IND NDA

Lab Market

SNDAs

Pre-IND EOPII Pre-NDA AdCommLabel

- 43 -

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

- 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

FACTOR 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

Inspectors

O ffice of Com plianceD ivision of N O !

D ivision ofEndless Q uestions

D ivis ion o f YES

O ffice of N ew Products

C enter D irector

(Dr. Elengold, CBER)

- 48 -

(Dr. Elengold, CBER)

FDA View of Pharmaceutical Company

R & D M an ufa ctu r ing

M arketingQ A R eg u la to ry

A ffa irs

Legal

CEO

- 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

Thank you!

Any Questions?