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THE FUTURE OF
DRUG SAFETY
PROMOTING AND PROTECTING THE HEALTH OF THE PUBLIC
THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. Washington, DC 20001
NOTICE: The project that is the subject of this report was approved by the Governing Board
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This study was supported by Contract No. 223-01-2460, Task Order No. 23; HH-
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Institute of Medicine (U.S.). Committee on the Assessment of the US Drug Safety System.
The future of drug safety : promoting and protecting the health of the public / Committee on
the Assessment of the US Drug Safety System, Board on Population Health and Public Health
Practice ; Alina Baciu, Kathleen Stratton, Sheila P. Burke, editors.
p. ; cm.
Includes bibliographical references.
ISBN 978-0-309-10304-6 (pbk.)
1. Pharmaceutical policy—United States. 2. United States. Food and Drug Administration. 3.
Drugs—Safety measures—United States. I. Baciu, Alina. II. Stratton, Kathleen R. III. Burke,
Sheila P. IV. Title.
[DNLM: 1. United States. Food and Drug Administration. 2. Drug Approval—United States.
3. United States Government Agencies—United States. QV 771 I5852f 2007]
RA401.A3.I568 2007
362.17′82—dc22
2006039224
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Reviewers
This report has been reviewed in draft form by individuals chosen for
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cedures approved by the NRC’s Report Review Committee. The purpose
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vii
viii REVIEWERS
Preface
The year 2006 marks the 100th anniversary of the signing of the Pure
Food and Drug Act. During that century, drug regulation at the Food and
Drug Administration (FDA) has evolved enormously, both in terms of statu-
tory reforms (with major legislation in 1938, 1962, 1992, 1997, and 2002)
and due to internal restructuring and growth in staff. Past changes have
frequently been responses to problems in the functioning of the drug regula-
tory process. Although the agency has gained great respect and importance
as one of the world’s premier regulatory bodies, recent drug safety events
have called into question FDA’s regulatory decision-making and oversight
processes, and caused the public to question its ability to accomplish a bal-
anced evaluation of the safety and efficacy of the drugs it reviews and after
their approval, of their performance under real-life conditions. In light of
these developments, the Institute of Medicine (IOM) was asked by FDA to
examine in detail the system of drug safety in this country. Our committee
has, in the course of the last 15 months, undertaken this assessment.
The result of our review is a series of recommendations that we believe
will improve the drug safety system by strengthening clinical and epide-
miological research, and the scientific basis of regulatory action. Although
mindful of recent actions by FDA to improve its postmarketing decision-
making process, the committee believes a more comprehensive response is
required that acknowledges the need for vigilance throughout the lifecycle
of a drug. Underlying our 25 recommendations is the fundamental view
that the interests of the public are best served when safety and efficacy
are considered together. However, factors including, but not limited to,
the current organizational culture of the Center for Drug Evaluation and
ix
PREFACE
Contents
SUMMARY 1
1 INTRODUCTION 15
Changes in the Broad Context of Drug Regulation, 19
Defining and Meeting the Charge, 21
3 A CULTURE OF SAFETY 65
Organizational Challenges, 65
The External Environment, 68
Structural Factors, Policies, and Procedures, 75
Proposed Solutions to CDER’s Organizational Dysfunction, 90
xi
xii CONTENTS
APPENDIXES
A Moving Target: Changes at FDA During the Course of the Study 205
B Acronyms 217
C PDUFA Performance Goals—All Years 221
D Committee on the Assessment of the US Drug Safety System
Meeting Agendas 255
E Summary, Preventing Medication Errors: Quality Chasm Series,
Institute of Medicine 267
F Committee Biographies 309
INDEX 319
THE FUTURE OF
DRUG SAFETY
PROMOTING AND PROTECTING THE HEALTH OF THE PUBLIC
Summary
Every day the Food and Drug Administration (FDA) works to balance
expeditious access to drugs with concerns for safety, consonant with its
mission to protect and advance the public health. The task is all the more
complex given the vast diversity of patients and how they respond to drugs,
the conditions being treated, and the range of pharmaceutical products and
supplements patients use. Reviewers in the Center for Drug Evaluation and
Research (CDER) at the FDA must weigh the information available about
a drug’s risk and benefit, make decisions in the context of scientific uncer-
tainty, and integrate emerging information bearing on a drug’s risk-benefit
profile throughout the lifecycle of a drug, from drug discovery to the end
of its useful life. These processes may have life-or-death consequences for
individual patients, and for drugs that are widely used, they may also affect
entire segments of the population. The distinction between individual and
population is important because it reflects complex determinations that
FDA must make when a drug that is life-saving for a specific patient may
pose substantial risk when viewed from a population health perspective. In
a physician’s office, the patient and the provider make decisions about the
risk and benefits of a given drug for that patient, whereas FDA has to assess
risks and benefits with a view toward their effects on the population. The
agency has made great efforts to balance the need for expeditious approvals
with great attention to safety, as reflected in its mission—to protect and
advance the health of the public.
In the first years of the 21st century, the issue of prescription drug safety
came to the attention of the public with renewed intensity. Drug withdraw-
als, apparent delays in warning the public about important drug risks, a
SUMMARY
BOX S-1
The Statement of Task
In response to growing public concern with health risks posed by
approved drugs, the FDA has requested that the Institute of Medicine
(IOM) convene an ad hoc committee of experts to conduct an inde-
pendent assessment of the current system for evaluating and ensuring
drug safety postmarketing and make recommendations to improve risk
assessment, surveillance, and the safe use of drugs. As part of its work,
the IOM committee will:
• examine the FDA’s current role and the role of other actors (e.g.,
health professionals, hospitals, patients, other public agencies)
in ensuring drug safety as part of the US health care delivery
system;
• examine the current efforts for the ongoing safety evaluation of
marketed drug products at the FDA and by the pharmaceutical
industry, the medical community, and public health authorities;
• evaluate the analytical and methodological tools employed by
FDA to identify and manage drug safety problems and make
recommendations for enhancement;
• evaluate FDA’s internal organizational structure and operations
around drug safety (including continuing postmarket assessment
of risk vs. benefit);
• consider FDA’s legal authorities for identifying and responding to
drug safety issues and current resources (financial and human)
dedicated to postmarketing safety activities;
• identify strengths, weaknesses, and limitations of the current
system; and
• make recommendations in the areas of organization, legislation,
regulation, and resources to improve risk assessment, surveil-
lance, and the safe use of drugs.
on drug safety? Does the center have the mix of expertise, technology, scien-
tific capacity, authority, and resources to achieve its share of FDA’s mission,
to protect and advance the health of the public? Do the political, social,
and economic aspects of the external environment and the expectations of
other stakeholders affect the agency’s functioning? To answer some of these
questions, the committee reviewed aspects of the drug safety system that it
believes can be transformed to improve the monitoring and evaluation of
drug safety signals and restore public confidence in the system, including:
SUMMARY
the lifecycle will require increased transparency toward FDA in the process
of elucidating and communicating emerging information about a drug,
and acceptance of changes intended to strengthen drug safety. Importantly,
FDA’s credibility is intertwined with that of the industry, and a more credible
drug safety system is in everyone’s best interest. For the health care delivery
system, a lifecycle approach to risk and benefit implies the need to heed
and follow FDA communication about drug safety matters and to exercise
appropriate caution in drug-related decision making (from formularies to
prescribing) in recognition of the limited information available at the time
of drug approval. Also, the health care delivery system would benefit from
consistently basing prescribing decisions on the science, and exercising cau-
tion in regard to the industry’s influence on the practice of medicine. Health
care organizations and professional societies could contribute to prescribers’
understanding of the evolving science behind the assessment of drug risk and
benefit. The academic research enterprise could enhance its contributions of
data to the assessment of risk and benefit at all points in a drug’s lifecycle,
continue its crucial advisory relationship with FDA, and uphold the value
of complete transparency in recognition of real and perceived conflicts as-
sociated with financial involvement with the industry. Other government
agencies could contribute to the lifecycle approach to drug risk and benefit
by collaborating with FDA and the private sector to ensure that data streams
from publicly funded health care settings contribute to an improved drug
safety system. The public and patients could do their part by communicat-
ing with their health care providers about the pharmaceutical products they
are using, learning about and discussing with their providers drug risks and
benefits in the context of their health needs and characteristics, informing
their providers about side effects they experience, and calling for more use-
ful and timelier information about drug benefits and risks associated with
new drugs. The public and other stakeholders could also urge Congress to
ensure and sustain adequate funding for FDA.
RECOMMENDATIONS
Organizational Culture
The Office of Drug Safety, now the Office of Surveillance and Epidemi-
ology (OSE), has not had a formal role in drug regulation—neither formal
opportunities to learn from and participate in relevant aspects of the review
process nor the authority to take action regarding postmarketing safety.
The Prescription Drug User Fee Act (PDUFA) mechanism that accounts
for over half of CDER’s funding and the reporting requirements associated
with the user-fee program are excessively oriented toward supporting speed
of approval and insufficiently attentive to safety.
SUMMARY
The report makes several recommendations (4.3, 4.5, 4.8, and 5.4 be-
low) intended to help CDER develop a more structured way to determine
the level of postmarketing scrutiny and data requirements, in other words,
to match the evaluation of drugs with the way that they will be used in the
population. Short-term preapproval trials do not provide adequate informa-
tion about the balance of risks and benefits of drugs that are used by many
people for many years.
Various public- and private-sector organizations possess increasingly
high-quality data resources and scientific capacity, and a concerted effort is
needed to ensure that those resources are used efficiently and effectively in
the service of drug safety.
The assessment of risks and benefits is an activity that does not end
at approval, and risk and benefit cannot be considered in isolation of one
another.
SUMMARY
The fast pace of review does not allow CDER reviewers to solicit con-
sistently needed input from the appropriate FDA advisory committee(s) on
issues such as postmarketing safety and the need for additional studies.
4.8: The committee recommends that FDA have its advisory com-
mittees review all NMEs either prior to approval or soon after ap-
proval to advise in the process of ensuring drug safety and efficacy
or managing drug risks.
4.9: The committee recommends that all FDA drug product ad-
visory committees, and any other peer-review effort such as men-
tioned above for CDER-reviewed product safety, include a pharma-
coepidemiologist or an individual with comparable public health
expertise in studying the safety of medical products.
FDA’s credibility is its most crucial asset and recent concerns about the
independence of advisory committee members (who advise CDER in its
regulatory decision making), along with broader concerns about scientific
independence in the biomedical research establishment, have cast a shadow
on the trustworthiness of the scientific advice received by the agency.
4.12: The committee recommends that FDA post all NDA review
packages on the agency’s Web site.
Regulation
SUMMARY 11
The symbol should remain on the drug label and related materials for
2 years unless FDA chooses to shorten or extend the period on a case-by-
case basis.
5.4: The committee recommends that FDA evaluate all new data
on new molecular entities no later than 5 years after approval.
Sponsors will submit a report of accumulated data relevant to
drug safety and efficacy, including any additional data published
in a peer-reviewed journal, and will report on the status of any
applicable conditions imposed on the distribution of the drug called
for at or after the time of approval.
Communication
The public would benefit from more information about how drugs are
studied before FDA approval, how drugs’ risks and benefits are assessed,
and what FDA review entails. Patients also need timely information about
emerging safety concerns and about a drug’s effectiveness. Such information
would help patients make better decisions in collaboration with their health
care providers. FDA does not have an adequate mechanism for seeking and
receiving specific scientific and patient/consumer advice on communication
matters.
SUMMARY 13
Resources
CDER’s culture, its authorities, its scientific capacity, and its ability to com-
municate with health care providers and the public. The committee believes
that the recommendations contained in this report, implemented together
and with adequate resources, will enable the center (and the agency) to
function more effectively in the present and to position itself for an even
more challenging future in advancing and protecting the health of patients
and the public.
REFERENCES
Consumers Union. 2005. NEWS—IOM Panel Urged to Immediately Recommend that Con-
gress Toughen Drug Safety Laws to Save Lives: Consumers Union Testifies Today That
Obvious Safety Problems Need Action Now. [Online]. Available: http://www.pharmalive.
com/news/print.cfm?articleid=247043 [accessed June 9, 2005].
Grassley C. 2005. S.930: A bill to amend the Federal Food, Drug, and Cosmetic Act with
respect to drug safety, and for other purposes. 109th Congress.
Harris Interactive. 2005. The Public Has Doubts About the Pharmaceutical Industry’s Will-
ingness to Publish Safety Information About Their Drugs in a Timely Manner. [Online].
Available: http://www.harrisinteractive.com/news/printerfriend/index.asp?NewsID=882
[accessed March 10, 2006].
NCL (National Consumers League). 2005. Comments of the National Consumers League to
DKT. No. 2005N-0394, Communication of Drug Safety Information. [Online]. Avail-
able: http://www.nclnet.org/advocacy/health/letter_drugsafety_01062006.htm [accessed
September 16, 2006].
PricewaterhouseCoopers’ Health Research Institute. 2005. Recapturing the Vision: Integrity
Driven Performance in the Pharmaceutical Industry. [Online]. Available: http://www.
pwc.com/extweb/pwcpublications.nsf/docid/EE74BACB6DE454768525702A00630CFF
[accessed February 20, 2006].
US PIRG (United States Public Interest Research Group). 2006. Drug Safety. [Online]. Available:
http://uspirg.org/uspirg.asp?id2=17568&id3=US& [accessed September 16, 2006].
Introduction
“. . . FDA has become synonymous with drug safety. In a sense, ‘FDA ap-
proved’ is the brand that the entire $216 billion US drug market is founded
upon. Dilute the confidence of the public in the agency, and many billions of
dollars in current and potential sales vanish overnight. That’s exactly what’s
happening right now in the wake of the biggest drug withdrawal ever” (Herper,
2005).
with a view to identify areas of vulnerability and facets of the system that
could be strengthened in order to improve its overall functioning in meeting
the needs of the American public.
Complaints about delayed patient access to drugs already approved
in other countries and the AIDS advocacy movement of the 1980s are
considered among the major factors that motivated legislative action to
speed up FDA’s drug approval process. However, criticism of the pace of
drug approval may be traced to the early 1970s. At that time, pharmaceu-
tical companies, scientists, and consumer organizations argued that the
1962 Drug Amendments to the Food, Drug, and Cosmetic Act, intended
to strengthen the drug approval process by requiring that sponsors dem-
onstrate efficacy, also stifled drug development and delayed drug approval
(DHEW, 1977). In the 1990s, FDA attributed the delays to shortages of
staff and computers (FDA, 2005b). Concern about the slow pace of drug
review finally led to PDUFA.
The enactment of PDUFA in 1992 resulted from a potent combination
of interests. Patient advocacy groups called for faster access to promising
therapies, the industry desired a more efficient regulatory process to enable
faster marketing of new drugs and a longer patent life, FDA needed more
resources to expand its review staff to meet demand for greater regulatory
expediency, and some members of Congress were concerned that new drug
approvals in the United States lagged behind those of comparable European
nations. With congressional oversight and input, PDUFA was enacted with
the goal of meeting the needs of FDA, industry, and patients. Although the
1992 PDUFA succeeded greatly in decreasing review times (FDA, 2005b),
its first two iterations (PDUFA I in 1992 and PDUFA II in 1997, see below)
specifically prohibited the use of fees for any postmarketing drug safety
activities. Also, the speeding up of the review process highlighted poten-
tial weaknesses and limited capability in the area of postmarketing safety.
By the latter part of the 1990s, various observers, including consumer
groups and researchers, became concerned that the increased pace of drug
approvals had unintentionally led to a neglect of—or at least insufficient
attention to—safety considerations, resulting in what was seen as a greater
rate of drug withdrawals (Lurie and Wolfe, 1988; Hart, 1999; Tone, 1999).
Numerous journal editorials and articles by scientists, consumer advocates,
and agency leadership continued the dialogue (Kleinke and Gottlieb, 1998;
Wood et al., 1998; Friedman et al., 1999; Landow, 1999; Lurie and Sasich,
1999). In response to mounting unease, FDA Commissioner Jane Henney
convened “a Task Force to evaluate the system for managing the risks of
FDA-approved medical products” (DHHS/FDA, May 1999). Although
the task force found that rates of withdrawals were low (the limitations
of treating withdrawals as a safety metric are discussed below), the group
identified process, resource, and statutory constraints on FDA’s ability to
INTRODUCTION 17
INTRODUCTION 19
The year 2006 is technically the centennial of the 1906 Pure Food and Drug Act, but the
FDA asserts that “the modern era of the FDA dates to 1906 with the passage of the Federal
Food and Drugs Act” (CDER, 1998).
The administration of multiple drugs concurrently, with the concomitant increased risk of
drug interactions.
INTRODUCTION 21
Quality of care also has become a major issue for consumers. Pharmaceuti-
cal and health plan offerings are promoted to consumers now empowered
to be decision-makers. Patients have unprecedented access to information
about drugs, their benefits, and side effects. This is due in part to changes in
the information environment. Promotion of drugs to patients has increased,
including broadcast direct-to-consumer advertising. Access to the Internet
has become widespread; this powerful tool provides access to information
that varies greatly in accuracy, quality, and completeness (Tatsioni et al.,
2003). The relationship between patients and their physicians has changed
as patients have become more engaged and knowledgeable. Third, a cat-
egory of “lifestyle” drugs has arrived in the marketplace. Two decades ago,
patients used drugs chronically for treatment for and control of serious
diseases. Today, many fundamentally healthy people take drugs long-term
for purposes ranging from cosmetic improvement (such as botox) to symp-
tomatic management (such as antihistamines) to performance enhancement
(such as erectile dysfunction). For people who need to take drugs for control
or treatment of serious diseases, the potential of adverse drug effects may
be of less concern than it is for people who take drugs for very minor issues
(see Box 1-1 for some FDA milestones).
BOX 1-1
Some Key Milestones in FDA History
The Pure Food and Drug Act of 1906 gave FDA’s predecessor, the Bu-
reau of Chemistry in the Department of Agriculture, its first regulatory powers.
At inception, the agency’s pharmaceutical regulatory work focused largely on
misbranding and adulteration of drugs. In 1937, elixir sulfanilamide caused
more than 100 deaths and led to the passing of the 1938 Federal Food, Drug,
and Cosmetic (FD&C) Act. The act prohibited false therapeutic claims for drugs
and for the first time required premarket notification of FDA by the sponsor for
all new drugs. This meant that a company submitted its New Drug Applica-
tion (NDA) and, if FDA did not explicitly prohibit marketing, the company was
free to market the product without any type of approval after 60 days (unless
FDA extended that period to 180 days), when the NDA became “effective.”
Although the FD&C Act required a manufacturer to prove a drug’s safety by
conducting preclinical toxicity testing and gathering and submitting drug safety
data, it did not require proof of efficacy (Swann, 1998; Stergachis and Hazlet,
2002). Some two decades later, thousands of children with birth defects were
born to European mothers who had taken the popular sedative thalidomide
for morning sickness. Marketing of thalidomide in the United States had been
held up in the approval process and this so-called near miss led to the Drug
Amendments of 1962. The drug amendments required companies to provide
proof of efficacy of a drug for it to be considered for marketing approval, and
the randomized controlled trial became established as the gold standard for
demonstrating efficacy (Stergachis and Hazlet, 2002).
In the 1980s, the public health crisis of HIV/AIDS motivated a powerful
advocacy movement whose aims included faster approval of drugs for patients
with incurable disorders. Other consumer and patient advocacy groups began
to call for changing the drug approval process to speed up the availability
of potentially life-saving or life-sustaining drugs to patients in need of them.
Consumer groups, regulators, the regulated industry, and others contributed
to and Congress passed the PDUFA legislation that aimed to ensure that FDA
had adequate resources to expand its drug review staff and capabilities, and
so to increase the pace of drug reviews. Agreements among FDA, industry,
and Congress are crystallized in a series of performance goals for FDA. These
are not part of the PDUFA statute, so they lack the force of law (Tauzin, 2002)
but they reflect activities the agency considers its obligations—“The letter out-
lines goals that the agency must meet, which help frame the basis to judge the
INTRODUCTION 23
user fee programs success” (Tauzin, 2002). These goals are contained in the
“PDUFA Reauthorization Performance Goals and Procedures,” or the PDUFA
“goals letter” (a letter with enclosures), which is transmitted by the Secretary
of HHS to Congress annually.
PDUFA required that FDA and specifically CDER review staff meet cer-
tain performance goals and report annually to Congress on their progress in
meeting those goals. PDUFA also required that companies pay three types of
fees to FDA, including a one-time fee submitted with each NDA, an establish-
ment fee, and a product fee (FDA, 2005a,b).* Congress reauthorized PDUFA
in 1997 (as part of the FDA Modernization Act) and in 2002 as part of the
Bioterrorism and Preparedness and Response Act. In PDUFA I and II, funds
were limited to use to the review of sponsor applications for new drugs and
indications. No PDUFA funds were allocated to postmarketing drug safety
activities until 2002, when limited funds were allocated for limited safety activi-
ties. The 1992 PDUFA Amendments to the FD&C Act stipulated that PDUFA
user fees must not be used in lieu of but to supplement appropriations. FDA
was authorized to assess user fees only if appropriations for drug review were
equal to or greater than appropriations for salaries and other FDA expenses
in 1992 (Zelenay, 2005). PDUFA II set the trigger at 1997 levels: “Fees under
subsection (a) of this section shall be refunded for a fiscal year beginning after
fiscal year 1997 unless appropriations for salaries and expenses of the Food
and Drug Administration for such fiscal year (excluding the amount of fees
appropriated for such fiscal year) are equal to or greater than the amount of
appropriations for the salaries and expenses of the Food and Drug Admin-
istration for the fiscal year 1997 (excluding the amount of fees appropriated
for such fiscal year) multiplied by the adjustment factor applicable to the
fiscal year involved” (21 US Code 379h(f)). The adjustment factor is based on
the Consumer Price Index (Zelenay, 2005), and that may help explain why,
although the agency has always met the trigger that allowed the collection of
user funds, appropriations have grown at a much lower rate than user fees
(FDA, 2005b). Appropriations have not only not kept pace, but they have
declined since 2003, as FDA’s payroll costs have increased (FDA, 2005b).
*For FY 2006, the application fee is $767,400, the establishment fee is $264,000,
and the product fee is $42,130 (FDA, 2005a).
BOX 1-2
The Statement of Task
In response to growing public concern with health risks posed by
approved drugs, the FDA has requested that the IOM convene an ad
hoc committee of experts to conduct an independent assessment of the
current system for evaluating and ensuring drug safety postmarketing and
make recommendations to improve risk assessment, surveillance, and the
safe use of drugs. As part of its work, the IOM committee will:
• examine the FDA’s current role and the role of other actors (e.g.,
health professionals, hospitals, patients, other public agencies)
in ensuring drug safety as part of the US health care delivery
system;
• examine the current efforts for the ongoing safety evaluation of
marketed drug products at the FDA and by the pharmaceutical
industry, the medical community, and public health authorities;
• evaluate the analytical and methodological tools employed by
FDA to identify and manage drug safety problems and make
recommendations for enhancement;
• evaluate FDA’s internal organizational structure and operations
around drug safety (including continuing postmarket assessment
of risk vs. benefit);
• consider FDA’s legal authorities for identifying and responding to
drug safety issues and current resources (financial and human)
dedicated to postmarketing safety activities;
• identify strengths, weaknesses, and limitations of the current
system; and
• make recommendations in the areas of organization, legislation,
regulation, and resources to improve risk assessment, surveil-
lance, and the safe use of drugs.
This report does not address the related area of medication errors. That
was the purview of the IOM Committee on Identifying and Preventing
Medication Errors, whose report was released July 2006 (see Appendix E
INTRODUCTION 25
for that report summary). The present report does not treat several very
important issues that were not in the charge given to the committee, includ-
ing the regulation or safety of medical devices or biological products other
than those regulated by CDER; pharmaceutical product abuse, overuse, or
misuse; over-the-counter (OTC) drugs or the switch from prescription to
OTC status; generic drugs; drug pricing; or the causes and consequences of
the current challenges in pharmaceutical innovation. Finally, although the
postapproval stage of a drug’s life cannot be discussed in isolation from the
preapproval stages, this report does not consider in any detail the complex
ethical, practical, economic, and scientific issues related to the Investigation-
al New Drug process or the clinical trial conduct in the testing of drugs.
Study Process
and those of academe (written by Brian Strom); these papers were based in
part on small meetings convened by the authors and can be found in the
public access file.
A list of materials reviewed by the committee (in the form in which they were reviewed),
including all submissions of information from the public and many items not cited in this
report, can be found in the study’s public access file, obtained from the National Academies
Public Access Records Office at (202) 334-3543 or http://www8.nationalacademies.org/cp/
ManageRequest.aspx?key=162.
INTRODUCTION 27
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31
work of the NDA review process in CDER’s Office of New Drugs (OND)
and its offices of drug evaluation which conduct premarket reviews, and
in CDER’s Office of Drug Safety (ODS) (which is now called the Office of
Surveillance and Epidemiology, OSE, because of a restructuring of CDER
in May 2005) and its Division of Drug Risk Evaluation (DDRE), which
monitors postmarket risks and undertakes risk assessments. (Other divisions
and offices of ODS/OSE address safety issues, such as medication errors and
drug names.) The chapter does not address Abbreviated NDAs for generic
drugs that go through CDER’s Office of Generic Drugs. Nor are drugs that
are on special tracks, such as accelerated approval or orphan-drug status,
specifically addressed in this general description of how a new drug moves
through the system.
For the remainder of this chapter, we will refer to this office as ODS/OSE.
Division of Surveillance, Research and Communication Support and Division of Medication
Errors & Technical Support.
the drug’s likely indication, and assemble a review team. The team includes
a project manager and several scientific reviewers from OND and other
CDER offices as required (CDER et al., 1998). The reviewers then have the
remainder of the 30-day period to determine whether safety concerns justify
placing a hold on the human trials. In the absence of FDA action to delay
or prevent a trial, the sponsor can begin testing the compound in humans
on day 31 (FDA and CDER, 2006b).
FDA typically allows human trials to proceed if no serious safety con-
cerns have surfaced (FDA and CDER, 2001a). As occurs throughout the
review process, safety assessments and regulatory actions are influenced by
evidence of the potential benefit of the product. For example, reviewers are
likely to tolerate a higher threshold of toxicity for a drug that will be used
to treat life-threatening cancer than for a new antihistamine similar to those
on the market.
BOX 2-1
Phases of Clinical Trials and Medicine Development
Phase 1
Clinical pharmacology studies in healthy volunteers (sometimes subjects)
to determine the safety and tolerability of the drug/product, other dynamic
effects, and the pharmacokinetic profile (absorption, distribution, metabo-
lism, and excretion).
