FDA Regulatory Affairs: A Guide for Prescription Drugs, Medical Devices, and Biologics

342 Pages·2003·12.6 MB·English

by  Douglas J. Pisano

FDA
REGULATORY
AFFAIRS
A Guide for Prescription Drugs,
Medical Devices, and Biologics
E
DITED BY
Douglas J. Pisano
David Mantus
CRC PR ESS
Boca Raton London New York Washington, D.C.
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Library of Congress Cataloging-in-Publication Data
FDA regulatory affairs : a guide for prescription drugs, medical devices, and biologics /
edited by Douglas J. Pisano, David Mantus.
p. cm.
Includes bibliographical references and index.
ISBN 1-58716-007-2
1. Drug development—United States. 2. United States Food and Drug
Administration—Rules and practice. 3. Pharmaceutical industry—United States. I. Pisano,
Douglas J. II. Mantus, David.
RM301.25.F37 2003
615¢.19¢00973—dc22 2003055779
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Preface
This book is a roadmap to the FDA, and drug, biologic, and medical device
development. It is written in plain English with an emphasis on easy access
to understanding how this agency operates with respect to practical aspects
of U.S. product approval. It is meant to be a concise reference offering current,
real-time information. It has been written as a handy reference to be used
by students, staff, and professionals at corporations, organizations, and
schools and colleges across the United States who are in need of a simple,
concise text from which to learn and teach. The topics are covered in a simple
and concise format. It is a compilation and commentary of selected laws and
regulations pertaining to the development and approval of drugs, biologics,
and medical devices in the United States. It is not intended to take the place
of an actual reading of the laws of the United States of America or the
regulations of the United States Food and Drug Administration, its agencies,
or any body that regulates the development or approval of drugs, biologics,
and medical devices in the United States.
Douglas J. Pisano, Ph.D., R.Ph.
Dean, School of Pharmacy – Worcester
Director, M.S. Degree Program in Regulatory Affairs and Health Policy
Massachusetts College of Pharmacy and Health Sciences
Worcester, MA
David Mantus, Ph.D.
Adjunct Assistant Professor
M.S. Degree Program in Regulatory Affairs and Health Policy
Massachusetts College of Pharmacy and Health Sciences
Vice President, Regulatory Affairs
Sention, Inc.
Providence, RI
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Editors
Douglas J. Pisano is an Associate Professor of Pharmacy Administration and
the dean of the newly established Massachusetts College of Pharmacy and
Health Sciences, Worcester Campus. The mission of the Worcester Campus
is to educate future pharmacists to be advanced level clinical practitioners
with special emphasis on community practice.
In addition, he serves as the Director of the Master of Science Degree
Program in Regulatory Affairs and Health Policy at the Boston campus of
the college. Since the Fall of 1984, he has maintained a full-time faculty
appointment and is a member of the graduate faculty.
Dr. Pisano earned a Bachelor of Science degree in Pharmacy from the
Massachusetts College of Pharmacy and Health Sciences, and state licensure
in 1981. He earned his Master of Science degree in Public Policy/Public
Affairs from the John W. McCormack Institute, University of Massachusetts
at Boston in 1989, and Doctor of Philosophy degree in Law, Policy, and
Society from Northeastern University in 1997.
His graduate and undergraduate teaching responsibilities include required
courses in pharmacy law, FDA regulation, pharmacy management, and
health policy. In 1999, Dr. Pisano was the recipient of the Trustee’s Award
for Teaching Excellence. In 2000, he received the Special Recognition Award
for Increasing Understanding of Regulatory Affairs from the Regulatory
Affairs Professionals Society.
Professor Pisano has numerous professional and peer-reviewed publica-
tions to his credit, including The Practical Guide to Pharmacy Law Series,
continuing education programs, two books, and numerous chapters in areas
relating to pharmacy law, drug regulation, professional malpractice, risk
management, drug utilization review, health policy, and other topics in
healthcare. He also has one book in development.
Professor Pisano’s research interests and grants cover studies in legal/
regulatory issues, cost effectiveness, professional malpractice, pharmacist/
patient communications, and healthcare practice dilemmas.
A national speaker and invited lecturer, Dr. Pisano has made several hun-
dred presentations to varied audiences of pharmacy and nonpharmacy pro-
fessionals, including the Judiciary Committee of the U.S. House of
Representatives, on the areas of pharmacy education, state and federal phar-
macy, drug and device law and regulation, professional liability, pharmacy
practice, health policy, and other related topics.
