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SECOND
Pharmaceutical Science EDITION S E C O N D E D I T I O N
about the book…

A Guide for Prescription Drugs, Medical Devices, and Biologics

Examines harmonization of the US Federal Food, Drug, and Cosmetic Act with international
regulations as they apply to human drug and device development, research, manufacturing,
and marketing. The Second Edition focuses on the new drug approval process, cGMPs,
GCPs, quality system compliance, and corresponding documentation requirements. Written
in a jargon-free style, it draws information from a wide range of resources. It demystifies the

FDA Regulatory Affairs

inner workings of the FDA and facilitates an understanding of how it operates with respect to
compliance and product approval.
FDA Regulatory Affairs:
s provides a blueprint to the FDA and drug, biologic, and medical device development
s offers current, real-time information in a simple and concise format
s contains a chapter highlighting the new drug application (NDA) process
s discusses FDA inspection processes and enforcement options
s includes contributions from experts at companies such as Millennium and Genzyme,
leading CRO’s such as PAREXEL and the Biologics Consulting Group, and the FDA
Three all-new chapters cover:
s clinical trial exemptions
s advisory committees
s provisions for fast track
about the editors...
DOUGLAS J. PISANO is Dean of the School of Pharmacy and Professor of Pharmacy
Administration, Massachusetts College of Pharmacy and Health Sciences, Boston,
Massachusetts, USA. Dr. Pisano received his Ph.D. in Law, Policy, and Society at Northeastern
University, Boston, Massachusetts, USA. He is an active member of several professional
organizations, including the American Association of Colleges of Pharmacy and the American
Pharmaceutical Association. A national speaker and invited lecturer, Dr. Pisano was the
recipient of the Special Service Award for the Enhancement of Regulatory Education from the
Regulatory Affairs Professionals Society in 2000. He has developed several courses and

FDA
programs at the Massachusetts College of Pharmacy and Health Sciences in such areas as
health policy, pharmacy and drug law, and regulatory affairs. Dr. Pisano, along with coeditor
Dr. David S. Mantus, is also the editor of the first edition of Informa Healthcare’s FDA Regulatory
Affairs: A Guide for Prescription Drugs, Medical Devices, and Biologics.

Regulatory
DAVID S. MANTUS is Vice President of Regulatory Affairs and Program Management, Cubist
Pharmaceuticals, Inc., Lexington; Adjunct Professor of Drug Regulatory Affairs, Massachusetts
College of Pharmacy and Health Sciences, Boston; and President, C After D Inc., Boston,

Affairs
Massachusetts, USA. Dr. Mantus received his Ph.D. in Chemistry from Cornell University,
Ithaca, New York, USA. He is an active member of the Regulatory Affairs Professional Society
and the American Chemical Society and is a frequent presenter and lecturer at national
conferences on biologics and biotechnology, regulatory affairs, and vaccine development.
Dr. Mantus has also served as chairperson for several conferences, including “Outsourcing
Pisano
Regulatory Affairs” and “Vaccine Development for the 21st Century.”
Printed in the United States of America (
— A Guide for Prescription Drugs,
Mantus
Medical Devices, and Biologics
Edited by
Douglas J. Pisano
David S. Mantus

Pisano_978-1420073546.indd 1 nC nM nY nK 7/3/08 10:20:54 AM

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

Edited by
Douglas J. Pisano
Massachusetts College of Pharmacy and Health Sciences
Boston, Massachusetts, USA
David S. Mantus
Cubist Pharmaceuticals, Inc.
Lexington, Massachusetts, USA
Informa Healthcare USA, Inc.
52 Vanderbilt Avenue
New York, NY 10017
# 2008 by Informa Healthcare USA, Inc.
Informa Healthcare is an Informa business

No claim to original U.S. Government works

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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 S. Mantus. — 2nd ed.
p. ; cm.
Includes bibliographical references and index.
ISBN-13: 978-1-4200-7354-6 (hb : alk. paper)
ISBN-10: 1-4200-7354-0 (hb : alk. paper) 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.
[DNLM: 1. United States. Food and Drug Administration. 2. Drug Industry—
standards—United States. 3. United States Government Agencies—United States.
4. Biological Products—standards—United States. 5. Equipment and Supplies—
standards—United States. 6. Government Regulation—United States. QV 1 F287
2008]
RM301.25.F37 2008
6150 .19—dc22
2008014296

For Corporate Sales and Reprint Permissions call 212-520-2700 or write to: Sales Department,
52 Vanderbilt Avenue, 7th floor, New York, NY 10017.