Phase 2
Clinical investigation studies in subjects with the target disease, to
determine efficacy, safety, and tolerability in carefully controlled dose-
ranging studies. Phase 2 studies are typically well controlled and closely
monitored.
Phase 3
Formal clinical trials. Large-scale placebo controlled and uncontrolled
studies in subjects to gather further information on efficacy and on the
safety and tolerability of the drug or product.
Phase 4
Postmarketing surveillance to expand safety and efficacy data in a large
population, including further formal therapeutic trials and comparisons
with other active comparators.
experience associated with the use of the drug that is both serious and un-
expected” or “any finding from tests in laboratory animals that suggests a
significant risk for human subjects including reports of mutagenicity, tera-
togenicity, or carcinogenicity” (21 CFR 312.33). The sponsor also submits
annual progress reports on the IND to FDA.
The regulators may direct the sponsor to undertake specific studies
or laboratory evaluations in studies to look for possible markers of safety
problems (such as liver toxicity or cardiovascular changes) on the basis of
previous experience or questions about the class of drugs or the mechanism
of action.
If the results of the early trials are promising, the sponsor and the review
team typically meet for an “end of phase 2 meeting” to discuss the upcom-
ing phase 3 trials. The phase 3 trials can involve fewer than 100 patients in
some cases or many thousands in others, depending on the target popula-
tion and the endpoints being evaluated (on the average, they involve about
600–3,000 patients). The drug is tested against a placebo or sometimes
against another drug (FDA, 2006c). The trials are designed and powered
to evaluate selected efficacy outcomes, not safety end points, although they
can generate safety signals to pursue. The “end of phase 2 meeting” can be
an important early point in the lifecycle of the drug to identify and track
potential safety issues and to ensure that the sponsor’s protocols address
key questions.
Roles of the Office of New Drugs and the Office of Drug Safety/Office of
Surveillance and Epidemiology Premarket Period
DNP and the Division of Psychiatry Products were combined in the past and were separated
in the 2005 reorganization of OND. They both continue to use the safety team, which now
officially reports to DNP.
safety team’s role is to quantify and set priorities among potential risks
posed by the drug they are reviewing. They do not make recommendations
on a drug’s approvability (Racoosin, 2006). The committee was told that
discussions have occurred in FDA about including a full-time safety officer
in the other ODS/ODE divisions. Two possible explanations for why that
has not occurred were offered: shortage of safety officers and the fact that
some divisions do not review enough applications to support a full-time
safety officer.
FDA may grant accelerated approval on the basis of surrogate endpoints, but approval is
conditional on sponsors’ undertaking or completing validation trials.
or millions of people use the drug (GAO, 1990; Okie, 2005; Racoosin,
2006). For example, bromfenac, a non-steroidal anti-inflammatory drug
(NSAID) marketed for 11 months in 1997–1998, was found to have serious
and sometimes fatal liver toxicity in about one in 20,000 people who used
the drug (Friedman et al., 1999); the NDA clinical trial base would have
had to include 60,000 patients to detect such an effect before marketing
(Friedman et al., 1999).
Preapproval clinical trials also have little information on the effects of
long-term exposure to the drug due to their often short duration. Further
more, clinical trials usually do not represent the full array of patients who
will use the product once it is approved. Trials often exclude patients with
comorbidities or those taking other medications, although both may be
common among future users of the marketed drugs. Elderly patients, ethnic
and racial minorities, and the very sick are underrepresented, and pregnant
women are generally excluded from trials. Drugs generally have not been
tested in children as part of the NDA, although patent-extension incentives
are aimed specifically at encouraging pediatric testing in children (Meadows,
2003).
Those limitations are inherent in the system and cannot be changed
without adding considerably to the time and expense of drug approvals,
which would delay patient access to potentially beneficial drugs. It is gener-
ally understood that it is not routinely realistic to require premarket trials on
tens or hundreds of thousands of subjects. Thus, inherent in the fundamental
design of the drug approval system is the delayed availability of important
safety data until a drug is used in larger and more diverse populations after
marketing. That approach means that the initial postmarket period is a criti-
cal time for developing a fuller understanding of a drug’s safety profile.
Premarket clinical trials are designed primarily with efficacy. Safety
issues sometimes surface, but the challenge is the possibility of unusual,
unexpected, undocumented risk. If sponsors and CDER reviewers are not
vigilant about identifying and pursuing safety signals in the trials, the op-
portunity to evaluate safety in the premarket trial period may be lost.
In the premarket period there usually is a shortage of information on
how a new drug compares with other treatments for the same indication.
Sponsors are not routinely required to submit such comparative trials to
obtain approval. Once a drug is on the market, it can be difficult to compel
sponsors or others to undertake appropriate comparative trials. Sponsors
usually do not initiate such trials unless they believe that their product has
a readily identified or demonstrable advantage. A postmarket comparative
trial of newer hypertension agents—angiotensin-converting enzyme (ACE)
inhibitors—against older diuretic drugs, for example, found the older drugs
to be more effective in reducing blood pressure (Appel, 2002). In addition,
comparative trials are expensive, and cost-benefit considerations are not
As trials are completed and analyzed, the sponsor meets with the review
team to go over the impending NDA submission; it is in the sponsor’s and
FDA’s interest to anticipate issues so that the NDA is complete when sub-
mitted. For example, a 2006 report indicated that when sponsors met with
CDER staff before submitting an NDA, there was a greater likelihood that
the drug was approved on the first cycle (FDA News, 2006b).
According to FDA documents, the discussions include development of
strategies to manage known risks (CDER, 2005b). ODS/OSE staff some-
times participate in the meetings; it may be the first time that ODS/OSE staff
become involved in the IND. (When OND is reviewing a supplemental NDA
for new labeling or manufacturing, ODS/OSE may be active in reviewing
available postmarket data on the approved indication.)
“Fast track is a process designed to facilitate the development, and expedite the review of
drugs to treat serious diseases and fill an unmet medical need. The purpose is to get important
new drugs to the patient earlier. Fast Track addresses a broad range of serious diseases” (FDA,
2006c).
leeway in how they present their summary safety and efficacy data and
where in this massive file they are found, reviewers must sometimes devote
considerable time to finding the critical safety data needed for the review.
ODS/OSE involvement is typically limited to meeting attendance and pro-
viding consults at this point in the process. The arrival of data on a rolling
basis can further complicate the process. Sponsors can submit materials
to the NDA fewer than two dozen times, as was the case with cinacalcet
hydrochloride (Meyer, 2004), or as many as 70 (or even more) times, as
occurred with sibutramine (Bilstad, 1997).
When FDA receives the final piece of an NDA the Prescription Drug
User Fee Act (PDUFA) clock begins ticking (FDA, 2005f). PDUFA was en-
acted in 1992 and reauthorized in 1997 (PDUFA II) and 2002 (PDUFA III).
It is up for reauthorization in 2007. The law provides for the pharmaceutical
industry to pay user fees to FDA to be used primarily to staff and resource
new drug (and biologic) review divisions, in exchange for which FDA agrees
to expedite drug reviews according to specific timetables. PDUFA has also
established deadlines to expedite the premarket review process, to schedule
meetings requested by industry, resolve disputes, to respond to questions
about study protocols, and develop guidances (see Box 2-2 and Appendix C
for the goals, and see Chapter 3 for additional discussion of PDUFA).
The PDUFA II and III goals call on FDA to review and act on 90 per-
cent of standard original NDAs within 10 months and 90 percent of prior-
ity NDAs in 6 months. A priority NDA review is intended for drugs that
“represent significant improvements compared with marketed products”
(FDA and CDER, 2005). PDUFA has resulted in a dramatic decline in new
drug review time. For standard NDA reviews, the median FDA review time
was 11.9 months in 2004, down from 20.8 months in 1993 (FDA, 2005d;
CDER, 2006). For priority NDA reviews, the median review time was 6.0
months in 2004, down from 16.3 months in 1993 (Weiss Smith, 2006).
Sponsor submitted data to FDA 19 times from September 8, 2003, through March 5,
2004.
Sponsor submitted data to FDA 85 times from August 7, 1995, through November 22,
1997.
substantive deficiencies in the file that cause FDA to “refuse to file” the ap-
plication (CDER et al., 1998). That occurs when the NDA has such critical
deficiencies that it clearly is not approvable as submitted. When submitted,
the NDA is also designated as a standard (10-month timetable) or priority
(6-month timetable) review by the division office or office director. A minor-
ity of NDAs have been designated as priority reviews. In 2004, for example,
29 of the 119 NDAs submitted were priority reviews, and the remaining
90 were standard reviews. Most priority reviews involve new molecular
entities (NMEs). An NME is defined as “a medication containing an active
substance that has never before been approved for marketing in any form in
the United States” (FDA and CDER, 2001b). Of the 119 NDAs submitted
in 2004, 36 were for NMEs, and 21 of these were assigned priority status.
(See Table 2-1 for past NME priority and standard approval numbers.)
There are inconsistencies in CDER documents in the use of medical review or clinical review.
They appear to be interchangeable terms. It has been suggested that use of clinical review indi-
cates that a primary reviewer need not necessarily be a physician, although most of them are.
In this report, we will use the more inclusive term clinical review or clinical reviewer.
BOX 2-2
Select PDUFA Goals
Clinical Development
Under PDUFA, FDA’s goal is to reply to a sponsor’s complete response to a
clinical hold within 30 days of the agency’s receipt of the submission of such
sponsor response, and do this for at least 90% of such submissions. Rapid
resolution of safety issues that lead to clinical hold helps ensure patient safety
while enabling access to the experimental treatment.
preparing and signing the written review of the NDA. The primary review
summarizes and analyzes the clinical data in the NDA and provides the
reviewer’s assessment and conclusions regarding the effectiveness and safety
data. It also sets out the reviewer’s assessment of the proposed directions
for use and includes a recommendation for regulatory action. The other sci-
entific reviewers will each write and sign “discipline reviews” that evaluate
the NDA from the point of view of their expertise, and the primary review
includes a summary of those reviews. The team leader will sign off on the
primary review, sometimes adding a memo that summarizes broader issues
or professional disagreements raised by the NDA (CDER, 2004).
If the NDA is for an NME—that is, an active substance that has not been
approved before—the OND office director or deputy director must sign off
on the approval. When it is not for an NME, the director or deputy director
of the review division in OND can sign off on the approval decision.
The NDA contains data from animal and human studies; it is illegal to
exclude any pertinent data. It also has information on product manufac-
turing and characteristics, packaging and labeling for both physician and
consumer, IND data, and the results of any additional toxicologic studies
that were not included in the IND (21 CFR 314.50) (CDER et al., 1998).
Data on the use of the drug outside the United States may be included in
the NDA. In the early 1980s, only about 2 or 3 percent of new drugs were
first marketed in the United States, so useful safety data on use abroad could
sometimes be included (Friedman et al., 1999). By 1998, that proportion
grew to 50 percent and the proportion of drugs launched in the United States
first has increased with each reauthorization of PDUFA: I, 25.23 percent; II,
47.19 percent; and III, 50 percent (FDA, 2005d; Okie, 2005).
Unlike their European counterparts who generally rely on the sponsor’s
summaries, FDA reviewers compile and reanalyze the data submitted by
the sponsor and use the analyses, as well as the one done by the sponsor, to
inform their decision about the drug.
Throughout the review process, the sponsor may be submitting amend-
ments in response to FDA requests or to complete work identified in the
pre-NDA meeting. If major amendments arrive in the last 3 months of
the review, the PDUFA clock may be extended (FDA, 2002). As issues
arise, the sponsor or FDA may request formal meetings during the process
to resolve disputes or discuss pending concerns. The number of such meet-
ings varies, but it is not uncommon for several meetings to be held while
the application is under review.
PDUFA establishes specific timelines for FDA to respond to an indus-
try request for a meeting, schedule the meeting, and distribute minutes
from it (FDA, 2005g). The PDUFA goals were associated with about a 33
percent increase in sponsor-requested meetings from fiscal year (FY) 1999
to FY 2004 (FDA, 2005d). That has required FDA staff to devote many
hours to planning, conducting, and following up on the meetings. Although
time-consuming and resource-intensive, the meetings can clarify issues and
improve the review process by reducing the risk of misunderstandings late
in the review process.
Advisory Committees
During the review process, a decision may be made, usually by the divi-
sion director, to convene an advisory committee meeting (see Box 2-3 for
deadlines to convene an advisory committee meeting). Advisory committees
are used as a source of independent advice from experts outside FDA (FDA,
2006b). Chapter 4 discusses advisory committees in more detail.
BOX 2-3
Timeline for Planning an Advisory Committee Meeting
Planning of an advisory committee meeting takes roughly 4 months and
involves the following:
logic drugs (FDA, 2006a). Advisory committees roughly match the medical
specialties of the review divisions in OND. In addition, the Drug Safety and
Risk Management Advisory Committee provides guidance on issues related
to safety and research methods (CDER, 2005a).
Typically, advisory committees are convened when applications involve
new or complex technologies or to address controversies (FDA, 2006b).
Sometimes, they are used to address general concerns not related to the ap-
proval of a specific product, such as the acceptability of a particular study
design or the use of a particular endpoint as a surrogate (FDA, 2006b).
Committees convened to assess an NDA may be asked to comment on
whether the data support product approval; on some unique aspect of safety,
effectiveness, or clinical development of the product; on whether additional
studies are needed; or on whether changes should be made in a drug’s label
or other action should be taken in response to new risk information after
a drug is approved.
After presentations by the sponsor and agency representatives and a
public comment period, the committee members usually vote on the ques-
tions posed to them by FDA staff. The votes are not binding (FDA, 2006b),
but FDA decisions usually are consistent with the majority vote. The meet-
ings can lead FDA to request additional information from the sponsors.
Safety Tracking
Dispute Resolution
10This MAPP provides a new pilot procedure for CDER staff to express their differing pro-
fessional opinions (DPOs) concerning regulatory actions or policy decisions with substantial
public health implications in instances when the normal procedures for resolving internal dis-
putes are not sufficient. The DPO procedure provides short timeframes for hearing a differing
professional opinion so that it can be resolved expeditiously, review of the DPO by qualified
staff not directly involved in the decisions, and evaluation of the pilot after 1 year to determine
whether it adds value to the regulatory decision-making process.
tor level. No CDER employees have used the program as of early 2006,
however.
The inclination of senior management at CDER to intervene at earlier
stages when disputes occur in CDER may be a function of management style
and the existence of processes that make them aware of developing issues, as
well as competing demands on their time. Senior managers are responsible
to constituencies both in CDER and outside CDER, such as the Office of
the Commissioner and Congress.
Some approval plans for NDAs include risk minimization action plans
(RiskMAPs), strategic plans developed by the sponsor to minimize known
risks posed by a product while preserving its benefits (DHHS et al., 2005).
They go beyond the requirements for all sponsors to minimize risks through
such efforts as accurate labeling and adverse event reporting. RiskMAPs ap-
ply primarily to products that “may pose a clinically important and unusual
type or level of risk” (DHHS et al., 2005). PDUFA (III) requires ODS/OSE
to be involved in reviewing RiskMAPs.
As part of PDUFA (III), OND and ODS/OSE (and FDA’s Center for
Biologics) developed guidance documents for industry on how to develop
RiskMAPS to assess, manage, and monitor known risks posed by a product
(both before and after approval). In its guidance (FDA, 2005b), FDA notes
that risk management (defined as risk assessment and minimization) is an
iterative process and sets out four steps: (1) assessing a product’s benefit/risk
balance, (2) developing and implementing tools to minimize the risks associ-
ated with it while preserving its benefits, (3) evaluating the effectiveness of
the tools and reassessing the benefit-risk balance, and (4) making appropri-
ate adjustments to the risk minimization tools to improve the benefit-risk
balance further. FDA calls for those four steps to be ongoing throughout
a product’s lifecycle, with the results of risk assessment informing the
sponsor’s decisions regarding risk minimization (FDA, 2005b).
RiskMAPS are relatively new and still a work in progress. CDER staff
have challenging scientific, policy, and resource issues to work out, both in
general and for specific drugs or classes of drugs.
specific medicines (as of July 2003) (Kennedy et al., 2004; FDA and Office
of Women’s Health, 2006).
Negotiations about the wording of a drug label also come late in the
process, when all the information about the drug has been pulled together.
The label specifies conditions of safe use of the drug (CDER et al., 1998).
It is the official description of a drug product and includes the drug’s indi-
cation; who should take it; adverse effects; special instructions for use of
the drug in pregnant women, children, and other populations; and safety
information for the patient. Although FDA can refuse to approve a drug if
the sponsor fails to agree to what the regulators want in the label, the final
label is typically a result of negotiations between regulators and sponsor.
In the case of serious safety concerns, FDA may direct the sponsor to
highlight a safety warning in the label by putting a black box around it.
These may be added to marketed drugs when new data become available.
A recent example are antidepressant medications, which now require a
black box warning describing the risk and emphasizing the need for close
monitoring of suicidality of patients (FDA News, 2004).
Although the product labeling is intended to guide prescribers in use of
a drug, studies show that prescribers often fail to follow the label (Public
Health Newswire, 2006). For example, cisapride was contraindicated in pa-
tients at increased risk for cardiac arrhythmias, but 20 percent of its use was
in such patients (Ray and Stein, 2006). The label for troglitazone specified
that liver-function tests were required, but often they were not performed
(Ray and Stein, 2006).
Some approved drugs (such as cisapride) have a narrow therapeutic
index; that is, the toxic dose is close to the effective dose so that there is a
small margin of error for triggering safety problems. Such drugs make it
incumbent on the sponsor and FDA to develop careful risk management
strategies and incumbent on practitioners to be cognizant of proper use.
The Institute of Medicine report Preventing Medication Errors discusses
matters related to patient comprehension of and adherence to medication
labeling (IOM, 2007). In an effort to improve awareness of labeling direc-
tions, FDA in January 2006 announced a revision of the label format (FDA
News, 2006a) (see Appendix A for more detail).
FDA requires sponsors to provide patient medication guides (known as
MedGuides) for drugs with “special risk management information” (FDA
and CDER, 2006a). There are 42 medications marketed by brand name
and 38 by active ingredient that have MedGuides that must accompany
them when they are dispensed (Wolfe and Public Citizen’s Health Research
Group, 2005; CDER, 2006) (see Chapter 6 for additional discussion).
FDA has imposed restrictions on the distribution of some new drugs
(such as drugs containing isotretinoin) which are discussed in Chapter 4.
But there appears to be a lack of clarity about the scope of FDA’s authority
under the Food, Drug, and Cosmetic (FD&C) Act to restrict distribution.
General counsels to FDA have apparently differed in their interpretation of
the FD&C Act in that regard over the last decade. The statute governing
medical-device regulation, which was enacted more recently than the FD&C
Act, is more explicit about FDA’s authority to restrict product distribution
to protect the public health.
Site Inspections
FDA may send the sponsor a “not approvable” letter that explains
why an application cannot be approved on the basis of current informa-
tion, an “approvable” letter stating that the product could be approved if
specified additional actions were taken, or an “approval” letter indicating
that the product has been approved with specified labeling and postmarket
requirements (21 CFR 314.100a [2001]). The review team participates in
the drafting of the letter, and it is signed by the division director or office
director, depending on the product. (See Box 2-4 for a list of NDA review
elements.)
POSTMARKET PERIOD
Historically, drugs undergoing premarket review have received more
attention in and outside FDA than drugs that are in the marketplace. There
is now growing awareness that a robust drug safety system requires a life-
cycle approach (Crawford, 2005) and that drug approval triggers a critical
period for monitoring safety. The budget for postmarketing surveillance and
assessment is not commensurate with FDA’s growing scope.
DDRE in ODS/OSE monitors marketed drugs and prepares safety
reviews and risk assessments. Although ODS/OSE staff may contribute to
the development of risk management plans, it is OND that has responsibility
for deciding what regulatory action to take in response to new safety infor-
mation. ODS/OSE has undergone enormous change in the last decade, with
BOX 2-4
Current Review Elements for New Drug Approval
• Periodic team progress check-ins
• Midcycle review meeting
• Team or subgroup interaction on particular issues
• Primary review completion
• Secondary (team leader or branch chief) review
• Review division director, or higher level, review
• Consult review input
• Advisory committee meetings
• Internal briefings for signatory authority
• Wrap-up (integration of review, consult, and inspection input)
• Preapproval safety conference (CDER)
• Preapproval facility inspections (BLAs)
• Labeling negotiation
• Issuance of action letter by PDUFA goal date
Since 1997, when FDA eased rules for DTC advertising, companies have
greatly expanded their use of it to promote drugs via the mass media (Gahart
et al., 2003; Gilhooley, 2005). According to a 2004 study (Brownfield et al.,
2004), the average television viewer spends 100 minutes watching DTC
advertising for every minute in a doctor’s office. Typically, less is known
about the safety of a new drug than of an older drug on the market, but the
public is not likely to be aware of this and may simply assume that a new
drug is a better drug.
The FDA’s primary source for managing and monitoring new adverse
effects of marketed drugs is the Adverse Event Reporting System (AERS),
an automated system for storing and analyzing safety reports. ODS/OSE
has primary responsibility for AERS (FDA, 2004c).
Adverse event reports have several sources. When an adverse event is
both serious11 and unexpected (not listed in the drug product’s current la-
beling), drug sponsors are required to report it to FDA within 15 calendar
days (“15-day reports”). Sponsors must also submit periodic reports that
summarize all adverse events quarterly for the first 3 years after the NDA
was approved and annually over multiple years (FDA, 2005a).
Another source of spontaneous reports is FDA’s voluntary reporting
system, MedWatch, which covers drugs and other FDA-regulated products.
MedWatch enables health care professionals and consumers to file adverse
event reports directly to FDA via telephone, completion of FDA Form 3500
online, or via fax or mail (FDA, 2003).
FDA receives more than 400,000 spontaneous reports each year as part
of the surveillance system. In FY 2004, for example, ODS/OSE received
422,889 adverse event reports (see Box 2-5 for a breakdown) (FDA and
CDER, 2005). Although exact figures are not available, that is assumed
to represent a small fraction of all adverse effects of drugs. The system
contains 3–4 million reports accumulated from multiple years (FDA and
CDER, 2005).
Most adverse event reports arrive on paper via fax. ODS/OSE has
placed a high priority on increasing the number of reports filed electroni-
cally to both expedite and reduce the cost of receiving and processing the
report. In FY 2004, 16 percent of all reports were submitted electronically,
up from 10 percent in FY 2003 (FDA and CDER, 2005). In the European
11A serious adverse event is any untoward medical occurrence that at any dose: results in
death, is life threatening, requires inpatient hospitalization or prolongs existing hospitalization,
results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect
(CFR 312.32).
BOX 2-5
Adverse Event Reporting in 2004
In 2004, FDA received 422,889 reports of suspected drug-related ad-
verse events:
Although AERS data may provide the initial signal of a safety problem,
other studies and databases are typically needed to investigate associations.
Those data include results of clinical trials and epidemiologic studies that
are conducted, or whose results are available, after a drug is approved.
The sponsors’ phase 4 trials are intended to expand the understanding
of the safety and efficacy profile, of selected drugs. However, many of these
studies are not completed (or even begun), for various reasons described
above. FDA lacks the regulatory tools to adequately compel sponsors to
complete appropriate studies (see Chapter 5 for more information). Accord-
ing to a March 2006 report, out of 1,231 agreed-on (by the sponsor) open
postmarket commitments of drugs and biologics, 797 (65 percent) have yet
to be started12 (FDA, 2006d).
Another source of postmarket safety data is studies of marketed drugs
designed to investigate new or expanded indications. Sponsors may include
these studies in an efficacy supplement submitted to FDA seeking expanded
label indications. Sometimes these studies may yield important data. For
example, the APPROVe (Adenomatous Polyp Prevention on Vioxx) trial
was designed to identify a new application for rofecoxib and showed an
increased risk of serious cardiovascular events with rofecoxib compared
with placebo—this cardiovascular impact was a secondary consideration
(FDA, 2004b). Post-marketing safety information may also be generated by
sponsors through the establishment of active surveillance systems, such as
pregnancy-exposure registries (Ackermann Shiff et al., 2006).
The National Institutes of Health (NIH) or other agencies may also
sponsor trials to gain new information about marketed drugs. Examples
are the NIH-funded randomized controlled primary prevention trial, the
Women’s Health Initiative, which reported on adverse health effects of
and benefits from use of combined estrogen and progestin (Rossouw et al.,
2002). An earlier NIH-funded study, the cardiac arrhythmia suppression
trial, found that drug treatment for asymptomatic ventricular arrhythmia in
patients who had a heart attack did not prevent—and in fact substantially
increased the risk of—sudden cardiac death. FDA had used a drug’s effect on
12231 (19%) are ongoing; 28 (2%) are delayed; 3 (1%) have been terminated; 172 (14%)
have been submitted.
the case in Med Watch; they would prefer that similar studies be published
together giving physicians and patients the opportunity to see the data in
context (Agres, 2006). This has prompted FDA to rethink the program, so
launch of that program has been delayed (FDA, 2005c,e).
To help to resolve uncertainties, discuss issues publicly, or consider
regulatory strategies to address a risk, an advisory committee meeting may
be held. Members of the Drug Safety and Risk Management Advisory Com-
mittee and the committee with expertise in the specific class of drugs are
typically involved.
Regulatory Actions
staff respondents about how safety issues are handled (DHHS/OIG, 2003)
although senior management has strongly defended controversial actions
(IOM Staff Notes, 2005–2006). FDA does not routinely conduct “postmor-
tems” of drug withdrawals as a basis for examining and possibly improving
its procedures. Drugs withdrawn from the market have been reinstated by
FDA for use with restrictions at the request of the sponsor (see Box 2-6 for
summary of this case).
One important issue for FDA and all other stakeholders in drug safety
is the limited effectiveness of these regulatory warning tools in promoting
drug safety. Although changes in the information provided in a label is a key
tool for responding to and communicating new safety information, studies
show that many patients are at risk because providers and the patients do
not consistently heed labels, including the most serious black box warnings
(Lasser et al., 2006).
It is worth underscoring that the fundamental design of the drug ap-
proval system described above—separate from the quality of the data that
sponsors generate in compliance with it—inevitably puts drugs on the mar-
ket when safety information is incomplete. The obvious corollary is that the
postmarket monitoring system, as well as the premarket review processes,
must be as effective and efficient as possible.
