Download Regulatory Considerations in the Post-Vioxx Era

Regulatory
Considerations in
the Post-Vioxx Era
By Julia S. Rivers, MA
18
December 2009
The US environment for drug development and
registration has evolved as a result of many significant and public events that span the course of
the past century. In the early 1900s, public outcry
following the exposure of deplorable conditions
in meat packing plants and false claims about
patented medicines prompted enactment of the
Pure Food and Drug Act of 1906. This federal law
ultimately provided the foundation for what is
now the Food and Drug Administration (FDA).
In the 1930s, public awareness of the need for
greater federal regulation of drug safety resulted
from the sale of a poisonous elixir formulation
of sulfanilamide: this national tragedy prompted
Congress to pass the Federal Food, Drug, and
Cosmetic Act of 1938, which required premarket
demonstration of a new drug’s safety. The 1960s
brought a similar public health scare when evidence of the teratologic effects of thalidomide
became known. Although never approved for
use in the US, thalidomide was available for use
in some other countries and was being studied
in the US. The Kefauver-Harris Amendments were
subsequently passed by Congress, requiring premarket evidence of efficacy and safety of all new
drugs, both prescription and OTC, and requiring
adverse reaction reporting for the first time in
US history. In the early part of the 21st century,
another significant set of circumstances again led
to increased public awareness about the safety
of pharmaceutical products. Media, Congress,
consumer advocates, watchdog groups and the
pharmaceutical industry were engaged in dialogue. Would the existing drug development and
FDA approval process prove to be sufficient to
maintain public confidence in marketed drugs?
This article tells the story of a class of drugs
known as COX-2 selective inhibitors, which first
entered the US market in 1998. They were touted
as providing safe and effective treatment for various forms of pain and inflammatory illnesses,
and the early safety and efficacy profiles looked
favorable. Expanded use of these products and
postmarket studies generated ever-growing
databases of information about the safety and
efficacy profiles of COX-2s. Over the years that
followed, these data eventually prompted FDA,
pharmaceutical companies and Congress to take
action, and led to the further evolution of the US
drug development landscape.
Events Leading up to Withdrawal of
Vioxx
The backdrop of safety concerns about COX-2
selective inhibitors was established in December
1998, when Searle (now Pfizer), received
approval to market a novel COX-2 inhibitor,
Celebrex (celecoxib) capsules, indicated for the
treatment of signs and symptoms of osteoarthritis (OA) and rheumatoid arthritis (RA).
Safety concerns at this time were not based on
cardiovascular risk, but were focused instead
on gastrointestinal (GI) risk; long-term studies
to assess GI risks of Celebrex had not yet been
performed. Because of the limited data regarding
long-term use of Celebrex, the lowest possible
dosing was recommended (200 mg per day) and
alternative therapies for high-risk GI patients
were suggested.1
Only a few months later, in April 1999,
Merck’s Vioxx (rofecoxib) tablets got a unanimous recommendation by the Arthritis Drugs
Advisory Committee for approval for the treatment of signs and symptoms of OA and acute
pain. The NDA for Vioxx received a six-month
priority review by FDA because the drug
potentially provided a significant therapeutic
advantage over existing approved drugs due to
fewer GI side effects, including bleeding. In May
1999, Merck received approval to market Vioxx
tablets in the US for the relief of the signs and
symptoms of OA, management of acute pain in
adults, and treatment of menstrual pain, with
three strengths approved: 12.5 mg, 25 mg and
50 mg. The labeling included warnings on GI
risks that were almost identical to those on the
labeling for Celebrex, and this language was also
incorporated in the labeling for all nonspecific
nonsteroidal anti-inflammatory drugs (NSAIDs).
The original safety database for Vioxx included
almost 5,000 patients, and the adverse events
listed in the original approved labeling did not
show an increased risk of heart attack or stroke,2
although a prospective cardiovascular outcome
study was not part of the original NDA.