Visit the Informa Web site at

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and the Informa Healthcare Web site at

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 Preface

This book is a roadmap to the U.S. Food and Drug Administration 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 the practical aspects of U.S. product approval. It is meant to be a concise
reference that offers current, real-time information. It has been written as a
handy reference for use by students, staff, and professionals at corporations,
organizations, and schools and colleges across the United States in need of a
simple, concise text from which to learn and teach. The topics in FDA Regulatory
Affairs: A Guide for Prescription Drugs, Medical Devices, and Biologics, Second
Edition are covered in a straightforward format. It is a compilation and commen-
tary 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 U.S. Food and Drug Administration, it’s agencies or any
body that regulates the development or approval of drugs, biologics, and medical
devices in the United States.

Douglas J. Pisano
David S. Mantus

iii
 Contents

Preface . . . . . . . . . . . iii
Contributors . . . . . . . . vii

1. Overview of FDA and Drug Development . . . . . . . . . . . . . . . . . 1

Josephine C. Babiarz and Douglas J. Pisano

2. What Is an IND? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Michael R. Hamrell

3. The New Drug Application . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

Charles Monahan and Josephine C. Babiarz

4. Meeting with the FDA ............................. 109

Alberto Grignolo

5. FDA Medical Device Regulation ...................... 125

Barry Sall

6. The Development of Orphan Drugs ................... 167

Tan T. Nguyen

7. CMC Sections of Regulatory Filings and CMC

Regulatory Compliance During Investigational
and Postapproval Stages ........................... 187
Prabu Nambiar and Steven R. Koepke

8. Overview of the GxPs for the Regulatory Professional ...... 213

Bob Buckley and Robert Blanks

v
vi Contents

9. FDA Regulation of the Advertising and Promotion

of Prescription Drugs, Biologics, and Medical Devices ...... 267
Karen L. Drake

10. Electronic Submissions—A Guide for Electronic

Regulatory Submissions to FDA . . . . . . . . . . . . . . . . . . . . . . 289
Shylendra Kumar, Yolanda Hall, and Vahe´ Ghahraman

11. The Practice of Regulatory Affairs .................... 351

David S. Mantus

12. A Primer of Drug/Device Law: What’s the Law

and How Do I find It? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
Josephine C. Babiarz

13. FDA Advisory Committees . . . . . . . . . . . . . . . . . . . . . . . . . . 397

Christina A. McCarthy and David S. Mantus

14. Biologics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417

Timothy A. Keutzer

Index .... . 435

 Contributors

Josephine C. Babiarz MS Program in Regulatory Affairs, Massachusetts

College of Pharmacy and Health Sciences, Boston, Massachusetts, U.S.A.
Robert Blanks Idenix Pharmaceuticals, Inc., Cambridge, Massachusetts,
U.S.A.
Bob Buckley Idenix Pharmaceuticals, Inc., Cambridge, Massachusetts, U.S.A.
Karen L. Drake Cubist Pharmaceuticals, Inc., Lexington, Massachusetts,
U.S.A.
Vahé Ghahraman Regulatory Operations and Technology, Dyax Corporation,
Cambridge, Massachusetts, U.S.A.
Alberto Grignolo PAREXEL Consulting, Lowell, Massachusetts, U.S.A.
Yolanda Hall Datafarm, Inc., Marlborough, Massachusetts, U.S.A.
Michael R. Hamrell MORIAH Consultants, Yorba Linda, California, U.S.A.
Timothy A. Keutzer Cubist Pharmaceuticals, Inc., Lexington, Massachusetts,
U.S.A.
Steven R. Koepke SRK Consulting, LLC, Walkersville, Maryland, U.S.A.
Shylendra Kumar Datafarm, Inc., Marlborough, Massachusetts, U.S.A.
David S. Mantus Cubist Pharmaceuticals, Inc., Lexington, Massachusetts, U.S.A.
Christina A. McCarthy Cubist Pharmaceuticals, Inc., Lexington,
Massachusetts, U.S.A.
Charles Monahan Regulatory Affairs, Molecular Insight Pharmaceuticals,
Inc., Cambridge, Massachusetts, U.S.A.

vii
viii Contributors

Prabu Nambiar Vertex Pharmaceuticals, Inc., Cambridge, Massachusetts, U.S.A.