BOX 2-6
The Story of Alosetron (Lotronex)
November 1999—FDA advisory committee recommends approval
February 2000—FDA approves Alosetron for treatment of “diarrhea-
predominant irritable bowel syndrome” in women
June 2000—FDA advisory committee meeting discusses evidence of
serious adverse events and votes to retain the drug on the
market
November 2000—F DA and the sponsor meet, sponsor withdraws
Alosetron
December 2001—sponsor proposes returning Alosetron to market with
restrictions
April 2002—FDA advisory committee recommends return to market with
restrictions
June 2002—FDA approves Alosetron’s return to market, with less rigor-
ous restrictions than those recommended by the advisory
committee
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A Culture of Safety
ORGANIZATIONAL CHALLENGES
A number of highly publicized events, including the Vioxx withdrawal
and concern about other cox-2 inhibitors, and ongoing drug safety problems
including those related to salmeterol, Ketek, and others have brought FDA’s,
and specifically CDER’s, performance under the scrutiny of the American
public (via the mass media) and Congress (Harris, 2006b; Hendrick, 2006;
Washington Drug Letter, 2006). Critics have charged that there were fail-
ures or delays in informing patients about important drug risks, inadequate
postmarketing assessment of drug safety, and failures to follow up and
enforce sponsors’ postmarketing study commitments agreed on at the time
of approval. Others have expressed concern that the recent focus on safety
could reverse considerable gains in the pace of drug review and the speed
of approving new therapies.
65
A CULTURE OF SAFETY 67
BOX 3-1
Committee Information Gathering About CDER
Organizational Culture
To inform its deliberations, the committee held information-gathering
sessions to hear from FDA and other stakeholders (see Appendix D).
A small group of committee members and Institute of Medicine (IOM)
project staff visited CDER on October 11, 2005, and February 22, 2006.
From November 7, 2005, to May 2006, IOM staff with rotating committee
representation of one or two members also held confidential discus-
sions with over 30 current FDA staff, including personnel from the Office
of New Drugs (OND) and the Office of Drug Safety (recently renamed
Office of Surveillance and Epidemiology and referred to hereafter as
ODS/OSE), FDA and CDER management, and several former FDA staff
and leaders.*
The committee’s high regard for the professionals who perform CDER’s
preapproval and postapproval functions under considerable time and
resource constraints was reinforced by these conversations. As the com-
mittee gained greater understanding of CDER’s work and functioning,
committee members were able to identify or confirm a number of struc-
tural and related cultural challenges, including a troubling relationship
between OND and ODS/OSE, insufficient management and leadership
to address emerging problems and implement needed reforms, a lack of
clear and consistent processes (for example, for identifying and address
ing drug safety concerns both in the review process and in the post
marketing period, for determining the need for and nature of postmarket-
ing, or phase 4, studies), overextended human and financial resources,
and pressures added by the requirements of the current user-fee funding
mechanism that funds about 50% of CDER’s work (FDA, 2005b).
The major themes that emerged from the committee’s conversations
are consistent with those identified in government reports on FDA and
CDER. The committee also found it helpful to refer to assessments of
organizational problems in other government agencies that deal with risk
and uncertainty, albeit in very different contexts, such as the National
Aeronautics and Space Administration and the Federal Aviation Admin-
istration (GAO, 1996; Return to Flight Task Group, 2005).
*At the committee’s request, the CDER Director sent a letter to all center staff
urging them to contact IOM study staff if they wished to discuss issues related to
their work and recent concerns.
Source: http://www.fda.gov/cder/learn/CDERLearn/.
A CULTURE OF SAFETY 69
s ector counterparts because of a wide array of laws and regulations and the
requirement that they be responsive to the often conflicting expectations of
multiple constituencies (Ostroff, 2006).
For FDA, and specifically CDER, the environment is shaped by many
factors. First, the evolution of FDA’s regulatory role has been shaped by the
expectations of American society, as expressed through its national legisla-
ture, in its courts, and in the influence of its patient and consumer advocacy
movements. The American public desires timely access to effective and safe
therapies. Legislative attention to the regulation of drugs (and other prod-
ucts in FDA’s purview, has resulted in the statute that dictates FDA’s role: the
Food, Drug, and Cosmetic (FD&C) Act of 1938 and its many subsequent
amendments. Another influence on FDA’s work is the economic and political
agenda of a powerful and influential industry, whose concerns include the
potential of regulation to dampen innovation. The health care delivery sys-
tem (organizations, payors, pharmacies, etc.) and health care professionals
who act as intermediaries between patients and the drug development and
distribution system are another factor in FDA’s environment. Patients must
secure a prescription from a qualified health care provider, and health care
providers can only prescribe drugs that are approved by FDA. FDA actions,
including findings from postmarketing surveillance, inform drug formulary
and reimbursement decisions by payors. Although FDA does not regulate
drug pricing, and cost-effectiveness is not a consideration, these are impor-
tant issues to the health care delivery system, given financial constraints
and the diverse therapeutic needs of its patients. A final crucial dimension
of FDA’s external environment is the potential influence exercised by the
top levels of the executive branch (the White House, the Office of Manage-
ment and Budget) and the legislative branch. Congress plays an oversight
function and provides a forum for the push and pull of legislative factions
concerned with consumer safety and those inclined toward spurring eco-
nomic competitiveness. Congressional concern about the public’s safety may
be one contributing factor to what the industry and other critics have seen
as the agency’s historically risk-averse stance in carrying out its regulatory
duties. In their view, the agency has generally been more likely to err on
the side of greater caution in approving drugs than to err on the side of
faster approval, perhaps in response to the fact that congressional investiga-
tions generally focus on errors of commission (approving an unsafe drug)
rather than omission (not approving a potentially good drug) (Cohn, 2003;
Steenburg, 2006).
The multiple and often conflicting pressures of the external environ-
ment add to the complex nature of the agency’s work (science-based
decision making) and the enormous medical, social, and economic impact
of its regulatory decisions. FDA has a dual mission: to protect public
health “by assuring the safety, efficacy, and security of human . . . drugs”
and to advance public health “by helping to speed innovations that make
medicines . . . more effective, safer, and more affordable.” Balancing speed
and safety is not always easy. Many drugs are both life-saving, motivating
timely approval and release to the marketplace, and life-threatening, requir-
ing careful monitoring of safety and rapid action to address safety risks as
appropriate. The challenge in regulating prescription drugs is to weigh the
available evidence of efficacy and safety in the context of the prevalence and
severity of specific disorders, and the availability, safety and efficacy of other
approved therapies. Although FDA and the industry share an interest in
the discovery and development of beneficial products that improve health,
the decisions of regulators may affect the regulated industry’s success in the
marketplace (House of Commons Health Committee, 2005a,b).
Two dimensions of the external environment deserve more detailed dis-
cussion in the context of this report. These include the relationship between
FDA and the industry, which has been complicated by PDUFA, and FDA’s
relationships to Congress and to the White House.
The Critical Path initiative is an example of FDA’s interest in supporting innovation in drug
discovery; it maps the way forward for applying cutting-edge science to drug discovery.
A CULTURE OF SAFETY 71
However, it has had some drawbacks, including increasing the agency’s de-
pendence on industry funding for its drug review activities, severely skewing
CDER’s focus to facilitating review and approval perhaps at the expense of
other center activities, and creating an environment of intense pressure on
its reviewers (Zelenay, 2005). A Department of Health and Human Services
(DHHS) Office of the Inspector General (OIG) survey of CDER staff found
that 40 percent of “respondents who had been at FDA at least 5 years in-
dicated that the review process had worsened during their tenure in terms
of allowing for in-depth, science-based reviews. Respondents cited lack of
time as the main reason” (DHHS and OIG, 2003).
In discussions with FDA staff, the committee learned that the emphasis
on timely review that is at the core of PDUFA and is linked with specific
performance goals has added to reviewer workloads despite the increase
in review staff. FDA must report to Congress annually about its success in
reaching the performance goals. Some observers have charged that increased
speed of review has led to decreased safety, in part because the time de-
mands of PDUFA limit the ability of reviewers to examine safety signals as
thoroughly as they might like (Sasich, 2000; Wolfe SM, 2006). Performance
goals with reporting requirements for actions relating to review speed, but
not for other actions, such as postmarketing safety monitoring and risk
communication, may lead to the assigning of higher priority to those actions
that have associated performance goals.
There has been some debate about PDUFA’s effect on drug safety as
demonstrated by drug withdrawals. Abraham and Davis (2005) found that
in the period before enactment of PDUFA the United States had 50 percent
fewer drug withdrawals than the United Kingdom largely because of the
longer periods that the FDA took to review drug applications. They sug-
gested that US efforts to speed approval may be compromising drug safety
in the PDUFA era. However, drug withdrawals are very rare occurrences
in general, and the total number of withdrawals in the last two decades of
the 20th century represents a modest figure that may not be useful for gen-
eralization. For example, in reviewing 20 drug withdrawals in 1980–2004
(nearly half of which occurred before PDUFA was enacted), the Tufts
Center for the Study of Drug Development found that “no trend emerges
between speed of approval and withdrawal” (Tufts Center for the Study
of Drug Development, 2005). Drug withdrawals are just one indicator of
drug safety; the timeliness of a withdrawal may be more important than the
fact of the withdrawal. Furthermore, drug withdrawals say nothing about
the safety of drugs that remain on the market and continue to affect public
health. Olson (2002) makes the point that drug withdrawal data are of
limited value in drawing inferences about drug safety more generally and
instead focuses on adverse drug reactions among all new chemical entities
approved between 1990 and 1995. The Government Accountability Of-
BOX 3-2
A Short History of the Prescription Drug User Fee Act (PDUFA)
1992
Use revenues from user fees to achieve certain “performance goals”
• Primary focus: decrease review times
PDUFA I Commitments:
• Complete review of priority original new drug and biologic applications
and efficacy supplements (90% in 6 months)
• Complete review of standard original new drug and biologic applica-
tions and efficacy supplements (90% in 12 months)
• Complete review of priority supplements (90% in 6 months)
• Complete review of standard supplements (90% in 12 months)
• Complete review of supplements that do not require review of clinical
data (manufacturing supplements) (90% in 6 months)
• Complete review of resubmitted new drug and biologic applications
(90% in 6 months)
1997
PDUFA II was reauthorized for 5 years (FY 1998–2002) as part of Title I of
the Food and Drug Administration Modernization Act
• Primary focus: decrease review times and shorten development
times
New PDUFA II commitments:
• Complete review of resubmitted efficacy supplements (90% in 6
months)
• Respond to industry requests for meetings (90% within 14 days)
• Meet with industry within set times (90% within 30, 60, or 75 days
depending on type of meeting)
• Provide industry with meeting minutes (90% within 30 days)
• Communicate results of review of complete industry responses to FDA
clinical holds (90% within 30 days)
• Resolve major disputes appealed by industry (90% within 30 days)
• Complete review of special protocols (90% within 45 days)
A CULTURE OF SAFETY 73
2002
PDUFA III was reauthorized for 5 years (FY 2003–2007) as part of Public
Health Security and Bioterrorism Preparedness and Response Act
• Focus: expand interaction and communication in IND phase and during
first cycle review
• Includes some funding for postmarket safety for 2–3 years after drug
approval for drugs approved after 2002
New PDUFA III commitments:
• Discipline review letters for presubmitted “reviewable units” of new
drug and biologic applications (90% in 6 months)
• Report of substantive deficiencies (or lack thereof) (90% within 15
days of filling date)
Changes to commitments:
• Complete review of resubmitted efficacy supplements (90% of class
1 in 2 months and 90% of class 2 in 6 months instead of all in 6
months)
• Electronic application receipt and review (enhanced by end of FY
2007)
The second basic issue explored by the Panel was whether industry exerts undue
influence on FDA decisions. Many current and former FDA employees and
consultants had testified to Congressional committees that industry pressure
caused FDA officials to approve drugs that did not meet agency safety and effec-
tiveness standards and that those who attempted to oppose industry demands
were harshly and improperly treated by senior FDA officials. From detailed
investigations of these allegations by its staff, the Panel concluded that there
was no widespread use of improper influence by industry representatives. It did
identify several instances in which FDA supervisors unfairly disciplined dissent-
ing employees, but these lapses were found to result from poor management
rather than improper efforts of industry to control agency decision-making
[Dorsen and Miller, 1979:910].
A CULTURE OF SAFETY 75
A CULTURE OF SAFETY 77
BOX 3-3
Composition of the NDA Review Team
Review teams include a review project manager (RPM) and primary
reviewers, who complete the discipline reviews, as needed, in the follow-
ing disciplines:
• Medical/clinical*
• Pharmacology/toxicology
• Chemistry manufacturing, and controls
• Biometrics/statistical
• Clinical pharmacology and biopharmaceutics
• Clinical microbiology
• Bioresearch monitoring.
*CDER documents appear to use the terms “medical review” and “clinical review”
interchangeably. It has been suggested that use of the phrase “clinical review”
indicates that a primary reviewer need not necessarily be a physician, although
most of them are. In this report we will use the more inclusive term “clinical review”
or “clinical reviewer.”
A CULTURE OF SAFETY 79
Management
There have been many opportunities for CDER and FDA leadership to
acknowledge to the committee and to others that there is a culture problem
BOX 3-4
Clinical Review Template—Postmarketing Actions
In July 2004 CDER issued MAPP 6010.3, the Clinical Review
emplate (CDER, 2004a), which established procedures for document-
T
ing the primary clinical review of NDAs. The clinical review is one of the
discipline reviews prepared in response to an original or supplemental
NDA (or Biologic License Application reviewed by CDER), amendments
in response to action letters, and efficacy supplements. The MAPP
describes the format of the discipline review and the responsibilities of
the reviewers, other team members, and those in the supervisory chain.
The review template includes 11 sections:
1. Executive Summary
2. Introduction and Background
3. Significant Findings from Other Review Disciplines
4. Data Sources, Review Strategy, and Data Integrity
5. Clinical Pharmacology
6. Integrated Review of Efficacy
7. Integrated Review of Safety
8. Additional Clinical Issues
9. Overall Assessment
10. Appendices
11. References
A CULTURE OF SAFETY 81
A CULTURE OF SAFETY 83
Interoffice Polarization
A CULTURE OF SAFETY 85
In August 2006, the Union of Concerned Scientists (UCS) and Public Employees for Envi-
ronmental Responsibility released their survey of FDA, which included the survey instrument
used in the 2003 DHHS OIG survey. UCS findings echoed those reported by OIG in 2003,
including the response to “Have you ever been pressured to approve or recommend approval
for an NDA despite reservations about the safety, efficacy, or quality of the drug?” Of 217
CDER staff who responded to this question, nearly 19% (41) said “yes” (UCS, 2006a,b). Af-
ter the UCS release, FDA Acting Commissioner Andrew von Eschenbach met with UCS staff,
acknowledged his concern about the issues related to morale identified in the survey, and also
vowed to work to create “an environment where there is free, open and vigorous debate and
discussion” (UCS, 2006a,b). In the course of Senate committee questioning during the August
1, 2006, nomination hearing, Dr. von Eschenbach was asked about the UCS survey question
regarding “pressure to approve . . . despite reservations.” The acting commissioner stated that
“no one should ever alter the data or the scientific facts” (von Eschenbach, 2006).
A CULTURE OF SAFETY 87
clear whether DSB can on its own initiative address an issue of which it has
become aware if it is not formally referred to them. The DSB emerged as part
of the agency’s response to congressional and public concern over highly
publicized drug safety problems. Because many critics called for independent
external oversight of drug safety, the creation of the board was believed by
some to be a solution to address that particular concern (FDA, 2005c). The
composition of the board caused confusion and gave rise to criticism that
the board as constituted was not independent. That confusion was furthered
by FDA’s silence on the board’s actual (and potentially useful) function, and
the underlying public and legislative concern about independence was left
unaddressed. Because the DSB has been in operation for only a short time,
it is too early to judge its effectiveness, but some of its drug safety problem
resolution, management, and policy functions seem to constitute a sensible
approach. DSB is analogous to industry practices of bringing together lead-
ers of different groups in a company to consult with a group facing a difficult
problem. However, the committee believes that the external communication
function of the board seems to be a vastly different and equally important
set of concerns that should be handled by a different entity in CDER (see
Chapter 6). That would allow the DSB to focus its energies and resources
on addressing the internal management of drug safety issues.
There has been additional confusion about the apparent overlap between
the Drug Safety and Risk Management Advisory Committee (DSaRM) and
DSB. CDER management has described the latter as a “venue for resolv-
ing CDER organizational drug safety disputes” and “discussing [the] need
for AC [advisory committee] meetings about emerging safety information”
whereas DSaRM has been described as a way to obtain public input and fa-
cilitate discussion to inform CDER decision making. The committee believes
that DSaRM fulfills the function of the sought-after independent, external
safety advisory and review body, in contrast with DSB, which is intended to
bring serious and complex internal safety issues to resolution.
Inconsistency
For example, one division’s model for ensuring internal safety capacity by
establishing its own safety team of epidemiologists has attracted interest in
CDER and from drug safety advocates but has not yet been replicated in any
other division (the committee has heard that this model may be expanded
to other divisions).
That is the Neuropyschiatry Drug Products Division was recently split into two, a Neurol-
ogy Products Division and a Psychiatry Products Division. The safety team currently resides
in the Division of Neurology Products but supports both divisions.
A CULTURE OF SAFETY 89
a commissioner, arguing that the industry and the nation needed “strong
leadership from an FDA commissioner with vision and experience in science,
medicine and administration” (BIO, 2002). In the same year, the PhRMA
president and CEO reported that the industry was challenged by the absence
of agency leadership and that PDUFA negotiations were slowed down by
the absence of a commissioner (National Journal’s Congress Daily, 2002;
Validation Times, 2002). Former commissioner Jane Henney stated that in
the absence of leadership, “industry loses because it needs predictable and
strong signals about the review process, the consumers need to make sure
somebody is in charge and the FDA staff needs somebody who can take the
heat if necessary” (Kaufman, 2004a). In 2002, FDA staff were questioned
in a congressional hearing without the support of a Senate-confirmed com-
missioner (Kaufman, 2004a). In the 2005 Senate committee session on the
nomination of the then Acting Commissioner, Senator Enzi cited a letter
from the Senate committee to the president urging the nomination of a
commissioner “to provide the agency with greater clarity and certainty in
its mission,” and stated that a “fully confirmed Commissioner is essential
to ensuring that these medical breakthroughs can be brought to the market
safely and effectively. Consumers deserve to have a fully functional FDA
that can oversee the industry with confidence and authority and harness the
technical achievements that can improve and save lives” (Senate Executive
Session, July 18, 2005).
Management literature has made it clear that organizations, including
government agencies, cannot function well without effective leadership to
set them and keep them on course to achieve their mission (GAO, 1996).
In the last 30 years, FDA has had eight commissioners and seven acting
commissioners (including the current acting commissioner) or, when the
post was vacant, an acting principal deputy commissioner. The eight com-
missioners have served an average of 2.5 years with a range of 2 months to
6.3 years (FDA, 2006b). That instability is thought to have contributed to
CDER’s problems. CDER is the largest center in the agency, the center direc-
tor reports to the commissioner, and the center’s decisions and their reper-
cussions are highly visible and sometimes controversial, as was the case with
the Plan B over-the-counter switch application (GAO, 2005). The committee
believes that turnover and instability in the commissioner’s office leave the
agency without effective leadership or the potential to emphasize safety as
having high priority in the work of the agency. Without stable leadership
strongly and visibly committed to drug safety, all other efforts to improve
the effectiveness of the agency or position it effectively for the future will be
seriously, if not fatally, compromised. A priority for the agency should be to
regain the trust of the public while positioning itself for the future.
The controversy over the emergency contraceptive Plan B has further
highlighted the power of the commissioner. In this area, the political environ-
A CULTURE OF SAFETY 91
Agency Leadership
In 1996, Congress asked GAO to determine whether performance problems at the Federal
Aviation Administration were related to its organizational culture. GAO found that the cul-
ture impeded the agency’s work. Characteristics highlighted included a system of bureaucratic
incentives that rewarded staff who preserved the status quo and punished those who identified
problems (GAO, 1996). Assessments of government agency performance and examples from
the management literature have shown repeatedly that organizational cultures that stifle dis-
sent, exclude staff from decisions about the organization’s vision, and allow cultural problems
to linger unaddressed are not healthy cultures, and those problems interfere with their ability
to achieve their goals (Weick and Sutcliffe, 2001; Heifetz and Laurie, 1998; Khademian, 2002;
Return to Flight Task Group, 2005; O’Leary R, 2006).
emerged that the basis for decision making was not scientific, but other
types of considerations (Bridges, 2006; Rockoff, 2006; Washington Drug
Letter, 2006).
Finally, the committee believes that a fixed-term appointment for the
FDA commissioner may help to lessen turnover. Reports from GAO and
from the National Academy of Sciences (NAS) have found that turnover in
government agency leadership is linked with a focus on short-term goals and
uncertain accountability and that fixed terms for presidential appointments
help to ensure stability and strengthen an agency’s leadership (GAO, 1996;
GAO, 2003). Currently, presidential appointment with Senate confirmation
positions for fixed terms include: surgeon general of the Public Health Ser-
vice, 4 years; director of the National Science Foundation (NSF), 6 years;
commissioner of the Bureau of Labor Statistics, 4 years; under secretary
for health in the Department of Veterans Affairs (also the Chief Executive
Officer of the Veterans Health Administration), 4 years; commissioner of
the Social Security Administration, 6 years; and commissioners of the Fed-
eral Communications Commission, 5 years. Another NAS committee that
recommended a 6-year term for the National Institutes of Health (NIH)
director concluded that the NSF director’s 6-year term “has been a good
model for creating a system of accountability and periodic review that has
the possibility of transcending changes in administration” (NRC, 2003).
Fixed terms can vary in length, be renewable or not, and have more or
less strict terms of removal, depending on the degree of insulation desired. In
all cases, to be constitutional, the president must retain the power of remov-
al—incumbents of term appointments should be accountable and subject to
removal by the president. On the one hand, establishing a term appointment
and specifying the reasons for which an appointee may be removed changes
the terms of removal to some extent. It creates a presumption that individu-
als in these positions should stay rather than be automatically removed with
every change in administration, and it requires an administration to give
good reasons for such a removal. On the other hand, the use of terms also
indicates that there should be periodic turnover—not for partisan reasons
but to ensure new blood and fresh ideas.
A CULTURE OF SAFETY 93
mittees: DHHS consults with the NAS on the composition of the National Vaccine Advisory
Committee, and the Consumer Product Safety Commission appoints a Chronic Hazard Ad-
visory Panel of independent scientific experts from nominations submitted by the president
of the NAS.
members would serve staggered 3-year terms that may be renewed once.
The board would meet no less frequently than twice a year.
The Management Advisory Board would assist FDA and CDER in their
efforts to understand how organizational culture in the center is shaped by
the environment, by a legacy of structural imbalance, and by management
problems. The committee has learned that a variety of promising steps have
been taken to improve interactions among offices, evaluate and improve in-
ternal processes, and even familiarize disciplines with one another. However,
given CDER’s long history of reorganizations, external studies, and fitful
change initiatives, the committee is not optimistic that current efforts will
be sustained without the absolute commitment of managers and of center
and agency leaders to act on many different levels, with broad staff partici-
pation and input and in an atmosphere of openness, and to be “relentless”
in creating, seizing, and sustaining opportunities for change (Khademian,
2002:126). The committee believes that it is imperative that the director
of CDER, with support from the commissioner and the assistance of the
Management Advisory Board, take immediate steps to strengthen leader-
ship, organization, and function to create and visibly champion a culture
of drug safety in the center.
As part of the strategy for cultural change, the director of CDER should
establish an effective organizational development capability in CDER by
forming a staff working group consisting of people who represent diverse
disciplines, roles, and viewpoints and including one or two staff members
with organizational development expertise. The group would work with
and support the center director in providing meaningful opportunities for
two-way communication with staff, identifying and addressing culture
problems, and nurturing a culture that values disagreement and thinking
outside the box.
Structural Factors
A CULTURE OF SAFETY 95
A CULTURE OF SAFETY 97
External Environment
goals that drive CDER’s work, whether or not associated with PDUFA
funding. Introducing new safety goals would be consistent with the lifecycle
approach to regulation.
The committee offers a series of suggested goals to assist CDER in
thinking about ways to couple accountability for timeliness and safety. Such
goals will ideally be quantifiable. Whether or not PDUFA is reauthorized
the committee believes it is important to measure and report on achieving
safety goals.
A CULTURE OF SAFETY 99
10Including labeling changes, black boxes, and measures leading to drug withdrawal (see
Chapter 5 for discussion and recommendations on strengthening FDA’s authority).
Performance management:
• Convene an open forum 12–18 months before renewals of the
PDUFA to solicit public and industry comments on proposed and
existing safety goals for FDA.
• In the annual PDUFA performance report to Congress, include the
status of meeting of all agency safety goals.
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105
Murglitazar, a drug for diabetes that activates both alpha- and gamma-
peroxisome proliferator-activated receptors, was reviewed by FDA for ap-
proval during the committee’s work. In the preapproval trials, compared
with the other arms of the trials (some compared the drug with a placebo,
others with another diabetes medicine), murglitazar improved sensitivity
to insulin and the control of blood lipids in patients with type 2 diabetes.
Those efficacy outcomes are examples of surrogate endpoints because they
are expected to predict the occurrence of cardiovascular events. In the
same preapproval trials, however, patients randomized to murglitazar had
a significantly higher incidence of the combined outcomes of death, heart
attack, stroke, and heart failure. The reason for the discrepancy between
surrogate endpoints and health outcomes is not clear, but the case of mur-
glitazar illustrates the importance of verifying the assumed health benefits
of new drugs and of conducting more complete risk-benefit analyses (Nissen
et al., 2005).
As described in Chapters 2 and 3, OND clinical reviewers are primarily
responsible for assessing the safety information in an NDA, and interactions
and involvement of the Office of Drug Safety/Office of Surveillance and
Epidemiology (ODS/OSE) staff vary among OND offices. A recent time-
accounting exercise by CDER reports that OND devotes 51 percent of total
scientific and technical staff effort on safety-related activities (FDA, 2005a).
Despite that large investment of time and effort, the safety profile of a drug
at the time of NDA review is necessarily uncertain at the time of approval.
The only certainty at the time of approval is that the CDER official who
signed the approval letter has not identified safety problems that in his or
her best judgment outweigh the potential benefit of the drug for the specific
indication and population studied. However, to expect that premarket stud-
ies or FDA review of these studies can reveal all the information about the
risks and benefits of new drugs that is needed to make optimal treatment
decisions would occasion unreasonable delay in approval.
“real world.”