A third COX-2 selective inhibitor, Bextra
(valdecoxib) tablets from Searle, was approved
in November 2001 for the relief of signs and
symptoms of OA and adult RA, and for the treatment of primary dysmenorrhea. Once again, the
approved labeling included information regarding GI risks associated with NSAIDs, but did not
include information regarding concerns about
cardiovascular risk associated with either the
class of drug or Bextra itself.3
Celebrex, Vioxx and Bextra, all COX-2 selective inhibitors, are differentiated from other
NSAIDs (e.g., naproxen, ibuprofen, ketoprofen)
by limiting selectivity for the COX-1 inhibitor,
which helps to maintain a normal stomach lining. Before the development of COX-2 selective
inhibitors, NSAIDs inhibited both enzymes, so
while treating pain and inflammation they also
increased the risk of ulcers resulting from damage to the stomach lining. Celebrex, Vioxx and
Bextra offered the expected benefit of reducing
GI risks, but that benefit had not been fully demonstrated in controlled clinical trials at the time
these COX-2s were approved.
In an effort to explore longer-term GI
effects of Vioxx, Merck launched a postapproval
study, Vioxx GI Outcomes Research (VIGOR).
VIGOR was a large study of 8,000 patients with
RA requiring high doses of anti-inflammatory
medication. The study compared Vioxx 50 mg
once daily to naproxen 500 mg twice daily. There
was no placebo arm. The results were submitted
Regulatory Focus
19
Table 1. Key Events in the US Regulatory History of COX-2 Antagonists
Celebrex
12/31/1998
Celebrex initial approval: OA and RA
Vioxx
5/20/1999
Vioxx initial approval: OA, acute pain, primary dysmenorrhea
Celebrex
10/18/2001
Celebrex approved for acute pain and primary dysmenorrhea
Bextra
11/16/2001
Bextra initial approval: OA, RA, primary dysmenorrhea
Vioxx
4/11/2002
Vioxx approved for RA
Bextra
11/1/2002
Bextra: Labeling change to include risk of serious skin reaction
Vioxx
3/26/2004
Vioxx approved for acute treatment of migraine in adults
Vioxx
8/19/2004
Vioxx approved for Pediatric indication (Juvenile RA)
Vioxx
9/30/2004
Merck voluntarily withdraws Vioxx worldwide
Celebrex
Mar-05
FDA issues Alert regarding Celebrex and risk of CV events
Bextra
4/7/2005
FDA asks Pfizer to remove Bextra from the market
Celebrex
7/29/2005
Celebrex approved for ankylosing spondylitis
Celebrex
7/29/2005
Celebrex label changed to include boxed warning (additional CV risks)
Celebrex
12/15/2006
Celebrex approved for Pediatric indication (Juvenile RA)
Arcoxia
Apr-07
Merck receives a Not Approvable letter for Arcoxia
Prexige
Oct-07
Novartis receives a Not Approvable letter for Prexige
to FDA in June 2000. In April 2002, the data
from VIGOR and other studies resulted in the
approval of Vioxx for RA at a lower dose (25 mg)
and a change to the labeling regarding GI risk:
the new wording read, “risk of GI toxicity with
Vioxx 50 mg once daily is significantly less than
with naproxen 500 mg twice daily.”4 This data
from the VIGOR study provided an argument
for the GI-sparing benefit of Vioxx. Two additional safety flags were raised in FDA’s review of
this data, however. Of primary concern was the
apparent potential risk for cardiovascular events,
which was addressed via changes to the labeling. In addition, chronic use of the 50 mg dose of
Vioxx was not recommended.
Following the April 2002 approval of the
supplemental NDA for the RA indication for
Vioxx, FDA added cardiovascular risk monitoring as a requirement for all trials using Vioxx,
and required Merck to submit all cardiovascular data from ongoing trials. FDA also began
to monitor retrospective epidemiologic studies
for increased risk of cardiovascular events with
Vioxx.