Tan T. Nguyen Food and Drug Administration, Center for Devices and
Radiological Health, Rockville, Maryland, U.S.A.
Douglas J. Pisano School of Pharmacy, Massachusetts College of Pharmacy
and Health Sciences, Boston, Massachusetts, U.S.A.
Barry Sall PAREXEL Consulting, Waltham, Massachusetts, U.S.A.
 1
Overview of FDA and Drug Development

Josephine C. Babiarz
MS Program in Regulatory Affairs, Massachusetts College of Pharmacy
and Health Sciences, Boston, Massachusetts, U.S.A.
Douglas J. Pisano
School of Pharmacy, Massachusetts College of Pharmacy
and Health Sciences, Boston, Massachusetts, U.S.A.

INTRODUCTION
A single agency, the Food and Drug Administration (FDA), regulates a trillion dollars
of products, ranging from 80% of the U.S. food supply to all human health care
products, electronic products that emit radiation, animal products, and cosmetics. In
2006, that agency approved 101 new drugs, 10 biologic license applications, and 39
devices under the premarket approval process and cleared 3217 devices1 and recalled
4266 products in all categories.2 That single agency is responsible for shellfish, stents,
over-the-counter (OTC) cough syrups, tetanus shots, artificial sweeteners, mam-
mography standards, prescription drugs, vitamins, and lipsticks, not to mention the
readability of calorie and trans-fat information on a bag of potato chips. The economic
impact of the FDA is difficult to calculate, the scientific challenges and increasing
medical needs overwhelming, and the expectations contradictory.
The FDA is expected to protect us and our pets from harm, but allow us
access to unproven therapies that might cure or benefit us. The FDA is to act

1
See www.fda.gov/oc/FDA’s 2006 Accomplishments/healthcare.html.
2
See www.fda.gov/ora/about/enf_story/ch10/FY96toFY06Recalls.pdf.

1
2 Babiarz and Pisano

quickly to get products to market, but must be right the first time, and is criticized
as being too permissive or lax if a drug or device must be recalled later for safety
concerns or unpredicted adverse events. Given the pace of scientific advancement,
this is no small demand.
The FDA’s authority and influence are the product of compromise,
evolving over time. It is an agency that is governed as much by law as by
science. History shows us that the FDA’s authority has grown commensurate
with the magnitude of harm suffered by the public because of the food and drugs
consumed, as well as the devices used. The agency and its statutory framework
remain a work in progress. To better understand the FDA, its controlling laws,
and its role in public health, a brief summary is in order.
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 United States, 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, 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 United States, all food, drugs, cosmetics, and medical devices for
both humans and animals are regulated under the authority of the Food, Drug,
and Cosmetic Act (FDCA), which in turn establishes the FDA. The FDA and all
of its regulations were created by the government in response to the pressing
need to address the safety of 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 medical products in the United States. A historical
perspective is offered as a foundation for regulatory context. In addition, the chapter
will discuss the FDA’s regulatory oversight and that of other agencies, the drug
approval and development process, the mechanisms used to regulate manu-
facturing and marketing, as well as various violation and enforcement schemas.

THE EVOLUTION OF THE FDA—HOW THE PURE FOOD AND

DRUG ACT BECAME THE FOOD AND DRUG ADMINISTRATION
AMENDMENTS OF 2007

The History—1902 to 1972

Prior to 1902, the U.S. government took a hands-off approach to the regulation
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
Overview of FDA and Drug Development 3

United States Pharmacopoeia (USP) became a reality in 1820 as the first official
compendium of the United States. The USP set standards for strength and purity,
which could be used by physicians and pharmacists who needed centralized
guidelines to extract, compound, and otherwise utilize drug components that
existed at the time.3
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, Missouri.
Ten 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 serum, 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 United States Department of Agriculture (USDA) and
the forerunner for today’s FDA investigate the country’s foods and drugs. He
established the Hygienic Table, a group of young men who volunteered to serve
as human guinea pigs and who would allow Dr. Wiley to feed them a controlled
diet laced with a variety of preservatives and artificial colors. More popularly
known as the “Poison Squad,” they helped Dr. Wiley gather enough data to
prove that many of America’s foods and drugs were “adulterated,” the products’
strength or purity was suspect or “misbranded,” or the products had inadequate
or inaccurate labeling. Dr Wiley’s efforts, along with publication of Upton
Sinclair’s The Jungle (a book revealing the putrid conditions in America’s meat
industry), were rewarded when Congress passed America’s first food and drug
law, in 1906, the United States Pure Food and Drug Act (PFDA) (also known
as the Wiley Act). The Wiley Act prohibited interstate commerce of misbranded
foods or drugs based on their labeling. It did not affect unsafe drugs in that its
legal authority would only come to bear when a product’s ingredients were
falsely labeled. Even intentionally false therapeutic claims were not prohibited.
This began to change in 1911 with the enactment of the Sherley
Amendment, which prohibited the labeling of medications with false therapeutic
claims that were intended to defraud the purchaser. These amendments, how-
ever, required the government to find proof of intentional labeling fraud.
Later, in 1937, a sentinel event occurred that changed the entire regulatory
picture. Sulfa became the miracle drug of the time and was used to treat many
life-threatening infections. It tasted bad and was hard to swallow, which led