David Mantus is an Adjunct Assistant Professor in the Master of Science
degree program in Regulatory Affairs and Health Policy at the Massachusetts
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College of Pharmacy and Health Sciences (MCPHS). In addition, he serves
as Vice President, Regulatory Affairs at Sention Inc., a pharmaceutical devel-
opment company focused on the discovery and development of drugs to
treat memory impairment and other central nervous system disorders.
Dr. Mantus received his Bachelor of Science degree in Chemistry from the
College of William and Mary, and his Master of Science and Doctorate in
Chemistry from Cornell University. He was also a postdoctoral fellow in
Biomedical Engineering at the University of Washington, conducting research
on the surface properties of biomaterials intended for medical implants.
Dr. Mantus has previously held regulatory and project management posi-
tions at Procter and Gamble Pharmaceuticals, the Massachusetts Public
Health Biological Laboratories, PAREXEL, and Shire Biologics. In these posi-
tions he has worked on a range of drug development issues, from initial
concept and strategy review up to and including post-approval issues in
advertising, promotion, and manufacturing and compliance. Dr. Mantus has
shepherded multiple products through development, and while at Shire
Biologics managed their first product approval in the United States.
Dr. Mantus has published and presented on a range of topics, including
analytical chemistry, materials science, clinical trial design, clinical data qual-
ity assurance, project management and regulatory affairs. He was recognized
by the World Health Organization (WHO) for his contributions teaching
regulatory authorities from the developing world as part of the International
Vaccine Program. He has both presented and chaired conferences in the U.S.
and abroad. In his academic capacity, Dr. Mantus teaches a two-semester
course at MCPHS on drug development and regulation, affectionately
referred to as “FDA I and II.” His students hold, and have gone on to hold,
a variety of regulatory and quality assurance positions at pharmaceutical
companies and the Food and Drug Administration (FDA).
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Contributors
Josephine C. Babiarz Massachusetts College of Pharmacy and Health
Sciences, Worcester, MA
Robert Buckley GelTex Pharmaceuticals, Waltham, MA
Thomas Class Millennium Pharmaceuticals, Inc., Cambridge, MA
Jacqueline A. Dombroski Telik, Inc., South San Francisco, CA
Vahe Ghahraman Datafarm, Inc., Marlboro, MA
Alberto Grignolo PAREXEL International, Waltham, MA
Marlene E. Haffner U.S. Food & Drug Administration, Rockville, MD
Catherine Hay Massachusetts Biologic Laboratory, Boston, MA
John J. Jessop The Biologics Consulting Group, Alexandria, VA
Florence Kaltovich SAIC, Frederick, MD
James G. Kenimer The Biologics Consulting Group, Alexandria, VA
Shylendra Kumar Medical Imaging Perceptive Informatics Inc., Waltham,
MA
David S. Mantus Sention, Providence, RI
Robert G. Pietrusko Millennium Pharmaceuticals, Inc., Cambridge, MA
Douglas J. Pisano Massachusetts College of Pharmacy & Health Sciences,
Worcester, MA
David J. Pizzi PAREXEL International Corp., Waltham, MA
Janet C. Rae PAREXEL International Corp., Waltham, MA
Barry Sall PAREXEL International Corp., Waltham, MA
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Contents
1 Overview of Drug Development and the FDA...........................1
Douglas J. Pisano
2 Regulatory Strategy ...................................................................... 21
Jacqueline A. Dombroski
3 What Is an IND? ........................................................................... 39
Robert G. Pietrusko and Thomas Class
4 Formatting, Assembling, and Submitting the New Drug
Application (NDA) ....................................................................... 81
David J. Pizzi and Janet C. Rae
5 Meeting with the FDA ............................................................... 115
Alberto Grignolo
6 Biologics....................................................................................... 129
James G. Kenimer and John J. Jessop
7 FDA Medical Device Regulation .............................................. 153
Barry Sall
8 The Development of Orphan Drugs......................................... 195
Marlene E. Haffner
9 Good Clinical Practices.............................................................. 207
Robert Buckley
10 Good Manufacturing Practices (GMPs) and Enforcement
Actions.......................................................................................... 233
Catherine A. Hay and Florence A. Kaltovich
11 Electronic Submissions: A Guide for Electronic Regulatory
Submissions to the FDA ............................................................ 249
Shylendra Kumar and Vahé Ghahraman
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12 The Practice of Regulatory Affairs........................................... 303
David S. Mantus
13 A Primer of Drug/Device Law or What’s the Law and How
Do I Find It? ................................................................................ 321
Josephine C. Babiarz
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1
Overview of Drug Development and the FDA
Douglas J. Pisano
CONTENTS
1.1 Brief History of Drug Laws and Regulations...........................................2