Signal Generation
Although some safety signals are generated in laboratory tests and clini-
cal trials conducted in the preapproval setting or from known or suspected
biologic actions of a drug, the primary method by which FDA documents
new adverse events in the postmarket setting is monitoring of suspected ad-
verse drug reaction reports entered into the Adverse Event Reporting System
(AERS). AERS combines the voluntary adverse drug reaction reports from
MedWatch, such as direct reports from healthcare practitioners and con-
sumers, and the required reports from manufacturers—15-day expedited re-
ports of serious and unexpected adverse events and manufacturer periodic
reports. The information provided by this part-voluntary, part-mandatory
system of reporting forms the basis of detection of many safety signals and
has been useful in identifying rare adverse events.
Spontaneous AERSs have many limitations, but they offer the possibil-
ity of identifying rare serious adverse events in a timely manner among all
persons across the entire region to which the system applies. For example, if
there is a one-in-a-million serious adverse event applicable to those exposed
to a drug used in 10 million people per year in the United States, it might
never be observed in a database of several hundred thousand, or even several
million people in which the number exposed to the drug might be only a
few thousand per year. But in the entire United States it is not so unlikely
that at least one such event would get reported. Even a small number of
reports of events that are commonly caused by drug exposure, such as liver
or kidney failure, aplastic anemia, anaphylaxis, Stevens-Johnson syndrome,
A serious adverse event is any untoward medical occurrence that at any dose: results in
The committee does not intend that review of AE reports, whether sub-
mitted by manufacturers as mandatory under federal regulation or submit-
ted by patients or their providers through the MedWatch program, be the
primary tool used by CDER for postmarket safety analysis. The committee
does not support making AE reporting mandatory. Enforcing mandatory
reporting is difficult and the committee’s goal is to have better reporting
and better use of what is reported, not to increase the workload of CDER
safety evaluators with unhelpful information. The passive reporting system
in place today is capable of, and has made, important contributions, and
the committee hopes that CDER will work to make the current system more
efficient. In the next section, the committee offers recommendations for
tools that will supplement and complement the AERS system and provide
better data for regulatory and public health purposes.
upgrade of AERS.
Such as data sources, coding, quantity, quality of reports, and best use of CDER staff.
ous reports and should continue with more active methods of evaluating
signals.
Sometimes, the need for signal-strengthening studies is anticipated at
the time of approval. Just before approval, CDER negotiates about phase
4 studies that the company commits to conducting. Chapter 2 includes
information about the number of those studies that are not completed.
An exception to the inability of CDER to compel the studies is the case in
which a drug is approved under accelerated approval. Postmarketing stud-
ies range from simple pharmacokinetic studies through analysis of data in
administrative databases to controlled trials. The current approach, leaving
the negotiations of plans for postmarket studies to the late stages of the pre-
approval process, is not optimal and may lead to studies that are not well
designed. That is one of the reasons why a large proportion of postmarket
commitments are not started or completed. Another factor that could
contribute to suboptimal design is uncertainty of OND clinical reviewers
about the types and designs of postmarket studies that might be developed,
particularly observational studies. It is unusual for CDER to bring in outside
experts for independent review and advice about the hypotheses and design
of phase 4 studies committed to at the time of approval, but such advice
might be useful. As described in Chapter 2, input from advisory committees
is often not sought because of committee meeting schedules.
A strong postmarket safety system requires a wide array of data resourc-
es that permit continuing evaluations. Some may be directed at tracking
patterns of drug use, the indications for the use of a drug in the population,
and a general description of the types and frequencies of various AEs. Others
may be directed at signal generation. For instance, as electronic medical-
records databases are further developed, it may be possible to incorporate
real-time reporting of AEs that can be made available to FDA for analysis.
Such an effort would require considerable development.
Signals or hypotheses about safety issues may arise from other sources,
including known or suspected biologic drug effects that become evident
through animal and human studies. Once a potential signal is identified,
followup studies are likely to involve the use of a variety of study designs
and data sources, including large electronic administrative databases. ODS/
OSE has four task-order contracts for access to administrative databases
for epidemiologic research. The contractor sites are the HMO Research
Network, Ingenix Inc., the Kaiser Foundation Research Institute, and Van-
derbilt University (Seligman, 2005). Cumulatively, those organizations cover
23.5 million people, and each has characteristics that make it particularly
useful. For example, the Vanderbilt site uses Medicaid data from Tennessee
and Washington and thereby obtains information about high-risk and eth-
This program had previously been funded through a cooperative agreement mechanism.
nically diverse populations. The Ingenix site has access to some laboratory
data in addition to claims data, and the HMO Research Network and the
Kaiser Foundation Research Institute sites have access to electronic medical
records. Study designs for the contracted studies often are presented to the
Drug Safety and Risk Management Advisory Committee or involve other
outside experts through the special government employee mechanism for
review and comment as a form of scientific peer review.
The funding for the cooperative agreement program is severely limited
and the program has always been small. In 1985, the funding level was $1.2
million; since then, resources have varied. Despite inflation in the interim,
funding for FDA drug safety cooperative agreements reached a low of
$900,000 in 2000 (personal communication, Gerald Dal Pan, FDA, March
30, 2006). In fiscal year (FY) 2006, funding for FDA drug safety contracts
totals only $1.6 million, and it is scheduled to decrease to $900,000 in
FY 2007. According to an ODS annual report, the contract program in
2004 supported five feasibility studies and three in-depth studies, but in
FY 2006 the program will have sponsored feasibility studies for two drug
safety questions and will not have sufficient funds to execute one high-
priority in-depth study fully—on the cardiovascular risks posed by drugs
prescribed for attention deficit hyperactivity disorder (ADHD) (IOM Staff
Notes, 2005–2006). In contrast, a similar program funded by the Centers
for Disease Control and Prevention (CDC) to study safety problems associ-
ated with vaccines, the Vaccine Safety Datalink (VSD), included data on
more than 7 million people covered by eight managed-care organizations.
CDC supported the VSD with $13 million and eight full-time staff persons
in FY 2004 (Davis, 2004).
FDA also works with the CERTs that have access to large healthcare
databases, including the HMO Research Network and the Department of
Veterans Affairs (VA). CDER has internal access to the General Practice Re-
search Database (GPRD) and to proprietary databases that house exten-
sive information on drug use. Access to the GPRD was expected to provide
valuable information to CDER for drug safety purposes, but ODS/OSE has
struggled to get sufficient computer resources and staff trained to use it. Four
full-time safety evaluators now work with those databases, and two staff
epidemiologists work part-time with them in their research.10 CDER staff
presented their first findings from the GPRD at the 2006 summer meeting
of the International Society of Pharmacoepidemiology.
A feasibility study involves preliminary assessments of whether a database contains suf-
ficient exposures or outcomes in appropriate populations to answer the study question.
A computerized database of longitudinal medical records from primary care practices in the
United Kingdom and a source of data for many epidemiologic studies around the world.
Verispan, LLC; IMS Health; and Premier.
10Personal Communication, G. Dal Pan, FDA (ODS/OSE), 2006.
Other federal partners in the drug safety system (VA and the Centers for
Medicare and Medicaid Services, CMS, in particular) also use automated
databases and should work with CDER, as appropriate, to accomplish the
goal of improved formulation and testing of drug safety hypotheses for the
entire drug safety system. As will be described in Chapter 7, CDER and its
federal partners in the drug safety system will need increased resources to
accomplish these goals.
Confirmatory Studies
be reluctant to conduct them because of high costs and the possibility that
unfavorable results would negatively influence market share.
A significant impediment to the successful completion of studies is that
they are typically negotiated between CDER and the industry very late in
the approval process. The study designs can be inadequate, and there is
little opportunity given time constraints imposed by the Prescription Drug
User Fee Act (PDUFA), for CDER to bring in outside experts when they are
needed to help with study design. Experts who are in the pool of potential
special government employees (including advisory committee members) can
be consulted, but they must be screened for conflicts of interest, and only
one can be brought in at a time to comply with the Federal Advisory Com-
mittee Act. Although there may be legitimate reasons for abandoning some
of the phase 4 study commitments, many could be useful, especially with
study-design improvement.
Once a drug is approved, unless the industry sponsor is looking for a
new indication for the drug, CDER has no leverage to require further stud-
ies by the company. Pharmaceutical companies continue to conduct clinical
trials of their drugs, and there is an emerging recognition that these are
often marketing-driven and their designs may be inadequate for any reliable
assessment of safety or efficacy (Psaty et al., 2006), may underreport AEs,
may lead to selective publication of favorable results and non-publication
of studies whose findings are unfavorable for marketing (Psaty and Rennie,
2006), and therefore can be misleading. The concept of these “seeding” tri-
als, performed primarily for marketing purposes, is not new (Kessler et al.,
1994).
CDER does not have the resources to fund large randomized clinical
trials, nor was it ever intended to do so. The drug safety system is currently
dependent on the industry, the National Institutes of Health (NIH), or foun-
dations to fund such studies. Other groups have a strong interest in reducing
the uncertainty about therapeutic risks and benefits—health care payers, for
example—but they have not typically conducted large and expensive phase
4 trials. No entity is responsible for helping to set priorities among the drug
safety and drug efficacy questions that need to be examined, particularly
with resource-intensive controlled trials. Some studies are necessary for an-
swering questions for regulatory purposes (such as whether risks outweigh
benefits and what regulatory action should be taken); others are important
for public health purposes and are not likely to be funded by industry (such
as head-to-head trials of drugs approved for the same indication).
The potential cost of large safety trials has been a concern for many. A
model for “large, simple trials” was established in the United Kingdom in
the 1970s; a series of increasingly large randomized trials was conducted
to examine regimens for treatments to prevent cardiovascular mortality in
those at elevated risk. Those trials were conducted with very modest bud-
gets. Although the costing of trials in the United Kingdom and the United
States is admittedly very different due to differences in the way health care
and biomedical research are supported in the two countries, there may be
ways to conduct trials in the United States with substantially smaller budgets
than has been assumed. The increasing computerization of medical data and
move toward electronic medical records may facilitate the implementation
of more efficient trials with fewer personnel needs. Research into methods
for conducting simpler, less expensive trials that might be suitable for an-
swering straightforward but important safety questions is warranted, and
represents a logical area for FDA scientific involvement, even leadership.
ship. The committee is not aware of any collaborations with DoD on such
studies,11 but DoD provides health care coverage to over 9 million persons
and has excellent epidemiologic research capacity, easily accessible research
subjects, and a national interest in the safest and most effective use of drugs
for troop readiness and cost containment for the largest health care system
in the country. That is why the committee included DoD in the partnership.
NIH has supported many important such trials, and the committee expects
it will continue to do so. Each agency in the collaboration will need staff
dedicated to this work in addition to information-technology upgrades and
administrative support.
Discussions about needed confirmatory studies should include regula-
tory findings and related advisory committee input, should address major
study-design issues, and should lead to studies that supplement and comple-
ment those being done by industry sponsors as part of their postmarket
study commitments. The committee urges industry to use the expertise of the
proposed public-private partnership for comment on the design of studies
and for oversight of study conduct and analysis of results. Proposals for all
confirmatory drug safety studies, whether funded or conducted by public
or private entities, should be subject to a peer-review process modeled after
NIH study sections to ensure scientific excellence.
An important outcome of the partnership should be that federal agen-
cies provide FDA access to all administrative databases12 (under conditions
consistent with the protection of patient privacy) managed by the federal
government for purposes related to postmarketing surveillance, safety moni-
toring and analysis, and risk-benefit assessment of approved drugs.
Funding for the studies planned by the partnership would come from
different sources, including congressional appropriations, depending on
the questions to be addressed. Some studies planned under this partnership
would have been conducted absent the partnership; therefore, the resources
needed are not all additional costs to the system. It is hoped that the partner-
ship would help prioritize questions and advise on important study design
issues. The partnership might also facilitate collaborations that otherwise
would not occur. The committee believes that industry bears the respon-
sibility for paying for clinical trials and other observational studies which
support a product’s approval and its safe and effective use (e.g., specific
11DoD and other agencies have collaborated in planning and analyzing complementary stud-
ies of the safety of the smallpox and anthrax vaccines.
12This could be accomplished by training CDER staff to use the databases directly or to work
with staff in the other agencies. In either arrangement, new staff will be needed to implement
this recommendation. Access to the databases could be obtained through an interagency task
force (either existing or to be created) including representatives of FDA, representatives of
federal agencies that manage medical databases, and other members to coordinate and ensure
effective use by FDA of such medical databases for postmarketing drug safety.
NDAs for NMEs are required to include RiskMAPs, but at the time of
approval most non-NMEs will not need RiskMAPs. Known risks can be ad-
dressed through standard industry and CDER activities. Information about
possible risks can be sufficiently uncertain that appropriate minimization
strategies are not obvious.
RiskMAPs can also be developed or modified after marketing. Every
RiskMAP should be viewed as a “living document” that evolves throughout
the lifecycle of a drug. One of the best examples is the case of isotretinoin, a
teratogenic drug indicated for severe cystic acne. The risk minimization ac-
tivities for this drug have increased in complexity. The Pregnancy Prevention
Program (PPP) was established in 1988 in an attempt to prevent exposure of
pregnant women to isotretinoin. The PPP asked female users of isotretinoin
to enroll voluntarily in a survey administered by Boston University’s Sloane
Epidemiology Unit and enrolled 45 percent of women of reproductive age
who were using the drug. Of these women, 36 percent did not have any type
of pregnancy test before beginning treatment, and about 900 pregnancies
occurred among enrollees during 1989–1998 (No Author, 2000). A new
program, SMART (System to Manage Accutane Related Teratogenicity),
was implemented in 2002 (Levine A, 2002; Honein et al., 2004). SMART
retained the voluntary registration of PPP and
The FDA is the first gatekeeper regarding access to drugs in exercising ap-
proval authority. Some drugs, perhaps even many, will not and should not
be permitted to be used by patients who expect their medicines to be safe
and effective. Some believe that drugs should be made much more freely
available on the market for anyone who wishes to use them, particularly
if the patient has a fatal disease for which they are willing to take the
chance that a drug will have little benefit and possibly many serious risks
(Burroughs and Walker, 2006). For many of these situations, accelerated
approval was developed as a mechanism to make selected promising drugs
available early in their evaluation.13 However, it is widely accepted that the
FDA has the authority to determine whether the risk-benefit profile for a
drug is appropriate to release the drug on the market. Whether the “bar” for
approval is too high or too low for particular drugs has not been the focus
of this committee’s efforts. In practice, once a drug is approved, health care
providers and patients make many decisions about use of a drug. In this
section we discuss ways that the regulator can make those decisions easier,
by being more explicit about what is known and not known about the sum
total of a drug’s benefits and its risks.
As described elsewhere in this report, there are many uncertainties at
the time of approval. Eliminating all those uncertainties prior to approval
would require an unreasonable number of premarketing studies and would
have serious implications not only for pharmaceutical companies in terms of
research and development but also for patients awaiting new and important
medicines. What regulators and drug sponsors know about the drug at ap-
proval will change over time. Some of that new information will pertain to
the benefits of potential new indications for the drug and other new informa-
tion will pertain to the risks or adverse effects of the drug. For example, the
results of additional studies completed during a drug’s postapproval period
can alter our understanding and perception of the risk-benefit profile and
result in new actions on the part of FDA, clinicians, and the public.
FDA reviews a drug for benefits and risks from the perspective of its
intended use (the indication in a population), but in most instances, the drug
will not have been evaluated for so-called off-label use. Spontaneous reports
of adverse events may indicate a potential safety problem and warrant a
safety study. Safety and effectiveness data from studies on uses other than
the approved indication are gathered if the sponsoring company is studying
the drug in clinical trials for a supplemental NDA for a new indication or
if sufficient off-label use occurs. Formal studies of safety and/or effective-
ness can also be undertaken. There is a “rolling” or incremental increase
in information about the risk-benefit of most drugs after licensure and the
13Other mechanisms to increase access to drugs include compassionate use protocols and
enrollment in clinical trials.
risks and benefits are far from perfect. Some misleading analyses (with
resulting inappropriate regulatory or clinical decision making) are likely
because of imperfect information. Nevertheless, the potential advantages
of having a systematic approach to risk-benefit analysis for prescription
drugs include increasing consistency of approach to approval decisions
among the review divisions; a growing common understanding about the
criteria for approval and other regulatory actions; increased transparency
for the industry, health care providers, patients, and researchers; increased
credibility of FDA and CDER; and direct assessments of comparable drugs.
Ideally, the weighing of a product’s risks and benefits will be both transpar-
ent and reproducible.
The barriers to moving pharmaceutical risk-benefit assessment toward
a more systematic and scientific endeavor include those related to data and
to methods. Data are a primary rate-limiting factor in the evaluation of
risks and benefits. Information on a drug’s risks and benefits comes from
preclinical and clinical studies, but it is phase 3 clinical trials that provide
the bulk of the data used to make risk-benefit determinations at the time
of approval. Risk or safety assessment is limited by what is missing. Most
important for risk assessment is the lack of information that would enable
estimation of event rates, their comparison across treatment groups, and
evaluation of causality. Findings from preapproval clinical trials may suggest
safety signals, but the numbers of events tend to be small and may not lend
themselves to precise statistical analyses. The trials lack the ability, both
because of their size and because of the relative homogeneity of the typical
clinical trial population, to yield confident statements about the plausible
range of risks that would affect the populations who would actually take
the drug if it were approved. Therefore, when a safety signal is apparent but
uncertain, in some cases additional studies should be designed to reduce the
uncertainty about potential risk. Benefit data may also be limited by what is
missing, namely, information on health benefits if the approval was based on
surrogate endpoints rather than health outcomes. Also typically lacking is
information on risk-benefit relationships in important subgroups of patients
(such as those with severe disease or comorbidities), or large numbers of
patients exposed to the drug for long durations, or results of other treat-
ments (head-to-head trials), and on long-term health outcomes.
Regarding methods, a growing set of tools can be used to attempt to
quantify the value of research. Because the results of a research program
are intrinsically uncertain, the tools are based on a “value of information”
approach that identifies the value of research as the expected value of the
improvements in outcomes that would be generated by a research project
(Meltzer, 2001; Claxton et al., 2005b). The techniques to guide research
priorities are beginning to be used in other countries to assess when addi
tional research on a drug should be required as part of a regulatory deci-
sion. For example, in the United Kingdom the National Institute for Health
and Clinical Excellence has begun to explore the use of the approaches to
evaluate research priorities (Claxton et al., 2005a). Quantitative measures
of treatment benefits and the application of risk-benefit analysis should
consider such factors as the seriousness of a disease, its chronicity, and the
effect of a drug on quality of life or the disease process.
Metrics that have been used to measure benefits include absolute differ-
ences in event rates, mortality, number of lives saved, and quality-adjusted
life years (QALYs) (the relative differences are not nearly as helpful as the
absolute ones in this setting). Quantifying benefits in terms of those metrics
is difficult or impossible if efficacy is assessed only in terms of surrogate
endpoints. Risks can be summarized in terms of incidence, risk difference,
excess risk, severity, and duration. Rates and risks are quantitative, but only
the more common events that occur with enough frequency in premarket
clinical trials can be incorporated into the metrics with any precision. As
the comittee learned in its workshop (see Appendix D for the workshop
agenda), the science and the acceptance of approaches to simultaneously
and explicitly considering multiple benefits and risks for pharmaceuticals
and their preferences is evolving (Weiss Smith, 2006).
14FDA does not make coverage decisions or consider cost-effectiveness, but other partners
in the drug safety system do, and this information will be valuable.
15The committee has not done an independent assessment of how those options are used but
understands that they are all viable options.
BOX 4-1
History of Reports Regarding Research at FDA
In 1955, the report of the Citizen’s Advisory Committee on the Food
and Drug Administration to the secretary of health, education, and wel-
fare, stated: “Research is the heart of any scientific operation. Although
the FDA is primarily a regulatory agency, it must engage in research of
the sort that leads to more accurate scientific methods for determining
whether a food or drug is safe. Such research in scientific methodology,
and perhaps a limited amount of what might be termed ‘random research,’
can do much to upgrade the professional competence, elevate the morale
of scientific workers, and contribute to the general effectiveness of the
FDA.”
In May 1991, the final report of the Advisory Committee on the Food
and Drug Administration, convened by the secretary of health and human
services asserted: “In an era of rapid technological advancement, the
FDA must reaffirm its commitment to research as an integral component
of its activities. The FDA’s intramural and extramural research projects
must be linked to the Agency’s primary functions . . . High levels of scien-
tific expertise are required to review product applications and to respond
to public health crises . . . FDA scientists who are actively engaged in
research help build a vital foundation of Agency understanding and ex-
pertise. Without that foundation, the Agency’s ability to address emerging
regulatory problems is hampered. It is essential that the FDA avoid being
blind-sided by rapid advances in biomedical science and technology.”
For more information see: Science Board to the Food and Drug Admin-
istration. 1955. Appendix D, An Abbreviated History of at Least Four
Decades of Efforts to Upgrade the Quality of Science in the FDA.
Advisory Committees
Chapter 2 describes some basic characteristics of FDA drug-product
advisory committees. Those experts and their input constitute an important
resource for FDA in tackling particularly difficult or challenging questions
related to its regulated products. Scientific advances, changing technology,
and the increasing complexity of new drug products have necessitated the
establishment of a strong advisory committee system. Through its advisory
committees, FDA can seek advice experts from outside the agency who serve
as “special government employees”. The system enables FDA to tap into
critical expertise at major research institutions.
Advisory committees are used as a source of independent advice about
questions raised by the agency regarding new drugs in the review process,
16It is precisely the practice of following advisory committee recommendations that makes
the Plan B controversy so notable.
4.8: The committee recommends that FDA have its advisory com-
mittees review all NMEs either prior to approval or soon after ap-
proval to advise in the process of ensuring drug safety and efficacy
or managing drug risks.
4.9: The committee recommends that all FDA drug product ad-
visory committees, and any other peer review effort such as men-
tioned above for CDER-reviewed product safety, include a pharma-
coepidemiologist or an individual with comparable public health
expertise in studying the safety of medical products.
17A particular matter of general applicability is a matter that is focused on the interests of a
discrete and identifiable class of persons but does not involve specific parties. For example, a
guidance document that affects an entire class of products and all similarly situated manufac-
turers is a matter of general applicability. In addition, the use of a potential product solely as
a model or example for general discussion whose results will apply to a class of products may
be a matter of general applicability.
SGE is a federal
employee, and his agency
is conducting research
for one or more firms
with an interest in the
general matter before the
committee
continued
Remuneration is between
$100,000–$300,000
per source/year to
institution/$10,000–
$15,000 per source/year as
salary support to the SGE
and work on unrelated
matter is current or
completed within past 12
months
continued
SGE receives
less than $5,000
per source per
year and topic
is unrelated
and SGE is
compensated
SGE receives
less than $5,000
per source per
year and topic
is related but
SGE receives no
compensation
(including travel)
SGE receives
less than $5,000
per source per
year and topic is
related but not
specific to the
matter under
discussion by
the committee
and SGE is
compensated
Remuneration is between
$300,000–$600,000 per
source per year to SGE’s
department and work on
related matter has been
completed within the past
12 months and SGE had
only an administrative role
18A particular matter involving specific parties focuses on a specific product application or
other matter affecting a specific manufacturer and its competing products or manufacturers
(such as NDA, PMA, PLA or BLA, or efficacy supplement for a new indication). That is, it
focuses uniquely and distinctly on a given product/manufacturer.
19Including votes by advisory committee members with conflicts of interest related to rela-
tionships with companies that would be considered competitors to the drug whose approval
was being voted upon.
trials). NIH, for example, funds clinical trials, and investigators associated
with those would bring necessary practical expertise to a drug products
advisory committee. The committee also recognizes that financial conflicts
are not the only conflicts that could influence votes. It is hard to screen out
or to waive positions of intellectual bias (Stossel and Shaywitz, 2006). The
committee supports narrowing the policies in place today but acknowledges
the difficulties of convening sufficient experts for the numerous advisory
committees that review drug products. The committee supports a position
of nonwaivable limits, but not a zero-tolerance policy, for financial conflicts
of interest on FDA drug-product advisory committees.
Transparency
All stakeholders in the drug safety system have a legitimate interest in
understanding the data on which drug availability in the marketplace de-
pends. Not all people are interested in firsthand knowledge of the science
and depend on the decisions of others (such as their physicians and regula-
tor) to assure them that drugs they take are safe and effective. Others wish
to have more knowledge of the data. Many data are made public in some
form, at some time, and at some place on the FDA or another government or
industry Web site, but the process is not systematic, comprehensive, or well
organized. The committee believes strongly in the importance of increasing
the availability to the public and to researchers of information about drug
risks and benefits, whether specific study results or analyses of concerns by
agency staff, and it provides several recommendations related to clinical
trial registration and results reporting, Web-site posting of all NDA-review
packages, and timely public release of all CDER summaries of emerging data
relevant to the safety and effectiveness of a drug after approval.
As described in Chapters 2 and 3, information related to the efficacy
of drugs approved for use in the United States is examined in extensive
detail in the reviews prepared by CDER staff. Most of those review pack-
ages are posted on FDA’s Web site and summarize a significant amount of
data supporting the approval of the drug, yet these postings do not include
the entirety of what is known about a drug. A sponsor’s NDA is not made
public (even in redacted form to protect proprietary interests), and FDA
reviews of an NDA are not made public if approval is not granted. Those
reviews of unapproved NDAs could provide valuable information about a
drug if the application is a supplemental NDA or if it is for a new member
of a class of products already on the market. Although pharmaceutical
companies are required to submit to FDA information about all studies
conducted under an IND, results of studies that are not submitted as part of
a sponsor’s application package for approval or are finished after approval
are not necessarily disclosed to the public. There is no way to know the
results of clinical trials involving a drug if those results are not submitted to
the FDA as part of an NDA or other review package or are not published
in the scientific literature.
Several important efforts in recent years are aimed at increasing the
availability of at least a minimum of information about current or complet-
21Because the committee is not suggesting that raw data be posted, this recommendation
should provoke no concerns regarding patient privacy. The committee recognizes that this
recommendation will require significant additional resources to NIH, which runs clinicaltrials.
gov, and to FDA, for their role in developing the results format and vetting the submissions.
that are not vetted by the FDA are described completely, accurately, and in
an unbiased manner, clinicaltrials.gov would have to establish some form
of editorial review process. The National Library of Medicine, which runs
clinicaltrials.gov, will need to be provided the necessary authorization and
resources to accommodate results posting.
The format of clinical trial registration and results reporting should be
done in a way that harmonizes with emerging international standards (such
as those specified by WHO, for example, the minimum required dataset
for registration, and the requirements for results reporting, in the ICH E3
Summary of Clinical Trial Results). The committee notes with interest the
recent WHO call for registration of all interventional trials. The committee
strongly urges the Congress to consider the status and benefits of harmo-
nization with international standards when drafting legislative language to
implement this recommendation.