3
Valentino J. Practical uses for the USP: a legal perspective. In: Strauss’s Federal Drug Laws and
Examination Review. 5th ed. Lancaster, PA: Technomic Publishing Co., 1999:38.
4 Babiarz and Pisano

entrepreneurs to seek a palatable solution. S.E. Massingill Co. of Bristol,

Tennessee, developed what it thought was a palatable, raspberry-flavored liquid
product. However, it used diethylene glycol to solublize the sulfa. Six gallons
of this dangerous mixture, Elixir of Sulfanilamide, killed some 107 people,
mostly children.
The result was the passage of one of the most comprehensive statutes in the
history of American health law. The federal Food, Drug, and Cosmetic Act of
1938 (FDCA), repealed the Sherley Amendments and required that all new drugs
be tested by their manufacturers for safety and that those tests be submitted to
the government for marketing approval via a new drug application (NDA). The
FDCA also mandated that drugs be labeled with adequate directions if they were
shown to have had harmful effects. In addition, the FDCA authorized the FDA to
conduct unannounced inspections of drug manufacturing facilities. Though
amended many times since 1938, the FDCA is still the broad foundation for
statutory authority for the FDA as it exists today.
However, a new crisis loomed. Throughout the late 1950s, European and
Canadian physicians began to encounter a number of infants born with a curious
birth defect called “phocomeglia,” a defect that resulted in limbs that resembled
“flippers,” similar to those found on seals. These birth defects were traced back
to mothers who had been prescribed the drug thalidomide in an effort to relieve
morning sickness while pregnant. The manufacturer of this drug applied for the
U.S. marketing approval as a sleep aid. However, because of the efforts of
Dr. Frances O. Kelsey, the FDA’s chief medical officer at the time, a case was
made that the drug was not safe and therefore not effective for release in the U.S.
marketplace.
Dr. Kelsey’s efforts and decisive work by the U.S. Congress resulted in yet
another necessary amendment to the FDCA, in 1962, the Kefauver-Harris Act.
This act essentially closed many of the loopholes regarding drug safety in
American law. These “Drug Efficacy Amendments” now required drug manu-
facturers to prove safety and efficacy of their drug products, register with the
FDA and be inspected at least every two years, have their prescription drug
advertising approved by the FDA (this authority being transferred from the
Federal Trade Commission), provide and obtain documented “informed consent”
from research subjects prior to human trials, and increase controls over manu-
facturing and testing to determine drug effectiveness.
In an effort to address these new provisions of the act, the FDA contracted
with the National Academy of Sciences along with the National Research Council
to examine some 3400 drug products approved between 1938 and 1962 on the
basis of safety alone. Called the Drug Efficacy Study Implementation Review
of 1966 (DESI), it charged these organizations to determine whether post-1938
drug products were “effective” for the indications claimed in their labeling, or
“probably effective,” “possibly effective,” or “ineffective.” Those products not
deemed effective were removed from the marketplace, reformulated, or sold
with a clear warning to prescribers that the product was not deemed effective.
Overview of FDA and Drug Development 5