In May 2002, Novartis launched the
Therapeutic Arthritis Research & Gastrointestinal
Event Trial (TARGET) study of its investigational
COX-2 selective inhibitor drug Prexige (lumiracoxib), for the treatment of arthritis symptoms
and pain. The primary objective was to examine
the GI safety of Prexige compared with ibuprofen and naproxen, and a secondary endpoint
included cardiovascular risk, marking one of the
first times that cardiovascular risk was identified
as an endpoint in a clinical NSAID study. Based
on an evaluation of more than 18,000 patients,
results were published in August 2004 showing
a reduced GI risk for Prexige (0.32%) compared
to the NSAID comparators (0.91%). Further, the
results did not show that Prexige demonstrated a
difference in cardiovascular risk against NSAIDs
20
December 2009
overall.5 Although Prexige was approved for
marketing in the UK in 2005 and in the EU in
2006,6 the NDA submitted in 2002 did not result
in FDA approval. Based on study findings of
liver damage in patients taking Prexige, EMEA’s
Committee for Medicinal Products for Human
Use recommended withdrawal of the drug in
December 2007 and EMEA revoked the marketing authorization in March 2008.7,8
A retrospective study analyzing 6 million Kaiser patients taking COX-2 selective
and nonselective NSAIDs that had begun in
2002 (with partial FDA funding) showed a
fivefold increased risk of acute myocardial
infarction associated with the use of 50 mg/
day of Vioxx compared with 1000 mg/day of
Celebrex. The study results were presented
by David Graham, MD, of FDA’s Office of
Drug Safety at the International Conference on
Pharmacoepidemiology & Therapeutic Risk
Management meeting in France in August 2004,9
and the results prompted FDA to consider the
need for additional warnings on the Vioxx label.
During this same time period, Merck completed studies for expanded indications for Vioxx
and achieved FDA approval for the treatment of
migraine in adults (March 2004) and for juvenile
RA (August 2004).
Just after Dr. Graham’s presentation, in
September 2004, Merck announced the results
of its Adenomatous Polyp Prevention On Vioxx
(APPROVe) study—to investigate whether
Vioxx could prevent the recurrence of colon
polyps—which showed an increased risk of
thromboembolic events, particularly myocardial
infarction, in patients treated for more than 18
months with 25 mg Vioxx twice daily in comparison with placebo-treated patients. This study
was halted by its Data Safety Monitoring Board
due to the increased risk of cardiovascular events
in patients who received Vioxx. After meeting
with FDA on 28 September 2004 to discuss this
action, Merck publicly announced a voluntary,
worldwide withdrawal of Vioxx on 30 September
2004.
As a separate and interesting point, in 2004
both Vioxx and Celebrex were widely advertised
directly to consumers (DTC). Pfizer voluntarily
curtailed its DTC advertising of Celebrex following the Vioxx withdrawal, only recently
resuming it in 2007.
•
•
•
The Fallout
Fallout from the events leading up to the Vioxx
withdrawal was widespread and included
changes within and by FDA, as well as changes
initiated by Congress.
Changes at FDA
In November 2004, FDA announced its Drug
Safety Initiative,10 which included changes to
physician and patient information, restructuring
at the Center for Drug Evaluation and Research
(CDER), an effort to enhance the culture of safety
in CDER by creating the Drug Safety Oversight
Board,11 enhancements to risk communications
efforts, a focus on modernization of the drug
development process called the Critical Path
Initiative, and the development of data standards
and processes to improve sharing of drug safety
information.
Following discussions at the February 2005
joint meeting of the Arthritis and Drug Safety
and Risk Management Advisory Committees,
FDA published a summary of the cardiovascular
risk associated with the approved COX-2 inhibitor NSAIDs in April 2005:
• The approved COX-2 selective drugs
are associated with an increased risk of
serious adverse cardiovascular events,
at least at some doses, with reasonably
prolonged use, and currently available
data do not allow for a rank ordering of
these drugs with regard to cardiovascular risk.
• It was not possible to conclude that
the COX-2 selective drugs confer
an increased risk over nonselective
NSAIDs in chronic use.