The committee also encourages further steps to make drug safety and
effectiveness information available to the public. The committee believes
that CDER is the appropriate body to assume the responsibility for sharing
important safety and efficacy information promptly and dependably with
patients, providers, and researchers. One important source of this informa-
tion at the time of approval is the NDA review package.
In response to the Electronic Freedom of Information Act Amendments
of 1996, which were designed to broaden public access to government
documents in electronic form, CDER posts NDA review packages22 on its
Web site (at the “drugs@fda” portion of the site http://www.accessdata.fda.
gov/scripts/cder/drugsatfda/). As of April 2006, review packages for NMEs
approved from 1998 to the middle of February 2006 and non-NMEs ap-
proved in 1998–2001 are posted. There is a backlog for posting review
packages for non-NMEs approved after 2001.23 All other NDA approval
documents (that is, for drugs approved before 1998 and for all supplements)
are posted on completion of a Freedom of Information Act (FOIA) request
for that information (D. Henderson, personal communication).
4.12: The committee recommends that FDA post all NDA review
packages on the agency’s Web site. Regardless of whether they
were disclosed in response to a FOIA request, FDA should post all
supplemental-NDA review packages and continue to work to post
reviews for drugs approved before 1998 in a timely manner and as
22Review packages are described in Chapters 2 and 3 and refer to the set of documents pre-
pared by CDER staff. These packages provide the summary judgment that leads to decisions
regarding approval.
23Of 531 non-NME NDA approvals since 2001, 397 had been posted on the Web as of
March 31, 2006, as had all the non-NME NDAs approved in 1998–2001.
24Product safety specialists from the Center for Biologics Evaluation and Research routinely
develop reviews of the postmarket safety experience with a new vaccine within 2–3 years of
the time the vaccine is licensed. These reviews are published in journals and are available on
the FDA Web site’s VAERS (Vaccine Adverse Event System) page.
ment of innovative medicines, but to ensure that needed drugs are avail-
able to patients and that risk-benefit information is accurate and widely
available. The regulator must be the gatekeeper of the scientific foundation
on which regulatory decisions are made. CDER must have the best data
to review and an expert scientific staff to review them. Patients and their
physicians must be assured that the scientific foundation on which CDER
regulates drugs is credible.
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151
tory jurisdiction and its enforcement powers. The statute empowers FDA
to bring enforcement actions through administrative procedures (warning
letters, adverse publicity, recalls, and withdrawals of product approvals)
and judicial procedures (seizure, injunction, and prosecution) (Bass, 1997;
Levine, 2002). FDA’s enforcement authority is derived by delegation from
the secretary of the Department of Health and Human Services (DHHS) to
the commissioner of food and drugs (Bass, 1997). Regulations contained in
the Code of Federal Regulations empower FDA to enforce the FD&C Act
and other statutes, as appropriate. FDA’s ability to regulate is also influenced
by Congress and its “oversight jurisdiction” exercised by holding congres-
sional hearings (Hutt, 1991). The judiciary branch also may influence FDA
regulation, when FDA’s interpretations of the statute and its development
of regulations are successfully challenged in court.
on New Drug Regulation also found that the statute did not give FDA that
authority. Many of the Panel’s recommendations were incorporated into the
1979 Drug Regulation Reform Act (S. 1075, Kennedy) which passed Senate
but failed to garner support in the House (DHEW, 1977; Steenburg, 2006).
The panel’s final report asserted that “rather than delay approval of a drug
pending additional studies, FDA should have the authority to require a spon-
sor to conduct additional research as a condition of approval when a drug
has been shown to be safe and effective for its intended use, but questions
remain, for example, with regard to its long term effects” (DHEW, 1977).
The 1979 bill included a provision to allow FDA to require postapproval
studies (Dorsen and Miller, 1979). The 1996 Inspector General found that
the FDA “tradition” of asking for voluntary postmarketing studies was not
supported by statute in most cases (DHHS and OIG, 1996).
FDAMA (which included the reauthorization of PDUFA) added a provi-
sion to the FD&C Act requiring sponsor submission of annual updates on
progress in meeting postmarketing study commitments. However, PDUFA
provided no resources or new authorities to enable the agency to enforce
that provision. FDA was required to develop and publish a rule on the
reporting format and to report annually on sponsor performance in the
Federal Register. The 2005 Federal Register notice on sponsor progress in
meeting postmarketing study commitments showed that 797 (65 percent)
of New Drug Applications (NDAs) and abbreviated NDA-related post-
marketing commitments are “pending” (they are neither “ongoing” nor
“delayed”) and 47 percent of annual reports on studies that were due were
not submitted to FDA. FDA’s limited authority after marketing and its in-
ability to enforce implementation and fulfillment of important and necessary
postmarketing commitments have been at the core of many proposals for
strengthening FDA’s authority (GAO, 2002b; van der Linden et al., 2003;
Ganslaw, 2005; Grassley, 2005; Thaul, 2005). A recent DHHS Office of
the Inspector General (OIG) report on FDA’s monitoring of postmarketing
commitments noted that FDA has authority to require postmarketing stud-
ies only in certain cases (such as accelerated approval) and that 91 percent
of postmarketing commitments between 1990 and 2004 were requested by
the agency rather than being required by statute or regulation (DHHS and
OIG, 2006). The report also found that postmarketing study commitments
do not have a high priority in FDA, the agency lacks a system for managing
postmarketing study commitments and the existing database of commit-
ments is not consistently populated with information from commitment
letters or from annual status reports, one-third of annual status (required
by FDAMA) reports on postmarketing commitments are not submitted or
are incomplete, and many completed reports lack useful information. The
OIG report also concluded that FDA has no recourse when sponsors do not
make progress or do not report on their commitments (DHHS and OIG,
products determined by FDA to have “serious and significant public health concern requiring
distribution of FDA-approved patient information” (21 CFR 208.1, 4-1-05 Edition, p. 114)
(CDER, 2006).
use of more costly but no more effective therapies at the expense of older,
cheaper options (e.g., generics).
As a communication or educational tool, DTC advertising appears to
have mixed effects. There is evidence that advertisements have raised aware-
ness about certain health conditions and led people to visit their health
care provider and in some cases, receive needed diagnosis and treatment
(Ostrove, 2000; Calfee, 2002; Aikin, 2003; Almasi et al., 2006) (see Box 5-2
for a sample of public opinion of DTC advertising). Advertisements about
drugs may increase consumer familiarity with products available to treat
their particular condition(s), perhaps empowering them to initiate discus-
sion about therapy with their health care provider, and in some cases, to
alert a less well-informed provider to a particular therapy (Wilkes et al.,
2000; Lyles, 2002; Almasi et al., 2006). On a potentially more negative note,
viewers of television prescription drug advertisements may learn more about
the benefits than about the risks. Also, DTC advertising has been shown to
have an effect on physician prescribing patterns (Aikin, 2003; Mintzes et al.,
2003; Aikin et al., 2005; Weissman et al., 2004; Spence et al., 2005).
FDA’s authority to regulate prescription drug advertisements is found
in Section 502(n) of the FD&C Act, and Title 21 of the Code of Federal
Regulations (CFR) section 202.1 is the source of the implementing regula-
tions that describe the content required in such advertisements (Behrman,
2005). Specifically, regulations require that print advertisements must dis-
close every risk listed in the FDA-approved label as part of a brief summary,
but broadcast advertisements may either contain a brief summary of side
effects and contraindications or make “adequate provision” for conveying
the product’s complete labeling information, that is, a toll-free telephone
number or Web site. FDA can regulate advertising that is false or misleading,
but its regulatory actions must harmonize with First Amendment protec-
tions of truthful commercial speech.
FDA does not have the authority to approve drug advertisements or
require that advertising materials be reviewed prior to their use. The agency
can require and enforce corrective action only after a drug advertisement
has been broadcast (Woodcock et al., 2003). To avoid having to issue a cor-
rection after beginning a marketing activity, a majority of sponsors submit
advertising materials for comment to the CDER Division of Drug Market-
ing and Communication (DDMAC) before airing them (Woodcock et al.,
2003) (see Box 5-3).
The history of court challenges to restrictions on DTC advertising is
lengthy and instructive. Attempts to ban DTC advertising have foundered
due in part to uncertainty as to whether such a prohibition is constitu-
tional. Drug advertising has been held to be commercial speech deserving
First Amendment protection (Virginia State Board of Pharmacy v. Virginia
Citizens Consumer Council, Inc., 425 U.S. 748, 762 [1976]). In Central
BOX 5-1
History of FDA’s DTC Advertising Regulation
As a variety of social changes began to transform the passive patient
into an empowered seeker and contributor of knowledge and information, the
patient-provider relationship and other interactions and spheres of influence
around it changed as well. As early as 1968, FDA developed the first patient
package insert in recognition of the need to instruct patients on the use of a
drug, the inhalational product isoproterenol (Pines, 1999). In the 1970s and
1980s, more health-related information was made available to the general
public (such as the Physician’s Desk Reference), cable television experiment-
ed with physician-oriented channels, and pharmaceutical companies began
to advertise in print to patients. As FDA and the industry reoriented some of
their communication activities to target patients, the agency worked in two dif-
ferent directions: furthering its own role in communicating to patients through
patient package inserts (see Chapter 6) and making determinations about how
to regulate and ascertain the public health implications of emerging industry
promotional efforts directed at consumers (Pines, 1999; DHHS et al., 2005).
FDA’s authority in that respect originates in the FD&C Act, which gave
FDA authority over drug labeling and gave the Federal Trade Commission
(FTC) authority over advertising (Kaplan, 1995). Current statutes give FDA
and FTC overlapping and concurrent authority over the labeling of FDA-
regulated products and over advertising of prescription drugs and devices.
FTC is responsible for regulating false or deceptive claims about products
other than prescription drugs and FDA has primary jurisdiction over false and
misleading labeling of all jointly regulated products and, on the basis of the
definition of advertising as an extension of labeling, over DTC advertising
(Adams et al., 1997; Pines, 1999; Palumbo and Mullins, 2002).
In 1983, FDA requested a voluntary moratorium on all drug advertising to
Hudson Gas & Electric Corp. v. Public Service Commission (447 U.S. 557
(1980)), the Court stated that a governmental restriction upon commercial
speech is lawful only if the asserted governmental interest in the restriction
is substantial, that the speech restriction directly advances the governmental
interest asserted, and that the speech restriction is not more extensive than
is necessary to serve the asserted governmental interest. If the government
cannot demonstrate that it meets all three prongs of the Central Hudson test,
the speech restriction is unlawful. In Thompson v. Western States Medical
Center, 535 U.S. 357 (2002), the Supreme Court applied the Central Hudson
test and ruled that the statutory ban on advertising of compounded drugs
allow the agency to determine where there were adequate statutory protec-
tions for consumers (Palumbo and Mullins, 2002). After its internal decision
making and discussion with academic, consumer, health care, and other
communities, the agency concluded in the Federal Register (1985-Notice 50
FR 36677) that “current regulations governing prescription drug advertising
provide sufficient safeguards to protect consumers.” The notice also stated that
DTC advertising must meet the same requirements as advertising to physi-
cians, including the “brief summary” of risk information required by statute
(21 CFR 202.1).
In the 1990s, as DTC advertising progressed from print to television,
pharmaceutical companies found they could not make product claims in ad-
vertisements, because that required presenting the statutorily “brief summary”
of safety and contraindications information. The television equivalent of the
page of minuscule print on the back of magazine advertisements “would take a
minute or more at a barely readable scrolling rate” (Woodcock et al., 2003). For
this reason, DTC advertisements did not make product claims and generally
consisted of “help-seeking” and “reminder” advertisements. The former de-
scribed an identifiable condition and urged viewers to “see your doctor,” while
the latter mentioned the name of a product without the indication. Advertise-
ments that talked about the disease, but not the drug, or about the drug without
mentioning the indication left viewers confused and led FDA to reconsider the
entire subject of DTC advertising (Pines, 1999). In 1997, FDA produced the
draft Guidance for Industry: Consumer-Directed Broadcast Advertisements.
That document, issued in final form in 1999, allowed television product claim
advertisements, finding that they could meet the statutory requirement and
make “adequate provision” for the information contained in the brief summary
by providing a toll-free number or Web site where consumers could receive
the complete information contained in the drug’s label.
violated commercial speech rights. How the court would react to restric-
tions short of outright ban on DTC advertisements is unclear, but it is worth
noting that in the western states decision the court was unsympathetic to
the argument that DTC advertisements of compounded drugs might affect
physician prescribing practices, to the detriment of their patients. The same
court cases are relevant to whether FDA can require prior approval of the
advertisements. If courts were to conclude that this amounts to a “prior
restraint” on First Amendment protected speech, FDA would have to show
a compelling government purpose for such a policy.
FDA’s regulation of promotional activities was challenged in court by
BOX 5-2
Public Perspectives on DTC Advertising
It has been suggested that DTC advertising is associated with the
transformation in the role of patients from passive to actively contribut-
ing to the health care encounter (shared decision making). A study of
1999 Princeton Survey Research Associates data found that more than
40% of consumers have used DTC advertisement information in their
decision-making process and used information learned from a DTC ad-
vertisement to discuss a prescription drug with their health care provider
(Deshpande et al., 2004). The study also found that consumers believe
advertisements are more effective in communicating benefits than risks
of prescription drugs.
An online survey conducted for the Wall Street Journal in 2005 (Har-
ris Interactive, 2005) found that only 35% of American adults believe FDA
does a good or excellent job in its oversight of DTC advertising. When
asked whether they thought banning DTC advertising for a period of time
after a prescription drug is approved by FDA so “doctors have time to
become familiar with the drug,” 51% agreed. Only 26% of respondents
agreed that banning DTC advertising is not a good idea because “it is how
many patients learn about new treatments that might be right for them.”
BOX 5-3
The Division of Drug Marketing and Communication
The CDER office responsible for reviewing DTC advertisements and
other sponsor promotional materials is the Division of Drug Marketing and
Communication (DDMAC). Whether or not an advertisement is reviewed
in a timely manner depends on the resources available for review activi-
ties—DDMAC is small and has limited resources. A forthcoming report
from the Government Accountability Office reviews DDMAC’s work and
resources.
In 2005 the Division’s staff of 35 received 53,000 pieces of promo-
tional material (up from 36,700 in 2002) (Winter, 2005; Woodcock et al.,
2003). When a company submits material, the appropriate DDMAC staff
members (including a social scientist, regulatory counsel, and others)
meet to review the proposed promotional material and make a decision.
“Drugs that are new products, have new indications, are first in a class to
have broadcast advertisements, or are being advertised in a broadcast
medium for the first time have more extensive reviews” (Woodcock et al.,
2003). There are several regulatory tools CDER’s DDMAC can employ
against companies that engage in violative promotional practices. These
include
BOX 5-4
PhRMA’s 15 Guiding Principles on DTC Advertising (2005)
• Potential public health benefit
• Accurate and not misleading
• Educational
• Identify product as prescription not OTC
• Foster responsible communication between patient and provider
• Educate providers about new medicine or new indication for an ap-
propriate (given all facts about the drug, the condition, etc.) length of
time before beginning DTC advertising
• Working with FDA, alter or discontinue DTC advertising if indicated by
new risk information
• Submit all new DTC TV advertisements to FDA before releasing
them
• DTC TV and print advertisements should inform about non-drug op-
tions (e.g., lifestyle and diet change) when appropriate
• DTC advertisements that identify a product by name should include
indications and major risks
• Design advertisements to present benefits and risks in a balanced,
clear way
• Respect seriousness of conditions and drugs
• Content and placement should be age-appropriate
• Encouraged: promote health and disease awareness as part of DTC
advertising
• Encouraged: include information for uninsured and underinsured
where feasible
agency was able to use its bully pulpit to powerful effect in its interactions
with sponsors (IOM Staff Notes, 2005–2006). However, consumer organi-
zations, legislators, scientists, and others who have called for strengthening
and clarifying FDA regulatory authority have provided numerous examples
of cases where the agency was unable to effect desired changes. The com-
mittee asserts that the bully pulpit route leaves potentially critical regulatory
action vulnerable to a subjective and highly variable process of exercising
individual or agency influence, and to the vicissitudes of changing attitudes
toward regulation. That is why FDA’s authorities must be clarified and
strengthened to empower the agency to take rapid and decisive actions when
necessary and appropriate.
BOX 5-5
Two Exceptions in FDA’s Regulatory Authority
Pediatric drugs and accelerated approval drugs provide two impor-
tant incentive mechanisms with which to circumvent the imbalance in
regulatory authority pre- and postapproval, and may be instructive as
models for strengthening the statutory authorities available to FDA. The
FDA Modernization Act of 1997 included patent exclusivity provisions as
an incentive for sponsors who conducted studies of approved drugs in
pediatric populations, and the 2002 Best Pharmaceuticals for Children
Act renewed those incentives. That legislation exemplifies the “carrot”
approach to motivating conduct and completion of studies: no study, no
extended period of exclusivity. The “stick” approach to enforcing study
commitments, which has not worked so well, is illustrated by accelerated
approvals on the basis of surrogate endpoints (e.g., for cancer drugs)
“which allows products to be used in nonresearch clinical care settings
before they have been reliably established to have a favorable benefit-
to-risk profile” (Fleming, 2005). Here again, however, FDA’s authority to
enforce these commitments rests on withdrawing approval if the company
does not complete the requisite studies and the high value of such thera-
peutic agents makes withdrawal undesirable. FDA’s authority to enforce
should be made explicit, as it is for accelerated approvals, and the agency
should also be given additional tools to enforce that authority. The power
to withdraw is not a realistic tool as demonstrated by an FDA study of
8 drugs granted accelerated approvals. The average length of time for
completion of required validation studies was 10 years, and it is unclear
what FDA is able to do if studies are inconclusive (Fleming, 2005).
Approval Should Not Be the “Last Call” for Realistic Regulatory Action
on Safety
The committee has found that FDA has some ability to ask for and
egotiate with sponsors about various risk management and other ac-
n
tions. For example, marketing of isotretinoin is conditioned on a four-step
RiskMAP (iPLEDGE) that consists of: registration of and an educational
program for patients, pharmacies, prescribers, and distributors; implemen-
tation of an education program for the four groups just listed; implementa-
tion of a reporting and data collection system for serious AEs in compliance
with statutory requirements and as pertaining to the sale and dispensing
of isotretinoin outside the iPLEDGE program; and implementation of a
been used in some cases, but are often exercised at the point of approval.
In general, even if FDA is successful in placing a condition or restriction at
the time of approval, doing so after marketing is substantially more chal-
lenging. For example, FDA’s authority over labels is limited to approving
the contents of a label prepared by the sponsor, after a sometimes lengthy
process of negotiation about the language. Although FDA may disagree with
the sponsor and request certain changes, it is the committee’s understanding
that the agency cannot compel the sponsor to make changes.
rial nor unlimited. It does, however, provide the FDA with a wider range
of remedies and a stronger base from which to negotiate voluntary actions,
while still providing affected parties an avenue of relief from what they may
perceive as unwarranted or overly burdensome actions.
The committee also finds that FDA needs enforcement tools to ensure
that the regulatory requirements described above are applied and met.
Specifically, FDA does not have the set of flexible regulatory actions that
it needs to enforce necessary and important postmarketing commitments
effectively.
drugs approved for marketing (MHRA, 2006). The black triangle program
has an additional purpose of alerting National Health Service providers to
report all adverse reactions (rather than only serious ones) associated with
drugs labeled with the symbol. Study of reporting patterns indicates that
despite the request for both serious event and non-serious event reporting,
providers are five times more likely to report a serious than a non-serious
adverse drug reaction (Heeley et al., 2001). Therefore, it is not clear whether
the black triangle program in the United Kingdom was successful in increas-
ing provider reporting. However, the black triangle was not intended as a
tool to inform or educate consumers, so evidence from the United Kingdom
would not necessarily be informative in the case of a somewhat different
use for such a symbol. The committee believes that marking the label and
all promotional material for newly approved drugs or indications with a
special symbol and communicating its meaning to patients and consumers
may help to increase awareness of the nature of newly approved therapies,
for example, the incompleteness of information on safety.
The symbol should remain on the drug label and related materials for
2 years unless FDA chooses to shorten or extend the period on a case-by-
case basis. The committee believes that companies should refrain from DTC
advertising during the black triangle period, and would favor imposition of
a formal moratorium on such advertising. Such restraints may be necessary
because DTC advertising has the ability to dramatically increase the uptake
of a newly approved drug. In some cases, that may expose larger numbers
of people (compared with a lower-key market introduction) to a new drug
with not-yet-documented safety concerns. Recognizing the legal uncertain-
ties surrounding such an imposition, the committee suggests that at the very
least any DTC advertising during this period should include explicit notice
that the data related to risks and benefits associated with the product are
less extensive than those related to alternative products that have been in
use for a longer period and should include a caution to speak to one’s health
care provider about alternatives. If a moratorium on DTC advertising for
the time that the special symbol is in effect is deemed to be inconsistent with
First Amendment protections of commercial speech, the committee believes
In 1977, the Review Panel on New Drug Regulation found that “FDA
even lacks a basis for judging whether the approved drug and the approved
labeling are still correct, since there is no comprehensive system for gath-
ering and utilizing data on an approved drug’s performance and effect”
(Department of Health Review Panel on New Drug Regulation, 1977:91).
This continues to be the case.
The committee finds that a lifecycle approach to risk and benefit would
be facilitated by establishing a milestone in a drug’s lifecycle for a compre-
hensive review of consolidated safety and efficacy data and the status of
postmarketing conditions and commitments (see Chapter 4 for discussion of
the assessment of risks and benefits). There is no systematic CDER review of
accumulated knowledge about a drug a year or more after its approval for
marketing. In 2005, the European Medicines Agency enacted a new statute
requiring that prescription drug marketing authorizations in the European
Union be reviewed and, if appropriate, renewed at 5 years after initial ap-
proval (EMEA, 2005).
5.4: The committee recommends that FDA evaluate all new data
on new molecular entities no later than 5 years after approval.
Sponsors will submit a report of accumulated data relevant to
drug safety and efficacy, including any additional data published
in a peer-reviewed journal, and will report on the status of any
applicable conditions imposed on the distribution of the drug called
for at or after the time of approval.
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Patients use the medications approved by the Food and Drug Adminis-
tration (FDA) and prescribed by health care providers. Despite that, patients
historically have been left out of the loop in much of the communication that
has occurred among the biomedical research, health care, and pharmaceuti-
cal enterprises and government regulators. As described in Chapter 1, social
and technological changes have transformed the practice of medicine, the
role of patients, and the information environment that surrounds patients
and physicians and influences their interactions (Henwood et al., 2003).
Public interest in and knowledge about drugs have also evolved greatly due
to direct-to-consumer (DTC) prescription drug advertising, ever wider In-
ternet and e-mail access and breadth of information, a shift in the formerly
passive role of patient, and the emergence of a powerful patient advocacy
movement (Atkin and Wallack, 1990; Dupuits, 2002; Pew Internet and
American Life Project, 2003, 2004, 2005). Finally, the recent safety concerns
about widely used, well-known drugs and drug classes, from antidepres-
sants to anti-inflammatory drugs, have further mobilized public interest in
drug safety issues. As noted earlier, FDA, the pharmaceutical industry, the
health care delivery system, and other stakeholders have begun to grapple
with serious questions about when to inform patients and consumers about
risk, how to communicate effectively, and what information is needed for
personal health, health care system, and regulatory decision making.
This chapter is intended not to provide a comprehensive assessment of
communication issues in the drug system but rather to describe briefly major
http://www.fda.gov/opacom/backgrounders/miles.html.
177
The Committee on the Assessment of the Drug Safety System did not
endeavor to conduct a comprehensive examination of the communication
needs of patients and the general public. Another IOM committee addressed
these issues extensively in their report, Preventing Medication Errors (2007).
That report recommended specific steps the health care delivery system,
FDA, and other federal agencies could take to improve the availability, ac-
cessibility, quality, and quantity of patient and consumer information about
drugs and their risks and benefits (see Box 6-1 and Appendix A). The present
chapter focuses only on two areas where the committee believes FDA could
strengthen its programs targeting patients’ and consumers’ communication
needs.
Consumers and patients seek to access the information they need about
the drugs they use through an incomplete and imperfect patchwork of
sources (Brann and Anderson, 2002). These sources are of varying reliability
and usefulness, and they include health care providers and pharmacists,
DTC advertising, printed information made available by pharmacies, FDA-
required patient package inserts for a limited number of drugs, informa-
tion from a wide variety of sources made available on the Internet, and so
BOX 6-1
Recommendations Pertaining to Consumers from
Preventing Medication Errors
Recommendation 1: To improve the quality and safety of the medication-use
process, specific measures should be instituted to strengthen patients’ capaci-
ties for sound medication self-management. Specifically:
• Patients’ rights regarding safety and quality in health care and medi-
cation use should be formalized at the state and/or federal levels and
ensured at every point of care.
• Patients (or their surrogates) should maintain an active list of all
prescription drugs, over-the-counter (OTC) drugs, and dietary supple-
ments they are taking; the reasons for taking them; and any known
drug allergies. Every provider involved in the medication-use process
for a patient should have access to this list.
• Providers should take definitive action to educate patients (or their
surrogates) about the safe and effective use of medications. They
should provide information about side effects, contraindications, and
how to handle adverse reactions, as well as where to obtain additional
objective, high-quality information.
• Consultation on their medications should be available to patients at
key points along the medication-use process (during clinical decision
making in ambulatory and inpatient care, at hospital discharge, and at
the pharmacy).
public announcements about major health findings from them, good and
bad. Recent studies from the Women’s Health Initiative have generated such
communications (e.g., about the benefits and risks of Hormone Replacement
Therapy) in postmenopausal women. Through NLM, NIH also operates the
clinicaltrials.gov trial registration Web site (discussed in Chapter 4).
BOX 6-2
Recommendations Pertaining to Providers (and Patients) from
Preventing Medication Errors
Recommendation 3: All health care organizations should immediately make
complete patient-information and decision-support tools available to clinicians
and patients. Health care systems should capture information on medication
safety and use this information to improve the safety of their care delivery
systems. Health care organizations should implement the appropriate systems
to enable providers to:
• The NLM should take the lead in developing a common drug nomen-
clature for use in all clinical information technology systems based on
the standards for the national health information infrastructure.
• AHRQ should take the lead in organizing safety alert mechanisms by
severity, frequency, and clinical importance to improve clinical value
and acceptance.
• AHRQ should take the lead in developing intelligent prompting mecha-
nisms specific to a patient’s unique characteristics and needs; provider
prescribing, ordering, and error patterns; and evidence-based best-
practice guidelines.
• AHRQ should take the lead in developing user interface designs based
on the principles of cognitive and human factors and the context of the
clinical environment.