Later, in 1972, the FDA began to examine OTC drug products. Phase II of
the Drug Efficacy Amendments required the FDA to determine the efficacy of
OTC drug products. This project was much larger in scope than the analysis of
prescription drugs. In the America of the 1970s, consumers could choose from
more than 300,000 OTC drug products. The FDA soon realized that it did not
have the resources to evaluate each and every one. Hence, the FDA created advisory
panels of scientists, medical professionals, and consumers who were charged
with evaluating active ingredients used in OTC products within 80 defined
therapeutic categories. After examining both the scientific and medical literature
of the day, the advisory panels made decisions regarding active ingredients and
their labeling. The result was a “monograph” that described in detail acceptable
active ingredients and labeling for products within a therapeutic class. Products
that complied with monograph guidelines were deemed category I: safe and
effective, not misbranded. However, products not in compliance with monograph
guidelines were deemed category II: not safe and effective or misbranded.
Category II products were removed from the marketplace or reformulated.
Products for which data were insufficient for classification were deemed cate-
gory III and were allowed to continue in the market until substantive data could
be established or until they were reformulated and were in compliance with the
monograph. The OTC Drug Review took approximately 20 years to complete.
Although there were numerous other federal laws and regulations that were
passed throughout the 1970s, many were based on regulating the professional
practice of medical professionals or for the direct protection of consumers. For
example, the federal Controlled Substances Act (CSA), part of the Compre-
hensive Drug Abuse and Prevention Act of 1970, placed drugs with a relatively
high potential for abuse into five federal schedules along with a “closed record
keeping system,” designed to track federally controlled substances via a definite
paper trail, as they were ordered, prescribed, dispensed, and utilized throughout
the health care system.

1980—2004: AIDS, Orphans, Terrorism, and Economic Incentives

The 1980s also passed with significant regulatory changes. Biotechnology had
begun on a grand scale and the pharmaceutical industry was on its cutting edge.
Many of the medicinal compounds being discovered were shown to be very
expensive and have limited use in the general U.S. population. However, these
compounds could prove lifesaving to demographically small patient populations
who suffered from diseases and conditions that were considered rare. In an effort
to encourage these biotech pharmaceutical companies to continue to develop
these and other products, Congress passed the Orphan Drug Act in 1983. The
Act continues to allow manufacturers incentives for research, development, and
marketing of drug products used to treat rare diseases or conditions that would
otherwise be unprofitable via a system of market exclusivity, and substantial
breaks and deductions in a manufacturer’s corporate taxes. Though the success
6 Babiarz and Pisano

of the Orphan Drug Act proved of great medical benefit for a few, a scandal was
looming in other parts of the pharmaceutical industry.
The generic pharmaceutical industry experienced steady growth as many
of the exclusive patents enjoyed by major pharmaceutical companies for brand-
named products were beginning to expire. Generic versions of these now freely
copied products were appearing much more frequently in the marketplace.
However, these generic copies were required to undergo the same rigorous
testing that brand name, pioneer, or innovator products did, thereby increasing
costs, duplicating test results, and substantially slowing the availability of less
expensive but equivalent drugs. To speed access to cheaper therapies, Congress
passed the Price Competition and Patent Restoration Act in 1984. This Act, also
called the Waxman-Hatch Act after its sponsors, was designed to level the
playing field in the prescription drug industry with regard to patent-protected
prescription drug products and their generic copies.
The Waxman-Hatch Act was composed of two distinct parts or “titles.”
Title I was for the benefit of the generic pharmaceutical industry. It extended
the scope of the Abbreviated NDA (ANDA) to cover generic versions of post-
1962–approved drug products. It required that generic versions of pioneer or
innovator drugs have the same relevant aspects as those with regard to bio-
equivalence (rate and extent of absorption of the active drug in the human body)
and pharmaceutical equivalence (same dosage form as the pioneer drug to which
it is compared). Though somewhat simplified, the Waxman-Hatch Act permitted
easier market access to generic copies of pioneer drugs, provided they were not
significantly different from the pioneer drug in their absorption, action, and
dosage form. In addition, Title II of the act was designed to aid and encourage
research-based or innovator pharmaceutical companies in continuing their search
for new and useful medicinal compounds by extending the patent life of pioneer
drug products to compensate for marketing time lost during the FDA “review
period.”4
While the patent extension benefit has become somewhat moot because of
an overall reduction in the FDA review time as a result of prescription drug user
fees, the value of patent-protected drugs has skyrocketed, with so-called block-
buster drugs garnering millions of dollars in sales in less than a year. Market
exclusivity and patent extensions remain powerful motivators used to encourage
orphan drug development and, as discussed below in the section “The Food and
Drug Administration Amendments Act of 2007,” pediatric testing.
Congress recognized that counterfeit drugs, as well as improper control
over drug samples, and sales and marketing materials posed serious health