1.2 Regulatory Oversight of Pharmaceuticals.................................................6
1.3 New Drug Approval and Development....................................................8
1.4 Preclinical Investigation................................................................................8
1.5 Investigational New Drug Application (INDA).......................................9
1.6 Phase I ...........................................................................................................10
1.7 Phase II..........................................................................................................10
1.8 Phase III......................................................................................................... 11
1.9 New Drug Application (NDA).................................................................. 11
1.10 PDUFA/FDAMA Effects ............................................................................12
1.11 Biologics ........................................................................................................13
1.12 Orphan Drugs ..............................................................................................13
1.13 Abbreviated New Drug Applications (ANDA)......................................14
1.14 Phase IV and Postmarketing Surveillance ..............................................16
1.15 Over-The-Counter (OTC) Regulations.....................................................17
1.16 Regulating Marketing .................................................................................18
1.17 Violations and Enforcement.......................................................................19
1.18 Summary.......................................................................................................20
Regulations and laws are central social constructs that provide guidance for
all societies around the globe. Governments create laws in a number of ways
with various intents for a myriad of purposes. In the U.S., laws are created
by the Congress, a body of officials elected by the citizenry, who are charged
with the governance of the country by representing the common, public
good. The Congress proposes and passes laws that are relatively general in
nature and intended to address some particular issue in a fashion that can
be consistently applied by all who are affected by them. Once passed, laws
are remanded to the appropriate government or administrative agency
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2 FDA Regulatory Affairs: A Guide for Prescription Drugs
which then decides on how these laws are to be applied. These “applications
of law” are called regulations. Regulations serve as the practical foundation
from which citizens adhere to the law as it was originally intended.
In the U.S., all food, drugs, cosmetics, and medical devices for both humans
and animals are regulated under the authority of the Food and Drug Admin-
istration (FDA). The FDA and all of its regulations were created by the
government in response to the pressing need to address the safety of the
public with respect to its foods and medicinals. The purpose of this chapter
is to describe and explain the nature and extent of these regulations as they
apply to drugs in the U.S. An historical perspective is offered as a foundation
for regulatory context. In addition, the chapter will discuss the FDA’s regu-
latory oversight and that of other agencies, the drug approval and develop-
ment process, and the mechanisms used to regulate manufacturing and
marketing as well as various violation and enforcement schema.
1.1 Brief History of Drug Laws and Regulations
Prior to 1902, the U.S. government took a hands-off approach to the regula-
tion of drugs. Many of the drugs available were so-called “patent medicines”
which were so named because each had a more or less descriptive or patent
name. No laws, regulations or standards existed to any noticeable extent
even though the United States Pharmacopeia (USP) became a reality in 1820
as the first official compendium of the U.S. The USP set standards for strength
and purity that could be used by physicians and pharmacists who needed
centralized guidelines to extract, compound, and otherwise utilize drug
components that existed at the time.1
However, in 1848, the first American drug law, the Drug Importation Act,
was enacted when American troops serving in Mexico became seriously
affected when adulterated quinine, an antimalarial drug, was discovered.
This law required laboratory inspection, detention, and even destruction of
drugs that did not meet acceptable standards. Later, in 1902, the Virus, Serum
and Toxins Act (Biologics Control Act) was passed in response to tetanus-
infected diphtheria antitoxin which was manufactured by a small laboratory
in St. Louis, MO. Thirteen school children died as a result of the tainted
serum. No national standards were as yet in place for purity or potency.
The Act authorized the Public Health Service to license and regulate the
interstate sale of sera, vaccines, and related biologic products used to prevent
or treat disease.
This Act also spurred Dr. Harvey W. Wiley, chief chemist for the Bureau
of Chemistry, a branch of the U.S. Department of Agriculture (USDA) and
1 Valentino, J., Practical Uses for the USP: A Legal Perspective, in Strauss’ Federal Drug Laws and
Examination Review, 5th ed., Technomic Publishing Co., Lancaster, PA, 1999, p. 38.
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