• AHRQ should support additional research to determine specifications
for alert mechanisms and intelligent prompting, and optimum designs
for user interfaces.
The mention of the term consumer is not intended to reflect the committee’s views on its
validity. The committee is aware of the favorable sides of health consumerism—such as em-
powerment and self-management—and of the more unfavorable aspects, including the com-
modification of health. It is also aware of the reality that access to health care and the level of
health literacy (IOM, 2005) determine whether a patient has the opportunity to make health
care choices and to form productive relationships with health care providers.
BOX 6-3
FDA Response to the December 2005 Public Meeting Input
In December 2005, FDA held a public hearing on communication of
drug safety information. The hearing was intended to facilitate discussion
on FDA’s risk communication with health care providers and patients/
consumers. The following topics presented to FDA at the meeting were
noted as needing improvement and attention:
FDA uses the term labeling to refer to any FDA-approved materials based on the formal
label on which FDA and the sponsor agree at the time on approval or to change in the label
after marketing.
The action plan is available online at http://www.fda.gov/cder/offices/ods/keystone.pdf.
BOX 6-4
Criteria for Useful Consumer Medication Information
Written prescription medicine information should be
(1) scientifically accurate
(2) unbiased in content and tone
(3) sufficiently specific and comprehensive
(4) presented in an understandable and legible format that is readily
comprehensible to consumers
(5) timely and up-to-date
(6) useful
One function of the DSB (described in more detail in Chapter 3), now
located in the Office of Safety Policy and Communication, is to produce
patient information sheets for every drug, to be posted on the FDA/CDER
Web site. The sheets are intended to provide safety alerts and other emerging
information to consumers about specific drugs. However, a footnote to the
Drug Watch guidance developed by CDER seems to suggest that the center’s
long-term goal is to develop patient information sheets (and provider sheets)
for every drug on the market (FDA, 2005; Galson, 2005; confirmed by
S. Galson, personal communication, February 22, 2006).
http://www.fda.gov/cder/audiences/acspage/index.htm.
The proposed advisory committee should also have the role of devel-
oping and implementing a comprehensive consumer information program
at FDA. The expertise needed on the advisory committee may include
consumer and patient perspectives (adult, children, chronic conditions,
new reader, consumer organizations, disease specific advocacy groups, and
patient safety advocacy groups), risk communication, health literacy, social
marketing expertise, public relations expertise, social sciences expertise with
an emphasis on qualitative research and survey science, journalism, and eth-
ics. The advisory committee could develop standards for effective commu-
nication of risk and benefit information, patient-provider communication,
and patient participation in the generation of drug safety information and
data, and apply available expertise and evidence to refine the structure and
content of public health advisories, develop more robust standards for FDA’s
assessment of DTC advertising. It would, like all other advisory committees,
be based in the Office of the Commissioner, but it would work closely with
the new CDER Office of Safety Policy and Communication.
The scope of work for the new CDER Office of Safety Policy and Com-
munication is still under development. Given the reactive, fragmentary,
and short-lived nature of previous CDER initiatives and organizational
changes, the committee believes that special attention and commitment
will be required to allow the new office to succeed. It will be essential to
have its scope and goals clearly defined, and for its work to be given a high
priority in CDER.
The Advisory Committee Oversight and Management Staff in the Office of the Commis-
sioner works in collaboration with FDA centers to ensure consistent development, implementa-
tion, and operations of the FDA advisory committees (FDA, 2003).
BOX 6-5
Examples of Federal Advisory Committees
on Consumer Issues
Two DHHS agencies have successfully used consumer advisory
committees to obtain input from consumers. The NIH Director’s Council
of Public Representatives (COPR) advises the NIH director on “mat-
ters related to medical research, NIH policies and programs, and public
participation in agency activities.” The COPR has held workshops and
issued reports on enhancing public input in research priority-setting, on
strengthening public trust in the research enterprise, and on the orga-
nizational structure and management of NIH. The COPR Web site also
provides information about the cost of running the council: $222,351
for operations and member expenses and $124,118 for 1.30 full-time
equivalents of staff. NIH sponsors a public lecture series at which NIH
scientists discuss their work in a manner appropriate for a lay audience
(NIH, 2006); this series is another example of reaching out to understand
consumer concerns.
The National Cancer Institute (NCI) Office of Liaison Activities
launched the Director’s Consumer Liaison Group (DCLG) in 1997; it is
NCI’s first and only consumer advisory group. The DCLG makes recom-
mendations to the director of NCI from the consumer advocate perspec-
tive on a wide variety of issues, programs, and research priorities. The
15 members include advocates, survivors, family members, and health
care professionals and are chosen by the NCI director from a pool of ap-
plicants. The DCLG complies with the provisions of the Federal Advisory
Committee Act. (NCI, 2006a,b). It also provides a forum for the cancer
advocacy community. At the time of this writing, plans were being made
for a summit titled “Listening and Learning Together: Building a Bridge of
Trust” to bring together many segments of the cancer community to give
them a voice in shaping the interaction and collaboration between NCI
and consumers (NCI, 2006c). In 2003, NCI contracted with a consulting
firm to conduct a survey of the cancer advocacy community and, among
other things, to measure and track advocacy organizations’ perceptions of
the DCLG. The survey found that DCLG was known in the cancer advo-
cacy community, and 69% percent of respondents thought that the group
would be more effective if it worked strategically with NCI rather than
monitoring or participating in the implementation of NCI’s strategic plan.
Respondents also wanted to see the DCLG more involved in research,
clinical trials, survivorship, health disparities, and communication.
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House of Representatives.
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tion Before the Subcommittee on Oversight and Investigations before the Committee on
Energy and Commerce, US House of Representatives.
The Food and Drug Administration (FDA) lacks the resources needed to
accomplish its large and complex mission today, let alone to position itself
for an increasingly challenging future. Despite the fact that so much has
changed in drug discovery and development, in the number and complexity
of FDA’s congressionally mandated responsibilities, in the practice of medi-
cine, the structuring and delivery of health care, the way drugs are used,
the role of patients and consumers, and the information environment, FDA
appropriations for new drug review have remained roughly flat (in constant
dollars) since the passing of the Prescription Drug User Fee Act (PDUFA)
(Thompson, 2000; GAO, 2002). User fees have led to an overall increase
in resources for new drug review, but activities not funded by user fees
have received a smaller portion of FDA’s total budget. There is little dispute
that FDA in general is, and the Center for Drug Evaluation and Research
(CDER) specifically remains, severely underfunded (Goldhammer, 2005;
Wolfe, 2006). There is widespread agreement that resources for postmar-
keting drug safety work are especially inadequate and that resource limita-
tions have hobbled the agency’s ability to improve and expand this essential
Also of note: “Total FDA appropriations each year (exclusive of user fees and rent pay-
ments to GSA) must total at least as much as FDA received in FY 1997, adjusted for inflation
at the rate of change in the Consumer Price index since FY 1997. . . . FDA meets this trigger
consistently, even though for most years since FY 1997 FDA did not receive increases to cover
the cost of pay increases and inflation for its core programs—which was the original intent of
this trigger. FDA meets this trigger primarily because FDA has received appropriation increases
earmarked for specific initiatives since FY 1997 (e.g., food safety, tobacco, counter-terrorism)”
(FDA, 2003).
193
$500.0
$450.0 Appropriations
User Fees
$400.0 Total Funding
$350.0
Amount (millions)
$300.0
$250.0
$200.0
$150.0
$100.0
$50.0
$0.0
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004
Year
fig 7-1
3000
Total Process FTEs
User Fee FTEs
2500
Non-User Fee FTEs
2000
FTEs
1500
1000
500
0
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004
Fiscal Year
fig 7-2
2003). These restrictions have contributed to a troubling resource imbalance
between OND and other CDER units (e.g., postmarketing safety activities,
compliance). Some effects or correlates of the resource imbalance between
OND and the Office of Drug Safety (ODS)/ Office of Surveillance and Epi-
demiology (OSE) are discussed in Chapter 3.
The committee recognizes that the recommendations in this report come
with a price tag, one that is most likely large and believes it would be ill-
advised to expect CDER to take on the many new responsibilities called for
in this report without new funds for strengthening the number and expertise
of staff, for intramural and extramural research, and for information tech-
nology. On the other hand, the committee believes that full implementation
of the recommendations it offers is essential. Although some of the recom-
mendations are more far-reaching than others, the committee believes each
of its recommendations will serve to improve the drug safety system.
For the past 15 years, user fees have supported a steadily increasing
share of CDER’s work. Many have argued that relying so heavily on indus-
try funds is inherently inappropriate and damaging to the reputation and
functioning of CDER, indeed, of any regulatory entity. Some CDER staff,
as well as some public advocates (Wolfe, 2006) have expressed discomfort
with this funding (DHHS and OIG, 2003; GAO, 2006; IOM Staff Notes,
5
Copyright National Academy of Sciences. All rights reserved.
The Future of Drug Safety: Promoting and Protecting the Health of the Public
“We share a concern with FDA about the current balance between the user
fee portion and the appropriated portion of the review process,” PhRMA’s
Goldhammer says. As industry funding approaches half of the review budget,
“it has led to a perceptual issue that industry is paying for the review process
and that the American public, through its tax moneys, is not. We would hope
that can be dealt with in some way because we don’t want there to be the
perception that this is an industry-driven program” (Thompson, 2000).
As described in Chapter 2, some CDER new drug review staff assert that the workload
pressures to meet PDUFA goals are compounded by industry submissions that are not well
organized, submissions that come in on paper or with data that are not easily reanalyzed, or
on suboptimal management by their direct supervisors or team leaders. Some of these CDER
staff also reported that the biggest pressures come from 6-month priority approvals and not
from standard applications, the goal for which is 10 months for approval.
Zelenay has proposed eliminating the PDUFA sunset clause as a means to reduce the
Adapted from the capture theory of regulation advanced by Stigler (1971) and critiqued by
Laffont and Tirole (1991) and by Carpenter and Ting (2004).
The industry has a powerful influence on the political process and on the regulatory envi-
agencies.
http://energycommerce.house.gov/107/hearings/03062002Hearing502/print.htm.
See Chapter 3 for a recommendation regarding institution of safety goals.
The committee is aware that other regulatory agencies, for example the Environmental
Protection Agency and the Federal Communications Commission, are supported in part by
specific user-fee programs. Some user fees go directly into the Treasury; other user fees go to
the agency and offset congressional appropriations. The committee has not done an exhaustive
analysis of other user-fee programs but is of the understanding that they are not associated with
significant requirements on how the agency uses the fees to achieve programmatic goals.
in staff to meet the new responsibilities described in this report. CDER will
require new staff, for example, to participate more actively in efforts to gen-
erate more and better safety analyses, such as through an expanded epide-
miology contracts program; participate in new drug review teams; develop
more consistent approaches to risk-benefit assessment both premarket and
postmarket; evaluate risk minimization action plans; work with other fed-
eral agencies and departments in their efforts to improve their drug safety-
related activities; evaluate industry-submitted 5-year reviews; routinely
assess and make public emerging safety and effectiveness information, and
consider appropriate imposition of the newly clarified conditions on dis-
tribution. The committee’s recommendations will require additional staff
throughout CDER and with varied expertise, for example, epidemiology,
statistics, public health, medicine, pharmacy, informatics, programming,
law, regulatory policy, communication, as well as project management and
administration.
The committee recognizes that increases in postmarket safety staff must
be phased in over time. As CDER begins to implement the recommenda-
tions in this report and gradually increase their staff, the size of the needed
increase will become apparent to CDER and the Congress. Congress can
ensure this by requesting that CDER perform and make publicly available
a formal evaluation of staff needs, perhaps in the form of a work audit.
The FDA commissioner can serve an important role as a champion within
the government and in discussions with Congress for needed resources. The
committee also recognizes that other federal partners in drug safety will re-
quire additional staff to achieve a fully functioning postmarket drug safety
system, as described in Chapter 4.
Research funds: ODS/OSE is the CDER component most likely to have
primary responsibility for implementing the extramural and intramural
research activities called for in the report. The committee was concerned
by the very small and inadequate amount of funds for the epidemiology
contracts programs in particular. CDER will also require funds for extra-
mural contracts to improve their passive and active surveillance activities, in
addition to increased intramural use of drug utilization databases and other
datasets such as the General Practice Research Database.
The committee provides several estimates of needed funds for intramu-
ral and extramural research. The committee‘s lower bound estimate is that
an expanded epidemiology contracts program would cost $10 million.11 The
committee estimates that other agencies/departments also require similar
resources for epidemiology research contracts. The committee offers as a
insufficient to complete one major study. The committee asserts that at least 10 drug safety
hypotheses could be explored through this or a similar program per year.
program would cost $50 million (Federal News Service, 2000). Using the Consumer Price
Index, this would cost $60 million in 2006.
13The Enhancing Drug Safety and Innovation Act of 2006 (S. 3807) authorizes appropria-
14For example, the Clinical Antipsychotic Trials of Intervention Effectiveness cost $42.6 mil-
lion; the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attacks trial cost
$125 million; the Study of Tamoxifen and Raloxifene trial cost $118 million.
role in assuring the safety and efficacy of prescription drugs now and in
the future. Also, PDUFA reauthorization is just months away, and major
legislation addressing drug regulation has been prepared and considered.15
These circumstances make this a golden moment of opportunity to im-
prove fundamentally the way FDA regulation considers and responds to
the evolving understanding of risks and benefits of drugs, and the way all
stakeholders in the drug safety system perceive, study, and communicate
about those risks and benefits. As described in Chapter 1, there have been
many commissions and reports addressing issues similar to those contained
in this report. It is the committee’s fervent hope that Congress, FDA, and
the other stakeholders will seize the gathering momentum to invigorate the
drug safety system. The agency’s credibility and its ability to protect and
promote optimally the health of the American people cannot wait another
year or another decade.
REFERENCES
Carpenter D, Ting MM. 2004. A Theory of Approval Regulation. [Online]. Available:
http://people.hmdc.harvard.edu/~dcarpent/endosub-20040214.pdf [accessed October
10, 2005].
DHHS (Department of Health and Human Services), OIG (Office of Inspector General). 2003.
FDA’s Review Process for New Drug Applications: a Management Review. OEI-01-01-
00590. Washington, DC: OIG, FDA.
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voted to Drug Safety. Submitted to the Institute of Medicine Committee on the Assessment
of the US Drug Safety System by FDA.
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Improving Performance in FDA Review of New Drug Applications. [Online]. Available:
http://www.fda.gov/oc/pdufa/PDUFAWhitePaper.pdf [accessed December 5, 2005].
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Ambulatory Care and Prevention Harvard Medical School Director of Research Harvard
Pilgrim Health Care.
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Withdrawals, and Other Agency Activities. GAO-02-958. Washington, DC: GAO.
GAO. 2006. Drug Safety: Improvement Needed in FDA’s Postmarket Decision-Making and
Oversight Process. GAO-06-402. Washington, DC: GAO.
Goldhammer A. 2005 (June 8). Statement of the Pharmaceutical Research and Manufacturers
of America to Institute of Medicine. Presentation to the Institute of Medicine Committee
on the Assessment of the US Drug Safety System. Washington, DC: IOM.
Laffont J, Tirole J. 1991. The politics of government decision-making: a theory of regulatory
capture. Quart J Econ 106(4):1089-1127.
Stigler G. 1971. The theory of economic regulation. Bell J Econ Manage Sci 2:2-21.
Thompson L. 2000. User fees for faster drug reviews. Are they helping or hurting the public
health? FDA Consum 34(5):25-29.
Union of Concerned Scientists (UCS). 2006. FDA Scientists Pressured to Exclude, Alter
Findings; Scientists Fear Retaliation for Voicing Safety Concerns. [Online]. Available:
http://www.ucsusa.org/news/press_release/fda-scientists-pressured.html [accessed July
24, 2006].
Wolfe S. 2006. Public Citizen: The 100th Anniversary of the FDA: The Sleeping Watchdog
Whose Master Is Increasingly the Regulated Industries. [Online]. Available: http://www.
pharmalive.com/News/index.cfm?articleid=353196&categoryid=54 [accessed July 11,
2006].
Zelenay JL. 2005. The Prescription Drug User Fee Act: is a faster Food and Drug Administra-
tion always a better Food and Drug Administration? Food Drug Law J 60(2):261-338.
Appendix A
This section was compiled by Institute of Medicine staff with guidance from the Committee
on the Assessment of the US Drug Safety System.
205
met nine times from its inception through June 2006, and it has generally
discussed Patient Information Sheets, Public Health Advisories distributed
by CDER, and ways to strengthen CDER’s risk communication efforts.
DRUG WATCH
A Drug Watch Web page was proposed as part of FDA’s drug safety
initiative in February 2005 to improve communication with the public on
drug safety issues by putting information out as quickly as possible in an
easily accessible format. The goal of the proposed Drug Watch program is to
help patients and health care professionals make informed decisions on the
use of prescription drugs. Drug Watch will include emerging data and risk
information in a consumer-friendly form (information sheets) for healthcare
professionals and patients regarding drugs for which FDA is actively assess-
ing incoming safety information (FDA, 2005b,d).
A draft guidance on Drug Watch released in May 2005 (FDA, 2005f)
discussed how the inclusion of a drug on Drug Watch would not signify
that the drug is dangerous or should not be used; it only means that FDA is
investigating emerging safety signals. The information on each drug would
vary but could include “factual information about newly observed, serious
adverse events associated with the use of a drug that have been reported
to FDA”; “information about significant emerging risks that FDA believes
may be associated with a drug, but that might be avoided by appropriate
patient selection, monitoring, or use of concomitant therapy”; and notice
of an important risk minimization procedure that has been put into place
by the sponsor to alert healthcare providers and patients that there has been
a change in how a drug should be prescribed, dispensed, or used (FDA,
2005f). The DSB role in overseeing the Drug Watch program was described
above.
APPENDIX A 207
Guidance Documents
In March 2005, FDA released three final guidance documents to help
develop new ways to improve methods of assessing and monitoring risks
associated with drugs in clinical development:
APPENDIX A 209
Reports
In November 2005, FDA announced the availability of a white paper
titled Prescription Drug User Fee Act (PDUFA): Adding Resources and
Improving Performance in FDA Review of New Drug Applications (FDA,
2005c). It was released shortly after FDA requested public input on PDUFA
provisions for FDA to consider during the renewal process for 2007 (FDA,
2005k). The white paper describes PDUFA goals, how they were imple-
mented or achieved by CDER, and the changes that have resulted from
PDUFA (that is, hiring of more medical reviewers, shorter approval times,
greater consistency, and increased workload) (FDA, 2005c).
In February 2006, a report commissioned by FDA, Evaluation of FDA’s
First Cycle Review Performance—Retrospective Analysis was released
(FDA News, 2006c). It showed a positive correlation between receiving ap-
proval on the first review cycle and pharmaceutical company consultation
with FDA before the beginning of the final phase of human testing (the end
of phase 2). The commissioner of FDA stated that “these meetings have
become one of the most valuable aspects of the drug development process”
(FDA News, 2006c). Deficiencies in safety assessment during the Investiga-
tional New Drug process were cited in the report as a main cause of multiple
review cycles, which potentially could have been avoided if a “milestone
meeting” had taken place where CDER staff could have made suggestions
for improving the quality of the initial applications (FDA News, 2006c).
Thereport was written by Booz Allen Hamilton in relation to the Prescription Drug User
Fee Amendments of 2002 (PDUFA III).
Labeling
On November 2, 2005, FDA started requiring that drug manufactur-
ers submit prescription drug label information to FDA in a new electronic
format. That was intended to allow patients and healthcare providers to
obtain information in FDA-approved package inserts (“labels”) with greater
ease (FDA News, 2006c). Drug manufacturers are now required to provide
FDA with accurate and up-to-date product and prescribing information in
a structured product labeling that can be electronically managed. These la-
bels will be the main source of information for a new interagency Web site,
“DailyMed,” a health information clearinghouse, which will provide up-
to-date information to consumers and healthcare providers free (National
Library of Medicine, 2006).
In January 2006, FDA announced a change in the prescription drug for-
mat for the package insert to provide clear and concise information so that
healthcare providers can make better use of the drug label to minimize risk
and medical errors in their patients (FDA News, 2006c). The final rule was
the first revision in 25 years and now requires that prescription information
for new and recently approved products meet new criteria. The change was
aimed at increasing the readability and accessibility of label information
and drawing health professionals and consumers’ attention to the most
important pieces of drug information before a product is prescribed. The
changes include the insertion of a “highlights” section that includes concise
information on the risks and benefits related to the drug, a table of contents
in the label, the date of initial approval of the drug, a toll-free number, and
Internet reporting information.
The labeling rule also established an important change in statutory in-
terpretation: preempting state product liability laws on the basis of FDA’s
approved label. The preamble to the labeling rule states that state laws
and judicial decisions that would have the effect of finding FDA-approved
labels inadequate or misleading are preempted by the federal rule (21 CFR
Parts 201, 314, and 601). That position has partial support in existing case
law, and FDA’s assertion of federal preemption under the new labeling rule
has not yet been tested in court (National Conference of State Legislatures,
2006).
APPENDIX A 211
Advisory Committees
In May 2006, CDER announced that it was launching an internal
assessment of its Advisory Committee meeting system to establish best
practices surrounding that process. The assessment will be led by senior
management in CDER and will take a comprehensive look at current prac-
tices for nominating committee members, screening for conflicts of interest,
choosing expertise for specific meeting topics, and utilizing Special Govern-
ment Employees.
Partnerships
In August 2005, FDA and the Association of American Medical Colleges
(AAMC) released the joint report Drug Development Science Obstacles and
Opportunities for Collaborations, which describes an array of opportuni-
ties for scientific breakthroughs to be undertaken through collaboration to
reach the goals of CPI (AAMC, 2006; AAMC et al., 2005; DeClaire, 2005).
The report states that those partnerships should focus on greater sharing
of knowledge, regulatory and legislative relief, earlier evaluation of drugs
in humans, and improved education and training for health professionals.
Some of the kinds of collaboration outlined in the report are to develop
mechanisms to learn from failed drug targets, establish joint models for
biomarker validation, set up a consortium to analyze and learn from failed
clinical trials, and develop agreements for sharing of information restricted
as intellectual property.
In November 2005, FDA, the European Commission, and the European
Medicines Agency extended by 5 years a confidentiality agreement that
began in September 2003 (FDA and EMEA, 2004; DeClaire, 2005; FDA
et al., 2005). The types of information covered by the agreement are legal
and regulatory issues, scientific advice, orphan drug designation, inspection
reports, marketing authorization procedures, and postmarketing surveil-
APPENDIX A 213
safety issues are usually found during clinical trials or when drugs are on
the market. Tests for finding safety problems earlier are few and not reli-
able. The CPI highlights that there are great efforts to be made and that a
new safety toolkit would include the ability to predict failures due to safety
before human testing in clinical trials and to demonstrate safety before a
drug is on the market. The safety toolkit would lead to better safety stan-
dards by helping to predict safety performance efficiently and quickly and
will decrease uncertainty.
FDA announced its partnership with the Critical Path Institute (C-Path)
in December 2005 to help it to reach the goals of the CPI (FDA, 2006d).
C-Path is an independent, publicly funded, nonprofit organization founded
by FDA, the University of Arizona, and SRI International. It was created to
fulfill the mission of the CPI, which is to “create innovative collaborations
in education and research that enable the safe acceleration of the process
for developing new medical products” (The Critical Path Institute, 2006).
FDA leaders stated that some of the projects developed by C-Path will help
to achieve many of the objectives outlined in the opportunities list discussed
above.
In March 2006, shortly after the release of the Opportunities Report,
FDA announced that it will be taking on an advisory role in the new Predic-
tive Safety Testing Consortium of C-Path and five pharmaceutical compa-
nies. The partnership will “share internally developed laboratory methods to
predict the safety of new treatments before they are tested in humans” (FDA,
2006b). The collaboration is in line with the public-private partnerships
stressed as a major need to improve drug development in the CPI. CDER’s
J. Woodcock commented that this is a “concrete example of the power of
the collaborative nature of the Critical Path Initiative.”
REFERENCES
AAMC (Association of American Medical Colleges), FDA, Center for Drug Development Sci-
ence at the University of California, San Francisco. 2005. Drug Development Science Ob-
stacles and Opportunities for Collaboration Among Academia, Industry and Government.
[Online]. Available: https://services.aamc.org/Publications/showfile.cfm?file=version45.
pdf [accessed October 10, 2005].
AAMC. 2006. Collaboration Key to Overcoming Obstacles to Drug Development. [Online].
Available: http://www.aamc.org/newsroom/pressrel/2005/050815.htm [accessed June
14, 2006].
CDER (Center for Drug Evaluation and Research). 2005. Drug Safety Oversight Board (DSB),
MAPP 4151-3. [Online]. Available: http://www.fda.gov/cder/mapp/4151-3.pdf [accessed
June 20, 2005].
CDER. 2006. Guidance for Industry, Investigators, and Reviewers Exploratory IND Studies.
Rockville, MD: CDER.
The Critical Path Institute. 2006. Welcome to C-Path. [Online]. Available: http://www.c-path.
org/ [accessed June 14, 2006].
DeClaire J. 2005. Which Drugs Should Health Plans Cover? [Online]. Available: http://
APPENDIX A 215
FDA, EU (European Union), EMEA. 2005. FDA and EU (European Commission and EMEA)
Extend Confidentiality Arrangements for Five More Years. [Online]. Available: http://
www.fda.gov/bbs/topics/news/2005/NEW01257.html [accessed June 6, 2005].
FDA News. 2005. FDA Issues Final Risk Management Guidance’s. [Online]. Available: http://
www.fda.gov/bbs/topics/news/2005/NEW01169.html [accessed March 24, 2005].
FDA News. 2006a. FDA Issues Advice to Make Earliest Stages of Clinical Drug Develop-
ment More Efficient. [Online]. Available: http://www.fda.gov/bbs/topics/news/2006/
NEW01296.html [accessed March 9, 2006].
FDA News. 2006b. FDA to Strengthen Research and Communication with AHRQ. [Online].
Available: http://www.fda.gov/bbs/topics/news/2005/NEW01286.html [accessed January
3, 2006].
FDA News. 2006c. FDA Announces New Prescription Drug Information Format to Improve
Patient Safety. [Online]. Available: http://www.fda.gov/bbs/topics/news/2005/NEW01272.
html [accessed March 9, 2006].
FDA News. 2006d. Report Demonstrates Benefits of Earlier Meetings with FDA to Make
Drug Review Process More Efficient. [Online]. Available: http://www.fda.gov/bbs/top-
ics/news/2006/NEW01312.html [accessed June 15, 2006].