• There are no data from long-term placebo-controlled trials for the nonselective
NSAIDs (other than the preliminary
data for naproxen) that are analogous to
the data available for the COX-2 selective agents.12
The recommendations from this report included:
• a black box warning and contraindication labeling for the NSAID class
• a Medication Guide for all prescription
NSAIDs13
•
•
a request to sponsors of all nonselective NSAIDs to conduct and submit for
FDA review a “comprehensive review
and analysis of all available data from
controlled clinical trials to further evaluate the potential risk of serious adverse
cardiovascular events”
no change to the availability of nonprescription NSAIDs
the addition of a black box warning for
Celebrex regarding cardiovascular risk
and a recommended postmarket study
commitment to further explore the longterm safety of Celebrex in comparison
to its competitors
withdrawal of Bextra from the market
(cardiovascular risk in this case was
compounded by the high rate of reporting of serious skin reactions; the drug
was subsequently withdrawn)
careful review of any proposal from
Merck to resume marketing of Vioxx,
including review by FDA’s Drug Safety
Oversight Board and an advisory
committee
Beyond this report, some other events followed
at FDA:
• The Office of Drug Safety was restructured to report directly to the director
of CDER.
• A new pilot program was put in place
to evaluate the safety status of new
molecular entities (NMEs), postmarket.
• FDA requested DTC advertising
changes.
• Lumiracoxib was not approved.
As a result of public concern over risks posed
by approved drugs, FDA and the Department
of Health and Human Services requested the
Institute of Medicine (IoM) to conduct a study on
drug safety. IoM’s report, “The Future of Drug
Safety: Promoting and Protecting the Health of
the Public,” released in September 2006, took
into consideration the full scale of safety-related
activities performed during drug development,
including the roles of FDA and other stakeholders that monitor, evaluate, improve and ensure
drug safety. A summary of the IoM report is provided in the sidebar.
FDA agreed that its responsibility includes
balancing expeditious access to drugs with concerns for safety. Three key efforts summarize
FDA’s response to the IoM report.
• FDA launched initiatives to: develop
new scientific approaches to detecting, understanding, predicting and
preventing adverse events; develop
and incorporate new quantitative
tools in the assessment of benefit and
risk; and conduct a pilot program to
review the safety profiles of certain
Regulatory Focus
21
•
•
newly approved drugs on a regularly
scheduled basis.
The agency focused on communication and information flow among all
stakeholders engaged in promoting the
safe use of medical products (e.g., an
advisory committee was established to
provide input to improve FDA’s risk
communication policies and practices,
a comprehensive review of public communication tools was performed and
a comprehensive risk communication
strategic plan was developed).
FDA announced its plans to improve
operations and management to ensure
implementation of the review, analysis,
consultation and communications processes needed to strengthen the drug
safety system.14
FDA’s Critical Path Initiative and Drug Safety
Initiative focus on incorporating cutting-edge
science into clinical drug development, using
tools to try to predict human safety outcomes
and using genomic
or other tools
to identify
those at high
risk for side
effects and
subgroups
with a high
probability
of positive
response.15
Congressional
Influence
As public awareness of the
cardiovascular safety concerns
regarding Vioxx grew, members of
Congress were vocal in expressing their
thoughts regarding drug safety and accountability in the drug development and approval
process. In response to these concerns and
growing pressure to reinforce the oversight
of postmarket activities, the Food and Drug
Administration Amendments Act of 2007 (FDAAA)
was signed into law on 27 September 2007. This
legislation has been described by FDA personnel as the most substantial change in drug law
since 1938. FDAAA gave FDA new authority to
mandate postapproval clinical trials and expedite mandatory safety-related labeling changes,
and introduced Risk Evaluation and Mitigation
Strategies (REMS) to replace the former
RiskMAP program.
Impact on Drug Development
FDA scrutiny of sponsors’ completion of
postmarket studies of approved products is
demonstrated by CDER’s publicly available
Postmarketing Study Commitments database16
22
December 2009
and the postmarketing commitments guidance
document issued in February 2006.17 Annual
reports from the database are sent to Congress
to show the percentage of completed and outstanding study commitments by sponsors. These
reports impact public perception of how seriously sponsors view commitments made during
the approval process for postmarket studies,
especially safety studies. Emphasis on these
studies will no doubt be bolstered further by
FDA’s new authority to mandate postapproval
clinical trials.
Risk management guidances including Guidance for Industry: Development and
Use of Risk Minimization Action Plans (March
2005), Guidance for Industry: Premarketing
Risk Assessment (March 2005) and Guidance
for Industry: Good Pharmacovigilance Practices
and Pharmacoepidemiologic Assessment (March
2005) have been issued. Originally scheduled
for release in 2004, FDA’s delivery of these
documents was likely impacted by the Vioxx
withdrawal. The agency published additional
guidance documents on safety topics, e.g.,
Drug Safety Information—FDA’s
Communication to the Public,
as mentioned earlier, and
a new Manual of Policies
and Procedures for the
Drug Safety and Oversight
Board.