4
No federal agency, including the FDA, can compel the manufacture of generic drugs once patent
rights have expired. In recent times, the Waxman-Hatch Act has come under criticism for that reason.
Under a free market system, companies that hold expired patents may, and some do, make “reverse
payments” to potential competitors to keep generic drugs off the market. This practice clearly
frustrates the spirit of the law; however, it is legal.
Overview of FDA and Drug Development 7

hazards. Accordingly, the Prescription Drug Marketing Act of 1988 requires that
all drugs be distributed through legitimate commercial channels, that pharma-
ceutical sales representatives maintain detailed accounts of drug samples (giving
birth to the term “detailer”), and that importation of drugs from foreign countries
be restricted.5
Nineteen ninety was a year when Congress focused on devices and
nutrition. The Safe Medical Devices Act of 1990 established a user reporting
system to improve device safety. If a medical device probably caused or con-
tributed to death, serious injury, or illness, representatives of the institution or
facility where the incident occurred were required to file a report with the FDA.
In turn, the device manufacturers were required to address or respond to the
incident. The statute also gives FDA the power and authority to recall devices,6
which it does not have in the case of drugs (drug recalls are voluntary actions by
the manufacturers; FDA can and will seize drug lots, however). This Act also
addressed combination products, establishing that the jurisdiction of the FDA
centers would be based on the primary indication of the product. Nineteen ninety
also brought regulation to food; the Nutrition Labeling and Education Act
requires nutrition labeling and health claims to be consistent with the format and
rules established by the FDA. This law brought new—and uniform—meaning to
the words “low fat” and “light.”7
Nineteen ninety-two saw three major laws enacted. An unintended side
effect of the Waxman-Hatch Act was a very public scandal in which a few
unscrupulous generic pharmaceutical companies took shortcuts in reporting
data, submitted fraudulent samples, and offered bribes to the FDA officials to
gain easy and rapid market approval of their products.8 The Generic Drug
Enforcement Act provided for debarment and other serious penalties for
bribery, fraud, or misconduct, among other deterrents.9 Congress also strengthened
device oversight; the Medical Device Amendments of 1992 added penalties
if a manufacturer did not comply with postmarketing surveillance testing and
reporting.10

5
Prescription Drug Marketing Act of 1988; Public Law 100–23. See www.fda.gov/opacom/back-
grounders/miles.html.
6
Ibid.
7
Ibid.
8
Sec. 306(k) of the FDCA [21 USC 335a(k)] requires that drug product applicants certify that they
did not and will not use in any capacity the services of any debarred persons in connection with a drug
product application. See www.fda.gov/cder/guidance/1700dft.pdf. Note that this certification applies
to combination products that include any drug component; this certificate is commonly used by
device manufacturers as well.
9
Generic Drug Enforcement Act of 1992; Public Law 102–282; See www.fda.gov/ora/compliance_ref/
debar/297_debar.htm.
10
See http://thomas.loc.gov/cgi-bin/bdquery/z?d102:SN02783:@@@D&summ2=m&jTOM:/bss/d102
query.html.j
8 Babiarz and Pisano

The most significant change of that year came in the form of the first
Prescription Drug User Fee Act (PDUFA).11 The Act was intended to help the
FDA generate additional funds to upgrade and modernize its operations and to
accelerate drug approval. It authorized FDA to charge pharmaceutical manu-
facturers a “user fee” to accelerate drug review. These funds in turn are used by
the FDA. Critics and supporters alike quickly point out that the user fee is fully
paid when the FDA approves a product—not if the final clinical results do not
prove the benefit outweighs the risk. This fee assessment has sparked a great deal
of debate about the real conflict of interest present when the FDA reviewers are
examining a product whose approval fees go directly to fund the reviewers’
employment. As will be discussed later, there are checks and balances in this
system, as Congress appropriates funds to cover FDA administration, including
reviewers’ salaries.
As a result of PDUFA, FDA has hired more personnel and reduced
approval time of new pharmaceutical products from greater than 30 months to
approximately 13 to 15 months today. However, the first act had a “sunset”
provision, which limited FDA’s authority to charge user fees to the year 1997.
The Act was so successful that PDUFA has been reauthorized and extended three
additional times, and the fee concept has been expanded to include medical
devices and biologics (Medical Device User Fee and Modernization Act of 2002,
MDUFMA),12 as well as voluntary review fees for television advertisements. The
most recent reauthorization, PDUFA IV, is part of the Food and Drug Adminis-
tration Amendments Act of 2007, discussed at length below.
Congress relaxed the regulation of certain industries. The Dietary Sup-
plement Health and Education Act (DSHEA) of 1994 shifted the burden of
proof from industry to the FDA. For drugs, devices, and biologics, a sponsor or
manufacturer must prove that the product is safe and effective for the indica-
tion claimed. The opposite is true of dietary supplements; thanks to this law,
FDA “bears the burden of proof . . . to show that a dietary supplement is
adulterated.”13
Congress continued to expand and enhance the scope and powers of the
FDA. One example is the FDA Modernization Act (FDAMA) of 1997.14 FDMA
not only extended user fee provisions but also waived some fees for small
companies and for developers of orphan products, manufacturers of pediatric
applications, and certain biologics. FDAMA also gave FDA authority to conduct
“fast track” product reviews to speed lifesaving drug therapies to market, per-
mitted an additional six-month patent exclusivity for pediatric prescription
drug products and required the National Institutes of Health (NIH) to build a