FDA Press Release. 2006 (April 5). FDA Awards Contract to Assess Postmarketing Study
Commitment Decision-Making Process Analysis Will Lead to a More Standardized
Approach. [Online]. Available: http://www.boozallen.com/home/industries_article/
2323260?1pid=386491 [accessed May 26, 2006].
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ing. [Online]. Available: http://www.ncsl.org/statefed/health/FDArule.htm [accessed July
3, 2006].
National Library of Medicine. 2006. About DailyMed. [Online]. Available: http://dailymed.
nlm.nih.gov/dailymed/about.cfm [August 28, 2006].
Appendix B
Acronyms
217
APPENDIX B 219
UK United Kingdom
USDA US Department of Agriculture
Appendix C
The following list presents by fiscal year the performance measures set
forth in the letters referenced in Section 102(3) of the PDUFA. In those let-
ters, the timing of a number of the goals was conditional either (1) on the
date (July 2, 1993) upon which a supplemental appropriation was enacted
to permit FDA to collect PDUFA user fees, or (2) a specific performance
interval (e.g., 6 or 12 months after submission). Table C-1 lists the 29 goals
by fiscal year with appropriate goal measurement dates:
Interim Goal of FY 94
1. Review and act upon 55 percent of complete NDA 12 months after Sept. 30,
and PLA/ELA submissions received during FY 94 end of FY 94 1995
within 12 months after submission date.
2. Review and act upon 55 percent of efficacy 12 months after Sept. 30,
supplementsb received during FY 94 within 12 months end of FY 94 1995
after submission date.
221
Interim Goals of FY 95
1. Review and act upon 70 percent of complete NDA 12 months after Sept. 30,
and PLA/ELA submissions received during FY 95 end of FY 95 1996
within 12 months after submission date.
2. Review and act upon 70 percent of efficacy 12 months after Sept. 30,
supplements received during FY 95 within 12 months end of FY 95 1996
after submission date.
3. Review and act upon 70 percent of manufacturing 6 months after Mar. 31,
supplements received during FY 95 within 6 months end of FY 95 1996
after submission date.
4. Review and act upon 70 percent of resubmitted 6 months after Mar. 31,
applications received during FY 95 within 6 months end of FY 95 1996
after the resubmission date.
5. Recruit and bring on board 50 percent of FDA 3 months after Dec. 31,
incremental review staff by first quarter of FY 95. end of FY 94 1994
6. Implement project management methodology for 18 months after Jan. 2, 1995
all PLA/ELA reviews within 18 months of user fee 7/2/93
payments.
7. Eliminate overdue backlogs of efficacy and 18 months after Jan. 2, 1995
manufacturing supplements to NDAs within 18 7/2/93
months of initiation of user fee payments.
8. Eliminate overdue of NDAs within 24 months of 24 months after Jan. 2, 1995
initiation of user fees. 7/2/93
9. Eliminate overdue backlogs of PLAs, ELAs and PLA/ 24 months after Jan. 2, 1995
ELA supplements within 24 months of initiation of 7/2/93
user fees.
10. Adopt uniform computer-assisted NDA standards End of FY 95 Sept. 30,
during FY 95. 1995
Interim Goals of FY 96
1. Review and act upon 80 percent of complete NDA 12 months after Sept. 30,
and PLA/ELA submissions receive during FY 96 end of FY 96 1997
within 12 months after submission date.
APPENDIX C 223
Five-Year Goals of FY 97
1. Review 90 percent of complete PLAs, ELAs, and 6 months after Mar. 31,
NDAs for priority applications within 6 months after end of FY 97 1998
submission date.
2. Review 90 percent of complete PLAs, ELAs, and 12 months after Sept. 30,
NDAs for standard applications within 12 months end of FY 97 1998
after submission date.
3. Review 90 percent of priority supplements to PLAs, 6 months after Mar. 31,
ELAs, and NDAs within 6 months after submission end of FY 97 1998
date.
4. Review 90 percent of standard supplements to PLAs, 12 months after Sept. 30,
ELAs, and NDAs that require review of clinical end of FY 97 1998
data (efficacy supplements) within 12 months after
submission.
5. Review 90 percent of supplements to PLAs, ELAs, 6 months after Mar. 31,
and NDAs that do not require review of clinical data end of FY 97 1998
(manufacturing supplements) within 6 months after
submission date.
6. Review 90 percent of complete applications 6 months after Mar. 31,
resubmitted following receipt of a non-approval letter end of FY 97 1998
within 6 months after the resubmission date.
7. Total review staff increment recruited and on board by End of FY 97 Sept. 30,
end of FY 97. 1997
aThe statute allows three additional months for review of original NDA, PLA, or ELA
submissions that involve major amendments within the last three months of their usual 6- or
12-month review intervals. In these cases, the measurement dates shown in this Appendix
move forward by 3 months.
bThe term “supplement” applies to both drug and biologic submissions. It includes
ENCLOSURE
PDUFA REAUTHORIZATION PERFORMANCE
GOALS AND PROCEDURES
The performance goals and procedures of the FDA Center for Drug Evalu-
ation and Research (CDER) and the Center for Biologics Evaluation and
Research (CBER), as agreed to under the reauthorization of the prescription
drug user fee program in the “Food and Drug Administration Moderniza-
tion Act of 1997,” are summarized as follows:
APPENDIX C 225
These review goals are summarized in Tables C-2, C-3, and C-4:
APPENDIX C 227
For biological products, for purposes of this performance goal, all original
BLAs/PLAs will be considered to be NMEs.
B. Scheduling Meetings:
1. Procedure: The meeting date should reflect the next available
date on which all applicable Center personnel are available to at-
tend, consistent with the component’s other business; however, the
meeting should be scheduled consistent with the type of meeting
requested. If the requested date for any of these types of meetings is
greater than 30, 60, or 75 calendar days (as appropriate) from the
date the request is received by the Agency, the meeting date should
be within 14 calendar days of the date requested.
Type A Meetings should occur within 30 calendar days of the
Agency receipt of the meeting request.
Type B Meetings should occur within 60 calendar days of the
Agency receipt of the meeting request.
Type C Meetings should occur within 75 calendar days of the
Agency receipt of the meeting request.
2. Performance Goal: 70 percent of meetings are held within the time-
frame (based on cohort year of request) starting in FY99; 80 percent
in FY00; and 90 percent in subsequent fiscal years.
C. Meeting Minutes:
1. Procedure: The Agency will prepare minutes which will be available
to the sponsor 30 calendar days after the meeting. The minutes will
clearly outline the important agreements, disagreements, issues for
further discussion, and action items from the meeting in bulleted
form and need not be in great detail.
2. Performance Goal: 70 percent of minutes are issued within 30
calendar days of date of meeting (based on cohort year of meeting)
starting in FY99; 80 percent in FY00; and 90 percent in subsequent
fiscal years.
D. Conditions:
For a meeting to qualify for these performance goals:
APPENDIX C 229
APPENDIX C 231
APPENDIX C 233
ENCLOSURE
PDUFA REAUTHORIZATION PERFORMANCE
GOALS AND PROCEDURES
The performance goals and procedures of the FDA Center for Drug Evalu-
ation and Research (CDER) and the Center for Biologics Evaluation and
Research (CDER), as agreed to under the reauthorization of the prescription
drug user fee program are summarized as follows:
APPENDIX C 235
APPENDIX C 237
B. Scheduling Meetings
1. Procedure: The meeting date should reflect the next available
date on which all applicable Center personnel are available to at-
tend, consistent with the component’s other business; however, the
meeting should be scheduled consistent with the type of meeting
requested. If the requested date for any of these types of meetings is
greater than 30, 60, or 75 calendar days (as appropriate) from the
date the request is received by the Agency, the meeting date should
be within 14 calendar days of the date requested.
Type A Meetings should occur within 30 calendar days of the
Agency receipt of the meeting request.
Type B Meetings should occur within 60 calendar days of the
Agency receipt of the meeting request.
Type C Meetings should occur within 75 calendar days of the
Agency receipt of the meeting request.
2. Performance goal: 90 percent of meetings are held within the time-
frame (based on cohort year of request) from FY 03 to FY 07.
C. Meeting Minutes
1. Procedure: The Agency will prepare minutes which will be available
to the sponsor 30 calendar days after the meeting. The minutes will
clearly outline the important agreements, disagreements, issues for
further discussion, and action items from the meeting in bulleted
form and need not be in great detail.
2. Performance Goal: 90 percent of minutes are issued within 30 cal-
endar days of date of meeting (based on cohort year of meeting) in
FY03 to FY07.
D. Conditions
For a meeting to qualify for these performance goals:
1. A written request (letter or fax) should be submitted to the review
division; and
2. The letter should provide:
a. A brief statement of the purpose of the meeting;
b. A listing of the specific objectives/outcomes the requester ex-
pects from the meeting;
c. A proposed agenda, including estimated times needed for each
agenda item;
d. A listing of planned external attendees;
APPENDIX C 239
APPENDIX C 241
APPENDIX C 243
FDA Modernization Act (21 U.S.C. 508), that are intended to treat
serious and/or life-threatening diseases, and that have been the sub-
ject of an end-of-phase 1 meeting. The pilot program is limited to
one Fast Track product in each CDER and CBER review division
over the course of the pilot program.
2. For drugs and biologics that meet these criteria, FDA may enter
into an agreement with the sponsor to initiate a formal program
of frequent scientific feedback and interactions regarding the drug
development program. The feedback and interactions may take
the form of regular meetings between the division and the spon-
sor at appropriate points during the development process, written
feedback from the division following review of the sponsor’s drug
development plan, written feedback from the division following
review of important new protocols, and written feedback from the
division following review of study summaries or complete study
reports submitted by the sponsor.
3. Decisions regarding what study reports would be reviewed as
summaries and what study reports would be reviewed as complete
study reports under this pilot program would be made in advance,
following discussions between the division and the sponsor of the
proposed drug development program. In making these decisions,
the review division will consider the importance of the study to
the drug development program, the nature of the study, and the
potential value of limited (i.e., based on summaries) versus more
thorough division review (i.e., based on complete study reports).
4. Guidance: FDA will develop and issue a joint CDER/CBER guidance
on how it intends to implement this pilot program by September
30, 2003. The guidance will describe the principles, processes, and
procedures that will be followed during the pilot program. The pilot
program will be implemented in FY 2004, after the final guidance
is issued and will continue through FY 2007. The full (unredacted)
study report will be provided to the FDA Commissioner and a ver-
sion of the study report redacted to remove confidential commercial
information or other information exempt from disclosure, will be
made available to the public.
APPENDIX C 245
APPENDIX C 247
C. Training: FDA will develop and implement a program for training all
review personnel, including current employees as well as future new
hires, on the good review management principles.
D. Evaluation: FDA will retain an independent expert consultant to under-
take a study to evaluate issues associated with the conduct of first cycle
reviews.
1. The study will be designed to assess current performance and
changes that occur after the guidance on GRMPs is published. The
study will include collection of various types of tracking data re-
garding actions that occur during the first cycle review, both from
an FDA and industry perspective (e.g., IR letters, DR letters, draft
labeling comments from FDA to the sponsor, sponsor response to
FDA requests for information).
2. The study will also include an assessment of the first cycle review
history of all NDAs for NMEs and all BLAs during PDUFA 3. This
assessment will include a more detailed evaluation of the events that
occurred during the review process with a focus on identifying best
practices by FDA and industry that facilitated the review process.
3. The study will also include an assessment of the effectiveness of the
training program implemented by FDA.
4. FDA will develop a statement of work for the study and will provide
the public an opportunity to review and comment on the statement
of work before the study is implemented. The consultant will pre-
pare annual reports of the findings of the study and a final study
report at the end of the 5-year study period. The full (un-redacted)
study reports will be provided to the FDA Commissioner and a
version of the study reports redacted to remove confidential com-
mercial information or other information exempt from disclosure,
will be made available to the public.
5. Development and implementation of the study of first cycle review
performance will be a component of the Performance Management
Plan conducted out of the Office of the Commissioner (see sec-
tion X).
6. Administrative oversight of the study will rest in the Office of the
Commissioner. The Office of the Commissioner will convene a
joint CDER/CBER review panel on a quarterly basis as a mecha-
nism for ongoing assessment of the application of Good Review
Management Principles to actions taken on original NDA/BLA
applications.
APPENDIX C 249
five years of PDUFA III funds for initiatives targeted to improve the drug
review process.
1. Funds would be made available by the Commissioner to the Cen-
ters based both on identified areas of greatest need for process
improvements as well as on achievement of previously identified
objectives.
2. Funds also could be used by the FDA Commissioner to diagnose
why objectives are not being met, or to examine areas of concern.
3. The studies conducted under this initiative would be intended to
foster:
a. Development of programs to improve access to internal and
external expertise
b. Reviewer development programs, particularly as they relate to
drug review processes,
c. Advancing science and use of information management tools
d. Improving both inter- and intra-Center consistency, efficiency,
and effectiveness
e. Improved reporting of management objectives
f. Increased accountability for use of user fee revenues
g. Focused investments on improvements in the process of drug
review
h. Improved communication between the FDA and industry
4. In deciding how to spend these funds, the Commissioner would
take into consideration how to achieve greater harmonization of
capabilities between CDER and CBER.
B. First Two Initiatives: Two specific initiatives will begin early in PDUFA
III and supported from performance management initiative funds 1)
evaluation of first cycle review performance, and 2) process review and
analysis within the two centers.
1. First Cycle Review Performance (See section X for details on this
proposed study.)
2. Process Review and Analysis
a. In FY 2003, FDA will contract with an outside consultant to
conduct a comprehensive process review and analysis within
CDER and CBER. This review will involve a thorough analysis
of information utilization, review management, and activity
cost.
b. The review is expected to take from 18–24 months, although
its duration will depend on the type and amount of complexity
of the issues uncovered during the review.
c. The outcome of this review will be a thorough documentation
APPENDIX C 251
D. FDA will deliver a single point of entry for the receipt and processing
of all electronic submissions in a highly secure environment. This will
support CBER, CDER, OC and ORA. The system should automate the
current electronic submission processes such as checking the content of
electronic submissions for completeness and electronically acknowledg-
ing submissions.
E. FDA will provide a specification format for the electronic submission of
the Common Technical Document (e-CTD), and provide an electronic
review system for this new format that will be used by CBER, CDER
and ORA reviewers. Implementation should include training to ensure
successful deployment. This project will serve as the foundation for au-
tomation of other types of electronic submissions. The review software
will be made available to the public.
F. Within the first 12 months, FDA will conduct an objective analysis and
develop a plan for consolidation of PDUFA III IT infrastructure and
desktop management services activities that will assess and prioritize
the consolidation possibilities among CBER, CDER, ORA and OC to
achieve technical efficiencies, target potential savings and realize cost
efficiencies. Based upon the results of this analysis, to the extent appro-
priate, establish common IT infrastructure and architecture components
according to specific milestones and dates. A documented summary of
the analysis will be forwarded to the Commissioner. A version of the
study report redacted to remove confidential commercial or security
information, or other information exempt from disclosure, will be made
available to the public.
G. FDA will implement Capability Maturity Model (CMM) in CBER,
CDER, ORA and OC for PDUFA IT infrastructure and investments,
and include other industry best practices to ensure that PDUFA III IT
products and projects are of high quality and produced with optimal
efficiency and cost effectiveness. This includes development of project
plans and schedules, goals, estimates of required resources, issues and
risks/mitigation plans for each PDUFA III IT initiative.
H. Where common business needs exist, CBER, CDER, ORA and OC will
use the same software applications, such as eCTD software, and COTS
solutions.
I. Within six months of authorization, a PDUFA III IT 5-year plan will be
developed. Progress will be measured against the milestones described
in the plan.
APPENDIX C 253
10. Other specific items may be added later as the Agency gains ex-
perience with the scheme and will be communicated via guidance
documents to industry.
E. Class 2 resubmissions are resubmissions that include any other items,
including any item that would require presentation to an advisory
committee.
F. A Type A Meeting is a meeting which is necessary for an other-
wise stalled drug development program to proceed (a “critical path”
meeting).
G. A Type B Meeting is a 1) pre-IND, 2) end of Phase 1 (for Subpart E
or Subpart H or similar products) or end of Phase 2/pre-Phase 3, or 3)
a pre-NDA/BLA meeting. Each requestor should usually only request
1 each of these Type B meetings for each potential application (NDA/
BLA) (or combination of closely related products, i.e., same active in-
gredient but different dosage forms being developed concurrently).
H. A Type C Meeting is any other type of meeting.
I. The performance goals and procedures also apply to original applica-
tions and supplements for human drugs initially marketed on an over-
the-counter (OTC) basis through an NDA or switched from prescription
to OTC status through an NDA or supplement.
Appendix D
MEETING ONE—AGENDA
The National Academies
Institute of Medicine
Committee on the Assessment of the US Drug Safety System
Meeting One
AGENDA
Steven Galson
Acting Director of the Center for Drug Evaluation
and Research
Food and Drug Administration
255
Janet Woodcock
Deputy Commissioner of Operations
Food and Drug Administration
10:35–11:00 a.m. Questions from the Committee
11:00–11:45 a.m. Perspectives of Pharmaceutical Manufacturers and
Payors
Amit Sachdev
Executive Vice President, Health
Biotechnology Industry Organization (BIO)
Christine Simmon
Vice President of Public Affairs and Development
Generic Pharmaceutical Association (GPhA)
J. Russell Teagarden
Vice President of Clinical Practices &
Therapeutics
Medco Health Solutions, Inc. (on behalf of the
Pharmaceutical Care Management Association)
Alan Goldhammer
Associate Vice President for Regulatory Affairs
Pharmaceutical Research and Manufacturers of
America (PhRMA)
11:45–12:00 p.m. Questions from the Committee
12:00–12:45 p.m. Consumer/Patient and Professional Organizations’
Perspectives
David Borenstein
Member, Board of Directors
American College of Rheumatology (ACR)
John A. Gans
Executive Vice-President and Chief Executive
Officer
American Pharmacists Association (APhA)
Bill Vaughan
Senior Policy Analyst
Consumers Union
Jeanne Ireland
Director of Public Policy
Elizabeth Glaser Pediatric AIDS Foundation
APPENDIX D 257
MEETING TWO—AGENDA
The National Academies
Institute of Medicine
Committee on the Assessment of the US Drug Safety System
Meeting Two
AGENDA
Speakers and Times Subject to Change
Tuesday, July 19, 2005
OPEN SESSION LECTURE ROOM
3:00–3:05 p.m. Welcome and Introductions
David Blumenthal
Sheila Burke
Co-Chairs, Committee on the Assessment of the
US Drug Safety System
3:05–6:00 p.m. Public Comment
Carla Saxton
Professional Affairs Manager
American Society of Consultant Pharmacists
Maryann Napoli
Center for Medical Consumers
John J. Pippin
Physicians Committee for Responsible Medicine
Patrick J. Madden
Lesley Maloney
American Society of Health-System Pharmacists
Marc Wheat
Chief Counsel and Staff Director
Subcommittee on Criminal Justice, Drug Policy,
and Human Resources
US House of Representatives
Lindsey Johnson
Consumer Advocate
U.S. Public Interest Research Group (US PIRG)
Alison Rein
Assistant Director
Food & Health Policy National Consumers
League
Beth A. McConnell
Director
PennPIRG and the PennPIRG Education Fund
Marion J. Goff
Donald Klein
American College of Neuropsychopharmacology
Tom Woodward
Director, Alliance for Human Resource Protection
(AHRP)
State Director, International Coalition of Drug
Awareness
6:00 p.m. Adjourn
David Blumenthal
Sheila Burke
Co-Chairs, Committee on the Assessment of the
US Drug Safety System
1:05–3:00 p.m. Food and Drug Administration’s (FDA’s) Drug Safety
Activities
Introduction and Overview
Paul J. Seligman
Director, Office of Pharmacoepidemiology and
Statistical Science
Center for Drug Evaluation and Research
Food and Drug Administration
APPENDIX D 259
John K. Jenkins
Director of the Office of New Drugs
Center for Drug Evaluation and Research
Food and Drug Administration
The Postmarketing Safety Assessment and the
Office of Drug Safety
Anne E. Trontell
Deputy Director, Office of Drug Safety
FDA Center for Drugs
Food and Drug Administration
Future of Safety Assessment
Paul J. Seligman
3:00–3:30 p.m. Questions from the Committee
3:30–3:45 p.m. Break
3:45–4:00 p.m. The Role of the Agency for Healthcare Research and
Quality (AHRQ) in the US Drug Safety System
Scott R. Smith
Center for Outcomes and Evidence
Agency for Healthcare Research and Quality
4:00–4:15 p.m. The Role of the Centers for Medicare and Medicaid
Services (CMS) in the US Drug Safety System
Speaker TBA
Centers for Medicare and Medicaid Services
4:15–4:45 p.m. Questions from the Committee
4:45–5:15 p.m. AHRQ-funded Centers for Education and Research
on Therapeutics (CERTs)
and
Contributions of Academia and the Pharmaceutical
Industry to Drug Safety Surveillance
Hugh Tilson
Chair, CERTs Steering Committee
WORKSHOP—AGENDA
The National Academies
Institute of Medicine
Committee on the Assessment of the US Drug Safety System
Advancing the Methods and Application of
Risk-Benefit Assessment of Medicines
January 17, 2006
The Keck Center, Room 100
500 Fifth Street, NW
Washington, DC 20001
Purpose of workshop:
1. Identify methodological approaches for performing integrated and
explicit assessments of risk-benefit of pharmaceuticals throughout
a product’s lifecycle, including identifying the type of information
that would be most useful to decision-makers.
2. Obtain expert input on the use of new methodological approaches
in pre- and postmarket risk assessment.
3. Identify opportunities and barriers in advancing a public health ap-
proach to balancing risks and benefits of pharmaceuticals for drug
regulation and risk management.
Tuesday, January 17, 2005
8:15 a.m. Opening Remarks
8:30 a.m. Overview of Pharmacoepidemiology: What Is the
Evidence Base?
Session 1: Assessing a product’s risk-benefit balance throughout its lifecycle
involves the use of a variety of epidemiological resources and methods,
including the use of ad hoc data sources, automated data systems, and
randomized trials. The choice of specific assessment methods involves a con-
sideration of many factors, including how well it informs decision making
intended to optimize a drug’s balance between benefits and risks.
APPENDIX D 261
APPENDIX D 263
MEETING FOUR—AGENDA
The National Academies
Institute of Medicine
Committee on the Assessment of the US Drug Safety System
AGENDA
APPENDIX D 265
Appendix E
Summary
267
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gressional charter to be an adviser to the federal government and, upon its own
initiative, to identify issues of medical care, research, and education. Dr. Harvey V.
Fineberg is president of the Institute of Medicine.
The National Research Council was organized by the National Academy of Sciences
in 1916 to associate the broad community of science and technology with the
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Functioning in accordance with general policies determined by the Academy, the
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www.national-academies.org
Study Staff
PHILIP ASPDEN, Study Director
JULIE A. WOLCOTT, Program Officer (to April 2006)
ANDREA M. SCHULTZ, Research Associate (from June 2006)
RYAN L. PALUGOD, Research Assistant (from December 2005)
TASHARA BASTIEN, Senior Program Assistant (to January 2006)
WILLIAM B. MCLEOD, Senior Librarian
GARY J. WALKER, Senior Financial Officer (from December 2005)
TERESA REDD, Financial Advisor (to December 2005)
ELIZABETH E. LAFALCE, Intern (April to May, 2005)
vi
Reviewers
This report has been reviewed in draft form by individuals chosen for
their diverse perspectives and technical expertise, in accordance with proce-
dures approved by the NRC’s Report Review Committee. The purpose of
this independent review is to provide candid and critical comments that will
assist the institution in making its published report as sound as possible and
to ensure that the report meets institutional standards for objectivity, evi-
dence, and responsiveness to the study charge. The review comments and
draft manuscript remain confidential to protect the integrity of the delibera-
tive process. We wish to thank the following individuals for their review of
this report:
vii
viii REVIEWERS
Preface
ix
x PREFACE
Acknowledgments
xi
xii ACKNOWLEDGMENTS
ACKNOWLEDGMENTS xiii
report To Err Is Human: Building a Safer Health System and the 2001 re-
port Crossing the Quality Chasm: A New Health System for the 21st Cen-
tury. The committee on Identifying Priority Areas for Quality Improvement
produced the 2003 report Priority Areas for National Action: Transforming
Health Care Quality.
Finally, funding for this project was provided by the Centers for Medi-
care and Medicaid Services. The committee extends special thanks for that
support.
Contents
SUMMARY 1
1 INTRODUCTION 25
PART I: UNDERSTANDING THE CAUSES AND COSTS OF
MEDICATION ERRORS 43
2 OVERVIEW OF THE DRUG DEVELOPMENT, REGULATION,
DISTRIBUTION, AND USE SYSTEM 50
3 MEDICATION ERRORS: INCIDENCE AND COST 105
PART II: MOVING TOWARD A PATIENT-CENTERED,
INTEGRATED MEDICATION-USE SYSTEM 143
4 ACTION AGENDA TO SUPPORT CONSUMER–PROVIDER
PARTNERSHIP 151
5 ACTION AGENDA FOR HEALTH CARE ORGANIZATIONS 221
6 ACTION AGENDA FOR THE PHARMACEUTICAL, MEDICAL
DEVICE, AND HEALTH INFORMATION TECHNOLOGY
INDUSTRIES 266
7 APPLIED RESEARCH AGENDA FOR SAFE MEDICATION
USE 310
8 ACTION AGENDAS FOR OVERSIGHT, REGULATION, AND
PAYMENT 328
xv
xvi CONTENTS
APPENDIXES
A BIOGRAPHICAL SKETCHES OF COMMITTEE MEMBERS 349
B GLOSSARY OF TERMS AND ACRONYMS 359
C MEDICATION ERRORS: INCIDENCE RATES 367
D MEDICATION ERRORS: PREVENTION STRATEGIES 409
INDEX 447
Summary
ABSTRACT
The use of medications is ubiquitous. In any given week, more
than four of five U.S. adults take at least one medication (prescrip-
tion or over-the-counter [OTC] drug, vitamin/mineral, or herbal
supplement), and almost a third take at least five different medica-
tions.1 Errors can occur with any of these products at any point in
the medication-use process and in any care setting. The frequency
of medication errors and preventable medication-related injuries
represents a very serious cause for concern.
The Centers for Medicare and Medicaid Services sponsored
this study by the Institute of Medicine (IOM) with the aim of
developing a national agenda for reducing medication errors based
on estimates of the incidence of such errors and evidence on the
efficacy of various prevention strategies. The study focused on the
safe, effective, and appropriate use of medications in the major
components of the medication-use system, addressing the use of
prescription drugs, OTC drugs, and complementary and alterna-
tive medications, in a wide range of care settings—hospital, long-
term, and community.