11
Public Law 102–571; 21 USC 379g and ff.
12
Public Law 107–250; 21 USC 379F et seq.
13
See www.fda.gov/opacom/laws/dshea.htmo#sec4.
14
Public Law 105–115; 21 USC 301 et seq.
Overview of FDA and Drug Development 9

publicly accessible database on clinical studies of investigational drugs or life-

threatening diseases.
FDAMA addressed the real dilemma of terminally ill patients, who were
routinely denied access to experimental drugs because of the lack of safety and
efficacy data on the drugs; FDA had no authority to allow the use of such drugs
outside enrollment in a controlled clinical investigation. However, pressures
from acquired immunodeficiency syndrome (AIDS) activists in particular moved
Congress to change the rules. Under FDAMA, there was expanded access to
unapproved drug and devices, specifically therapies and diagnostics for serious
diseases or life-threatening conditions.15 Individuals not enrolled in a formal
clinical trial could obtain unapproved products—i.e., products covered by an
investigational new drug (IND) or investigational device exemption (IDE)—
during emergencies or for personal use. Unapproved drugs are available under
“expanded access” or “compassionate use,”16 experimental devices are available
under the humanitarian device exemptions.17
FDAMA addressed, albeit briefly, issues of “off-label” promotion. Gen-
erally, a manufacturer may only advertise those claims and indications that are
stated in the label; any deviation can be prosecuted as misbranding.18 FDA took
the position that certain publications directed at prescribers were in fact off-label
promotion. Various critics, including the Washington Legal Foundation, felt that
this position violated the right of freedom of speech, guaranteed by the First
Amendment to the United States Constitution. A federal court agreed with the
foundation,19 and Congress was forced to address the issue. The fundamental
question was and remains how can the public be adequately protected if a man-
ufacturer is allowed to promote all the uses of a product and not only those that
FDA has determined to be supported by scientific evidence?
The compromise Congress crafted was to allow dissemination of infor-
mation on unapproved uses of products to a limited group of professionals—
i.e., physicians, insurance companies, and other health care practitioners. This
provision has expired,20 and the battlefront has shifted to the arena of post-
marketing surveillance and drug database registries, discussed below in the
section “The Food and Drug Administration Amendments Act of 2007.”
Imitation is the sincerest compliment—the success of PDUFA gave birth to
the Medical Device User Fee and Modernization Act (MDUFMA) in 2002.
MDUFMA was enacted “in order to provide the FDA with the resources necessary
to better review medical devices, to enact needed regulatory reforms so that medical

15
See 21 USC section 360bbb and following.
16
See www.fda.gov/cder/guidance/3647fnl.pdf.
17
See www.fda.gov/cdrh/ode/guidance/1381.html.
18
See 21 USC section 331 and following.
19
See Washington Legal Foundation v. Henney; Federal Appellate District DC US Court of Appeals,
Decided Feb 11, 2000; No. 99-5304.
20
See 21 USC section 360aaa and following.
10 Babiarz and Pisano