The committee estimates that on average, a hospital patient is
subject to at least one medication error per day, with considerable
1In this report, the terms medication and drug are used interchangeably.
STUDY SCOPE
The Institute of Medicine (IOM) report To Err Is Human: Building a
Safer Health System (IOM, 2000) accelerated existing efforts to prevent
medication errors and improve the quality of health care, efforts that are just
now gaining acceptance as a discipline requiring investment in individuals
who specialize in error prevention and quality improvement. Against this
background, at the urging of the Senate Finance Committee, the United States
SUMMARY 3
BOX S-1
Scope of the Study
Congress directed the Centers for Medicare and Medicaid Services (CMS) to
contract with the IOM for a study to formulate a national agenda for reduc-
ing medication errors by developing estimates of the incidence of such errors
and determining the efficacy of prevention strategies (see Box S-1).
BOX S-2
Key Definitions
Medication error: Any error occurring in the medication-use process (Bates et al.,
1995a). Examples include wrong dosage prescribed, wrong dosage administered
for a prescribed medication, or failure to give (by the provider) or take (by the
patient) a medication.
Adverse drug event: Any injury due to medication (Bates et al., 1995b). Exam-
ples include a wrong dosage leading to injury (e.g., rash, confusion, or loss of
function) or an allergic reaction occurring in a patient not known to be allergic to a
given medication.
SUMMARY 5
hospitals, nursing homes, and the outpatient setting. ADEs associated with
a medication error are considered preventable. The committee estimates
that at least 1.5 million preventable ADEs occur each year in the United
States:
care enrollees aged 65 and older. The cost in 2000 per preventable ADE
was estimated at $1,983, while national annual costs were estimated at
$887 million.
In addition to the likelihood of underestimation, the above estimates
are characterized by some important omissions. First, the costs of some
highly common medication errors, such as drug use without a medically
valid indication and failure to receive drugs that should have been pre-
scribed, were excluded from the Medicare study of ambulatory ADEs (Field
et al., 2005). Moreover, the costs of morbidity and mortality arising from
the failure of patients to comply with prescribed medication regimens were
not assessed. Second, all the studies omitted some important costs: lost
earnings, costs of not being able to carry out household duties (lost house-
hold production), and compensation for pain and suffering. Third, few data
are available for any setting regarding the costs of medication errors that do
not result in harm. While no injury is involved, these errors often create
extra work, and the costs involved may be substantial.
SUMMARY 7
Patient Rights
Patient rights are the foundation for the safe and ethical use of medica-
tions (see Box S-3). Ignoring these rights can have lethal consequences.
Millions of Americans take prescription drugs each year without being fully
informed by their providers about associated risks, contraindications, and
side effects. When clinically significant medication errors do occur, they
usually are not disclosed to patients or their surrogates unless injury or
death results.
Many but not all patient rights relating to medical care have been
established broadly in the U.S. Constitution (Amendments I and XIV) and
articulated by the courts through common law. Certain states have insti-
tuted a patient bill of rights relating to particular providers or care settings.
One important point not specifically addressed by these laws is the right for
a patient to be told when an adverse event occurs. Establishing a compre-
hensive set of patient rights in one document would facilitate patient and
BOX S-3
Patient Rights
• Be the source of control for all medication management decisions that af-
fect them (that is, the right to self-determination).
• Accept or reject medication therapy on the basis of their personal values.
• Be adequately informed about their medication therapy and alternative
treatments.
• Ask questions to better understand their medication regimen.
• Receive consultation about their medication regimen in all health settings
and at all points along the medication-use process.
• Designate a surrogate to assist them with all aspects of their medication
management.
• Expect providers to tell them when a clinically significant error has occurred,
what the effects of the event on their health (short- and long-term) will be, and
what care they will receive to restore their health.
• Ask their provider to report an adverse event and give them information
about how they can report the event themselves.
provider understanding and exercise of these rights and improve the safety
and quality of medication use.
2In this report, the term consumers is often used in referring to patients to emphasize the
active role individuals need to take in ensuring the quality of the health care services they are
purchasing.
SUMMARY 9
BOX S-4
Consumer Actions to Enhance Medication Safety
Personal/Home
• Have the prescriber provide in writing the name of the drug (brand and
generic names, if available), what it is for, its dosage, and how often to take it, or
provide other written material with this information.
• Have the prescriber explain how to use the drug properly.
• Ask about the side effects of the drug and what to do if you experience a
side effect.
Pharmacy
• Make sure the name of the drug (brand or generic) and the directions
for use received at the pharmacy are the same as what is written down by the
prescriber.
• Know that you can review your list of medications with the pharmacist for
additional safety.
• Know that you have the right to counseling by the pharmacist if you have
any questions; you can ask the pharmacist to explain how to take the drug pro-
perly, what side effects it has, and what to do if you experience them (just as you
did with your prescriber).
• Ask for written literature about the drug.
• Ask the doctor or nurse what drugs you are being given at the hospital.
• Do not take a drug without being told the reason for doing so.
• Exercise your right to have a surrogate present whenever you are receiving
medication and are unable to monitor the medication-use process yourself.
• Prior to surgery, ask whether there are medications, especially prescription
antibiotics, that you should take or any you should stop taking preoperatively.
• Prior to discharge, ask for a list of the medications you should be taking at
home, have a provider review them with you, and be sure you understand how the
medications should be taken.
BOX S-5
Issues for Discussion with Patients by Providers
(Physicians, Nurses, and Pharmacists)
• Review the patient’s medication list routinely and during care transitions.
• Review different treatment options.
• Review the name and purpose of the selected medication.
• Discuss when and how to take the medication.
• Discuss important and likely side effects and what to do about them.
• Discuss drug–drug, drug–food, and drug–disease interactions.
• Review the patient’s or surrogate’s role in achieving appropriate medication use.
• Review the role of medications in the overall context of the patient’s health.
their rights, including the right to have a surrogate present and involved
in their medication management whenever they are unable to monitor
their own medication use.
When communicating about medication errors that occur with the
potential for or actual harm, providers can tell patients how the error may
affect their health and what is being done to correct it. The vast majority of
patients want and expect to be told about errors, particularly those that
cause them harm.
SUMMARY 11
SUMMARY 13
Electronic Prescribing
Paper-based prescribing is associated with high error rates (Kaushal et
al., 2003). Having all pharmacies receive prescriptions electronically would
result in fewer errors than occur with current paper or oral approaches
(Bates, 2001). Electronic prescribing is safer (Bates et al., 1998) because it
eliminates handwriting and ensures that the key fields (for example, drug
name, dose, route, and frequency) include meaningful data. More impor-
tant, as noted above, computerization enables the delivery of clinical deci-
sion support (Evans et al., 1998), including checks for allergies, drug–drug
interactions, overly high doses, and clinical conditions, as well as sugges-
tions for appropriate dosages given the patient’s level of renal function and
age. It should be noted that recent studies have identified implementation
problems and the unintended occurrence of new types of errors with these
computerized approaches (for example, pharmacy inventory displays of
available drug doses being mistaken for the usual or minimally effective
doses). Avoiding these problems requires addressing business and cultural
issues before such strategies are implemented and aggressively solving tech-
nological problems during the implementation process. Regulatory issues
must also be addressed for electronic transmission of prescriptions to be
practical.
SUMMARY 15
ingly clear that the introduction of any of these technologies requires close
attention to business processes and ongoing maintenance. As noted above,
studies have shown that these tools can have unintended and adverse conse-
quences, and that avoiding these consequences requires addressing both
business and cultural issues.
SUMMARY 17
BOX S-6
Drug Naming, Labeling, and Packaging Problems
SUMMARY 19
SUMMARY 21
and prevention strategies. The committee believes the nation should invest
about $100 million annually in the research proposed below.
The primary focus of research on medication errors in the next decade
should be prevention strategies, recognizing that to plan an error prevention
study, it is essential to be able to measure the baseline rate of errors. Evidence
on the efficacy of prevention strategies for improving medication safety is
badly needed in a number of settings, including care transitions, ambulatory
care (particularly home care, self-care, and medication use in schools), pedi-
atric care, psychiatric care, and the use of OTC and complementary and
alternative medications. For hospitals, key areas are further investigation of
some prevention strategies (particularly bar coding and smart IV pumps) and
how to integrate electronic health records with computerized provider order
entry, clinical decision support, bar coding, and smart IV pumps.
Overall, most data on medication error incidence rates come from the
inpatient setting, but the magnitude of the problem is likely to be greater
outside the hospital. Areas of priority for research on medication error and
ADE incidence rates are care transitions, specialty ambulatory clinics, psy-
chiatric care, the administering of medications in schools, and the use of
OTC and complementary and alternative medications. Much more research
is needed as well on the patient’s role in the prevention of errors, specifi-
cally, what systems provide the most cost-effective support for safe and
effective medication self-management or for surrogate participation in medi-
cation use when a patient is unable to self-manage.
Most studies of the costs of medication errors relate to hospitals, and
some report data more than 10 years old (Bates et al., 1997). A better
understanding of the costs and consequences of medication errors in all
care settings is needed to help inform decisions about investing in medica-
tion error prevention strategies.
MOVING FORWARD
The American people expect safe medication care. In this report, the
committee proposes an ambitious agenda for making the use of medica-
tions safer. This agenda requires that all stakeholders—patients, care pro-
viders, payers, industry, and government, working together—commit to
preventing medication errors. Given that a large proportion of injurious
drug events are preventable, this proposed agenda should deliver early and
measurable benefits.
3Patient safety organizations are regulated through the Patient Safety and Quality Improve-
ment Act of 2005 (P.L. 109-41). Broadly, they are organizations separate from health care
providers that collect, manage, and analyze patient safety data, and advocate safety improve-
ments on the basis of analysis of the patient safety data they receive.
SUMMARY 23
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Appendix F
Committee Biographies
309
R. Alta Charo, JD, is the Warren P. Knowles Professor of Law and Bioethics
at the University of Wisconsin Law School and its Medical School’s Depart-
ment of Medical History & Bioethics. She teaches in the areas of Food and
APPENDIX F 311
APPENDIX F 313
George Hripcsak, MD, MS, is professor and vice chair of Columbia Univer-
sity’s Department of Biomedical Informatics, associate director of medical
informatics services for New York-Presbyterian Hospital, and senior infor-
matics advisor at the New York City Department of Health and Mental
Hygiene. He led the effort to create the Arden Syntax, a language for repre-
senting health knowledge that has become a national standard. His Applied
Informatics project—funded by the US Department of Commerce to link the
medical center, a home care agency, and the New York City Department of
Health to improve inner-city tuberculosis care—won the National Informa-
tion Infrastructure award. Dr. Hripcsak’s current research focus is on the
clinical information stored in electronic medical records. Using data mining
techniques, such as machine learning and natural language processing, he is
developing the methods necessary to support clinical research and patient
safety initiatives. Dr. Hripcsak was a elected fellow of the American College
of Medical Informatics in 1995 and served on the Board of Directors of the
American Medical Informatics Association (AMIA). As chair of the AMIA
Standards Committee, he coordinated the medical-informatics community
response to the Department of Health and Human Services for the health-
informatics standards rules under the Health Insurance Portability and Ac-
countability Act of 1996. He chaired the Biomedical Library and Informat-
ics Review Committee of the National Library of Medicine through 2005.
He is associate editor of the Journal of the American Medical Informatics
Association and of Computers in Biology and Medicine, and he is an edito-
rial board member of the Journal of Biomedical Informatics. He received
his MD and his MS in biostatistics from Columbia University.
David Korn, MD, is senior vice president for biomedical and health sciences
research at the Association of American Medical Colleges. He served as
Carl and Elizabeth Naumann Professor and dean of the Stanford University
School of Medicine from 1984 to 1995, and as vice president of Stanford
University from 1986 to 1995. Earlier, he had served as professor and chair-
man of the Department of Pathology at Stanford from 1968. Dr. Korn was
appointed by President Ronald Reagan as chairman of the National Cancer
Advisory Board from 1984 to 1991. He has been chairman of the Stanford
University Committee on Research, president of the American Association
of Pathologists (now the American Society for Investigative Pathology),
president of the Association of Pathology Chairmen; member of the Board
of Directors and the Executive Committee of the Federation of American
Societies for Experimental Biology, and member of the Board of Directors of
the Association of Academic Health Centers. He was also a founder of the
Woodrow A. Myers, Jr., MD, MBA, is the former executive vice president
and chief medical officer of WellPoint Health Networks. Dr. Myers man-
aged WellPoint’s Healthcare Quality Assurance Division, including medical
policy, clinical affairs, and health services operations. He was also respon-
sible for strategic initiatives designed to enhance the healthcare experience
for the company’s members and to simplify administration and improve
communications with physicians and other healthcare professionals. Be-
APPENDIX F 315
and the Women’s Health Initiative. He is the chair of the NIH Cardiovascu-
lar Disease and Sleep Epidemiology Study Section and chair of the Group
Health Research Committee. Earlier in his career, he was a Robert Wood
Johnson Clinical Scholar at the University of Washington. Dr. Psaty is a
member of the American Epidemiological Society as well as the American
Heart Association Council on Epidemiology and Prevention. In 2005, he
received the University of Washington Outstanding Public Service award.
He publishes regularly in peer-reviewed journals, including many articles
and editorials on the risks and benefits of a variety of drug therapies. Dr.
Psaty’s research interests include cardiovascular epidemiology, drug safety,
hypertension, epidemiologic methods, pharmacogenetics, and pharmacoepi-
demiology. He has served on three NIH-funded data monitoring commit-
tees. He received his MD and PhD from Indiana University and his MPH
from the University of Washington.
APPENDIX F 317
Index
319
INDEX 321
Critical Path Initiative (CPI), 33, 70n, 105, Development cost, of drugs, 32
201, 207, 211–213 DHEW. See Department of Health,
report on, 20 Education, and Welfare
Critical Path Opportunities Report, 212–213 DHHS. See Department of Health and
Culture of safety in CDER, 27, 65–104 Human Services
difficulties changing, 90 Dietary supplements, 153
the external environment, 68–75 Differing professional opinion (DPO)
organizational challenges, 65–100 procedure, 47n
solutions proposed for CDER’s Direct-to-consumer (DTC) advertising, 21,
organizational dysfunction, 90–100 52–53, 158–164, 167, 171–172
structural factors, policies, and court challenges to restricting, 159
procedures, 75–90 deterrence of excessive, 198
need for more robust standards of
assessment, 189
D recommendations concerning, 11–12,
169–172
“DailyMed” health information Director’s Consumer Liaison Group
clearinghouse, 210 (DCLG), 190
Data management, 39–40 Disagreement in the face of uncertainty, 127
Databases nurturing a culture that values, 94
automated, 56 scientific, 85–87
mining, 57, 157 Discipline reviews, 79
DCLG. See Director’s Consumer Liaison different perspectives of, 86
Group Disclaimers, 24–25
DDMAC. See Division of Drug Marketing Disclosure requirements, 141
and Communication Dispute resolution, 84
DDRE. See Division of Drug Risk Evaluation in NDAs, 47–48
“Dear Health Practitioner” letters, 58, 158 Division of Drug Marketing and
DEcIDE. See Developing Evidence Communication (DDMAC), 52,
to Inform Decisions about 78, 159, 163, 179
Effectiveness Network “DDMAC Watch,” 162
Decision-making Division of Drug Risk Evaluation (DDRE),
concerning postmarket safety of a 32, 36, 51, 56
drug, ix, 47 Division of Neurology Products (DNP), 36
political considerations in, 90 DoD. See Department of Defense
regulatory, by the FDA, ix DPO. See Differing professional opinion
science-based, 66, 129 procedure
Department of Defense (DoD), 118 Drug approval process
Department of Health and Human Services limitations on, 59
(DHHS), 2, 18, 41, 71, 74n, 93n, pressure to speed up, 22, 40
113, 153, 180, 205. See also Drug Development Science Obstacles and
Secretary of Health and Human Opportunities for Collaborations,
Services 211
Department of Health, Education, and Drug industry. See Pharmaceutical industry
Welfare (DHEW), 74n Drug Price Competition and Patent Term
Department of Veterans Affairs (VA), 21,
Extension Act, 152
92, 112–113, 201 Drug Regulation Reform Act, 156
“Detailing,” 18, 158, 183–184 Drug safety
academic, 183 communication about, 27, 177–192
Developing Evidence to Inform Decisions culture of safety in CDER, 27
about Effectiveness (DEcIDE) experts in, 66
Network, 113, 180
INDEX 323
FDAMA. See Food and Drug response to public meeting input, 185
Administration Modernization Act Science Board, 129
FD&C. See Food, Drug, and Cosmetic Act Food and Drug Administration (FDA)
Federal Advisory Committee Act, 116, 146, authority, 51, 151. See also Direct-
190 to-consumer (DTC) advertising;
Federal advisory committees, on consumer Strengthening FDA’s regulatory
issues, examples of, 190 authority
Federal Aviation Administration, after approval, 155–164
organizational problems at, 67, 91 to compel completion of
Federal Communications Commission, 92, postmarketing commitments,
197n 155–157
Federal Register, 45, 156, 161, 186 exceptions in, 165
Federal Trade Commission (FTC), 160 guidance documents, 41, 208–209
Financial resources. See Resources for the oversight of sponsor promotional
drug safety system activities, 158–164
First Amendment protections, of truthful preapproval, 37, 154–155
commercial speech, 159, 161–162, recommendations concerning, 11, 170
171, 183 to unilaterally impose risk-reducing
Food and Drug Administration (FDA), remedies, such as label changes and
ix–x, 1–12, 15, 23–25, 65, 105, distribution restrictions, 157–158
177, 180–181, 205. See also Food and Drug Administration
Commissioner of the FDA; Recent Modernization Act (FDAMA), 143,
FDA materials 152, 156
approval but not a lifetime guarantee, 2 Food, Drug, and Cosmetic (FD&C) Act, 16,
challenges in communicating to the 22–23, 48, 51, 69, 90, 152, 156,
public and patients, 184–190 159, 184
consumer medication information Drug Amendments to, 16, 152
from, 185–187 Food Research Laboratory, 129
credibility of, 4–5, 70, 85, 88, 132 FTC. See Federal Trade Commission
filing and review of submitted Funding. See Resources for the drug safety
marketing applications, PDUFA system; User-fee funding system
goal for, 43
history of drug regulation by, 152–153
history of DTC advertising regulation G
by, 160–161
Galson, CDER Director Steven, 207
improving communication with the
GAO. See Government Accountability
public, 187–190
Office
increasingly dependent on industry
Gates Foundation, 212
funding, 71
“General applicability” matters, 134n
interface with industry, 70–75
General Practice Research Database
need for greater accountability and
(GPRD), 112, 200
transparency by, 4
Generic drugs, 159
need for increased resources, 151, 193
Goals. See Performance goals
oversight and review of clinical trial
Government Accountability Office (GAO),
protocols during development,
36, 57, 66, 71–72, 92, 158, 163
PDUFA goal for, ix, 42
Government agencies
public confidence in eroded, 15
compared with private-sector
“regulatory capture” of, 73–74, 155,
counterparts, 68–69
196–197
roles of, 180–181
regulatory decision-making by, ix
GPRD. See General Practice Research
relevant changes at, 210
Database
reports from, 20, 209
INDEX 325
INDEX 327
INDEX 329
external Management Advisory Board, Resources for the drug safety system, 5,
6, 93–94 166, 193–204
FDA authority, 11, 170 levels required to enable CDER to
labeling, 11, 169–170 support the FDA mission, 4
NDA, 10, 144–146 recommendations concerning, 13–14,
NDA review teams, 6, 96 197–203
new molecular entities, 9, 12, 133– Review elements for new drug approval
134, 173 beginning in NDAs, 41, 43–44
Office of Drug Safety Policy and current, 52
Communication, 13, 189 data on NMEs, 172–173
organizational culture, 5–7 meetings key in NDAs, 48
peer-review, 12, 173 Review Panel on New Drug Regulation, 74,
pharmacoepidemiology, 9, 134–141 155–156, 172
postmarketing safety of a drug, 8, Review teams, 34
127–131 composition of, 78, 83
from Preventing Medication Errors, in NDAs, assembling, 41, 43–44
180–183 Risk-benefit analyses
for providers and patients, 182–183 for approval decisions, 106–107, 166
public-private partnership, 8, 117–119 evolving throughout the drug’s
regulation, 10–12 lifecycle, 2, 4, 96, 121–126
resources, 13–14, 197–203 recommendations concerning, 8,
risk-benefit analyses, 8, 125–126 125–126
risk management, 11, 169–170 Risk communication activities, 27
RiskMAPs, 8, 121 postmarket, 97
safety-related performance goals for Risk management
the PDUFA IV, 6–7, 98–100 postmarket, 97
for the Secretary of DHHS, 6, 8, recommendations concerning, 11,
93–94, 117–119 169–170
Reference information, access to Risk Minimization Action Plans
comprehensive, 182 (RiskMAPs), 119–121, 146, 167
Regulatory activities for safety, 4, 31. See developing and assessing, 57, 158
also Enforcement tools in NDAs, 48–49
in the postmarket period, 58–59 Rofecoxib, 17, 55, 168
realistic needed, without the “last call” Roles, of providers and patients (in drug
of approvals, 166 safety system), 5, 178–184
recommendations concerning, 10–12 Rolling reviews, 39–40
Regulatory authority necessary to provide
for drug safety, 4, 27, 151–176. See
also Food and Drug Administration S
authority
Safety data, gaps in, 37
an aging and inadequate statutory
Safety officers, 37
framework, 153–166
Safety-related performance goals for the
history of FDA drug regulation,
PDUFA IV, 98–100
152–153
expertise in preapproval evaluation, 98
strengthening FDA’s regulatory
monitoring of adverse drug reactions
authority, 167–173
and the AERS, 98
“Regulatory briefings,” 46
performance management, 100
“Regulatory capture” of the FDA, 73–74,
postmarketing risk communication
155, 196–197
activities and risk management, 99
Regulatory “tool kit,” 168, 213
postmarketing study commitments, 99
Research. See Academic research enterprise
INDEX 331
Safety signals, 27, 84. See also Spontaneous Special symbol needed to denote limited
safety signals in the postmarket knowledge about new drugs,
period 170–172. See also Black triangle
in generation, 108–110 Sponsors of drugs
reducing uncertainty about and benefit letters sent to, 51
after approval, 108–115 materials generated by, 52
in strengthening and testing, 110–115 meeting with FDA during clinical
Safety teams, of epidemiologists, 88 development, PDUFA goal for,
Safety “tool kits,” 213 42–43
Safety tracking, 46–47 non-compliance by, 18
in NDAs, 46–47 obligations of, 34
Science-based decision-making, 66, 129 Spontaneous safety signals in the
Science of safety, 27, 105–150 postmarket period
benefits after approval, 107–119, 122 AERS, 53–55
credibility of, 126–147 identifying and evaluating, 56–58
generating, 106–126 Stakeholders, 2, 4, 177. See also individual
and recommendations concerning stakeholders
expertise, 7–10 Statement of task. See The charge (to the
reducing uncertainty about, 107–119, committee)
122 Statutory framework (for drug regulation)
rigor in, 27 aging of, 153–166
risk-benefit analyses throughout the FDA authority after approval, 155–164
drug’s lifecycle, 121–126 FDA authority preapproval, 154–155
risk minimization action plans, inadequacy of, 153–166
119–121 rationale for strengthening, 164–166
understanding risk and benefit for Steering Committee for the Collaborative
approval decisions, 66, 106–107 Development of a Long-Range
Scientific advances, 28. See also Academic Action Plan for the Provision
research enterprise of Useful Prescription Medicine
increasing the numbers of targeted Information, 186
drugs, 20 Strengthening FDA’s regulatory authority,
Scientific disagreement, and CDER’s 167–173
organizational dysfunction, 85–87 conditions and restrictions on
Scientific reviewers, 34 distribution throughout the drug
Secretary of Health and Human Services, 6, lifecycle, 167–170
45, 93–94, 97 greater regulatory flexibility post
Sector maps, 110 approval, 166
Signals. See Safety signals periodic review of data on NMEs,
Site inspections, 51 172–173
in NDAs, 51 special symbol needed to denote
SMART (System to Manage Accutane limited knowledge about new
Related Teratogenicity), 120–121 drugs, 170–172
Social Security Administration, 92 Structural changes in the CDER, 206–207
Solutions proposed for CDER’s Structural factors in CDER’s organizational
organizational dysfunction, dysfunction, 75–77
90–100 solving, 94–97
agency leadership, 91–94 Study process, 25–26
external environment, 97–100 Supplemental NDAs, 31
management, 90–91 Supplements, dietary, 153
structural factors, 94–97 Surrogate endpoints, 107
“Special Government Employees,” 131, 211 Suspension of approval, 173
T V
Taxing prescriptions, 198 VA. See Department of Veterans Affairs
“Team approach,” 76. See also Review Vaccine Safety Datalink (VSD), 112
teams; Safety teams Valdecoxib, 17
Terfenadine, 109 Vanderbilt University, 111
Terminology coding, 54 Veterans Health Administration, 92
Thompson v. Western States Medical Vioxx, 65
Center, 160 Virginia State Board of Pharmacy v.
Throckmorton, CDER Deputy Director Virginia Citizens Consumer
Douglas, 207 Council, Inc., 159
Timeline, for planning advisory committee Vision. See New vision of drug safety
meetings, 45 von Eschenbach, FDA Acting Commissioner
Toxicologic studies, 44 Andrew, 86n
Transparency VSD. See Vaccine Safety Datalink
and the credibility of safety science,
142–147
need for greater, 4–5, 124, 127 W
Troglitazone, 17, 50, 109
Wall Street Journal, 162
Tufts Center for the Study of Drug
Warning the public about drug safety risks,
Development, 71
1. See also Black box warnings;
Labeling
Washington Legal Foundation, 162
U
Web sites, 25, 140, 142–143, 159, 172,
Uncertainty, disagreement in the face of, 179, 181, 187, 190, 210
127 WHI. See Women’s Health Initiative
Under-reporting of adverse events, WHO. See World Health Organization
substantial, 55, 109 Withdrawals, 1–2, 16, 165, 173
Union of Concerned Scientists, 86n Women’s Health Initiative (WHI), 55, 115,
University of Arizona, 213 123–124, 181
US drug safety system. See also Committee World Health Organization (WHO), 143,
on the Assessment of the US Drug 145, 212
Safety System
impaired by, 4
an improved, 13–14 Z
a transformed, 4
Zero-tolerance policy, regarding COI
Useful consumer medication information,
considerations, 140–141
criteria for, 187
User-fee funding system, 16, 23, 40, 70, 83,
196–197