device manufacturers can bring their safe and effective devices to the American
people at an earlier time, and to ensure that reprocessed medical devices are as safe
and effective as original devices.”21 MDUFMA continues to be strengthened and
is now reauthorized through 2012. This same fee scheme has been adapted by
veterinary medicines with ADUFA, the Animal Drug User Fee Act of 2003.22
In 2002 and again in 2003, Congress addressed the untested use of adult
drugs for pediatric indications, by passing the Best Pharmaceuticals for Children
Act in 2002.23 This law extended the six-month patent exclusivity, as a reward
for manufacturers who tested the formulation in pediatric indications, and
strengthened Health and Human Services (HHS) executive powers with respect
to pediatrics. This law was followed in 2003 by the Pediatric Research Equity
Act,24 which mandates that new drugs and biologics be tested in children if they
can be used by children; FDA can grant a waiver for this mandatory testing. FDA
takes the position that prescribing adult formulations for children without ade-
quate studies is off-label and in effect, constitutes unapproved and unmonitored
ongoing drug trials.
The events of 9/11 also impacted the FDA. The Public Health Security and
Bioterrorism Preparedness and Response Act of 200225 requires the stockpiling
of certain drugs and enhances protection of the food supply, among the measures
that address national emergency situations. The Project Bioshield Act of 200426
will “. . . provide protections and countermeasures against chemical, radiological,
or nuclear agents that may be used in a terrorist attack against the United
States . . . [by] streamlining the Food and Drug Administration approval process
of countermeasures.”

The Food and Drug Administration Amendments Act of 2007

The Food and Drug Administration Amendments Act of 200727 is broad detailed
legislation that impacts each pressure point, not only in drug and device
development but also throughout the FDA’s purview. The law extends PDUFA
and MDUFMA, addresses pediatrics in drugs and devices, and establishes new
and robust requirements for postmarketing surveillance. It creates the Regan-Udall
Foundation, whose mission is to spur public-private partnerships, modernize
the development of products regulated by the FDA, and accelerate medical

21
See www.fda.gov/cdrh/mdufma/whitepaper.html, citing Medical Device User Fee and Modern-
ization Act of 2002, Report 107–728 (October 7, 2002), p. 21.
22
Public Law 108–130 (Feb 20, 2003).
23
Public Law 107–109 (Jan 4 2002).
24
Public Law 108–155 (Dec 3, 2003).
25
Public Law 107–188 (June 12, 2002); See http://thomas.loc.gov/home/gpoxmlc110/h3580_rds.
xml#toc-H5597472044A142FBB29600862048CB39 for an electronic, linked version.
26
Public Law 108–276 (July 21, 2004).
27
Public Law 110–85 (Sept 27, 2007), H.R. 3580.
Overview of FDA and Drug Development 11

innovation. It improves food safety. Six months after its passage, the FDA and
industry are still learning its language and sections. A brief summary is in order.
Recapping the sections of this Act:28

1. The act reauthorized and expanded PDUFA. Under PDUFA of 2007, the
government estimates user fees for prescription drugs and biologics at
$392 million annually, an increase of $87 million over current fees, and a
tripling of fees for postmarketing surveillance. The total PDUFA increase
over five years is estimated to be $225 million.
2. Additionally, the Act authorizes the collection of user fees to review direct
to consumer (DTC) television advertisements, which are voluntarily sub-
mitted to the FDA for review. As of this print date, this provision is moot
because drug manufacturers did not file sufficient requests for review to
meet the minimum threshold.
3. The Act expands FDA’s implementation of guidance for product review,
and FDA is to develop in particular, guidelines for industry on clinical trial
design.
4. The fees will help move FDA and industry to all electronic environments.
5. Regarding devices, MDUFMA of 2007 also extended fees and appropri-
ations, estimated to generate $287 million by 2012. For the Center for
Devices and Radiological Health (CDRH), this Act allows accredited
outside firms to conduct manufacturing inspections, shifting FDA resources
to high-risk products. There will also be new guidance on in-vitro diagnostic
device development.
6. Two major pediatric initiatives, the Pediatric Research Equity Act and the
Best Pharmaceuticals Act are extended and a new one, the Pediatric
Medical Device Safety Act, is added. Under this new initiative, medical
devices must include a description of pediatric populations; FDA is to
track the number and type of devices specifically approved for children
and/or pediatric conditions. Additionally, FDA will report on approval
times for pediatric devices and humanitarian device exemptions. Manu-
facturers will still have the additional six-month exclusivity as incentive
for the FDA-requested studies.
7. The FDA is to set up an electronic surveillance system for using e-health
records and electronic health data sources for surveillance of adverse
events. This system will be implemented over time.
8. It improves clinical trial databases, a responsibility shared between the
FDA and NIH. The databases will be expanded in three phases. New
medications and devices must provide clinical trial registry information,
going beyond the currently published categories of serious, life-threatening
illness and will cover all trials beyond phase 1. Sponsors will be required to
post basic trial results on the databases for approved drugs and devices; the

28
Summary taken from www.fda.gov/bbs/transcripts/transcript092707.pdf.
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