New REMS provisions set forth by FDAAA
create a consistent set
of risk management
tools that can be
applied to both new
and approved drugs.
These tools enable
FDA to require labeling changes, including
the creation of Medication
Guides, communication
plans, implementation plans and
other elements to ensure safe use. By early 2009,
implementation of REMS impacted approval
timelines, with two- to nine-month delays for
products requiring a REMS.18 REMS requirements most frequently called for Medication
Guides.19 Approximately a third of all drug and
biologic applications approved in the past year
included a REMS. In the same time frame, CDER
required 46 postmarket safety-related studies
and 15 safety-related labeling changes for marketed products.20
Celebrex, continuously on the market since
1998, is now the only COX-2 available in the US
(see Table 1). No further COX-2 products have
been approved by FDA due to the requirement
to demonstrate benefit beyond noninferiority to
other marketed products in the class. Dr. John
Jenkins, director of CDER’s Office of New Drugs,
has acknowledged that the agency often holds
“me-too” products to a higher approval standard
due to the evolving regulatory landscape accompanying the approval of additional agents in a
class.21 Dr. Robert Temple, director of the Office
of Medical Policy at CDER, has suggested that
sponsors of new NSAIDs conduct a crossover
trial, in which patients who do not respond to a
marketed product are randomized to either continue taking the marketed product or to receive
the new drug.21
The Environment Today
Following the February 2005 joint meeting of its
Arthritis Advisory Committee and Drug Safety
and Risk Management Advisory Committee,
FDA mandated that all new NSAIDs would
require large outcome trials of 10,000 to 20,000
OA (and possibly RA) patients. These trials
would require a treatment duration of two
years for a substantial number of patients and a
controlled study design using naproxen and nonnaproxen NSAIDs as active comparators. These
data are now required in the initial NDA for
approval of an NSAID.
FDA’s Medication Guide for NSAIDs lists
both cardiovascular and GI effects as potential
serious side effects associated with the use of this
class of drugs.22
The story of COX-2 inhibitors demonstrates
how FDA is able to address serious drug development issues affecting a drug class. Actions
taken by Congress to confer additional legal
authority upon FDA demonstrate the governmental checks and balances system and federal
regulation change process in action. The public
nature of the withdrawal of Vioxx and Bextra
also raised consumer awareness about the
potential risks associated with pharmaceutical
products. Perhaps most important, what happened with Vioxx and Bextra highlights the
critical balance between the time needed to demonstrate safety with pharmaceuticals prescribed
for long-term use and the pressure to make
drugs commercially available to patients. Vioxx
may have put industry and FDA in a better position to address similar situations in the future.
The withdrawal of Vioxx triggered a flurry
of congressional hearings, during which FDA’s
ability to resolve drug safety problems came
under fire. Some members of Congress have
repeatedly criticized the agency for failing to
disseminate safety concerns about drugs such as
Vioxx as soon as initial, though nondefinitive,
safety signals were available.
According to remarks by former FDA
Commissioner Mark McClellan, who left the
agency in early 2004, pressure on FDA to hold
drugs to a higher standard of safety has increased
dramatically since Vioxx.23 FDA staffers reject the
bar-raising theory, pointing out that the ratio of
drugs approved to applications submitted has
held steady in recent years, but FDA approved
just 16 NME drug applications in 2007,24 a 20-year
low that is 36% below the annual average over
The Future of Drug Safety: Promoting and
Protecting the Health of the Public
(Institute of Medicine Report)
The Institute of Medicine report noted the
perception of crisis that compromised FDA’s
and industry’s credibility following the Vioxx
withdrawal. The report agreed on the need for
change and noted issues related to resource
constraints and an organizational culture at FDA
that was not optimally functional, unclear and
insufficient enforcement mechanisms and a
lack of consistently accountable and transparent processes to communicate safety concerns
to the public and healthcare professionals in a
timely and effective manner. Recommendations
in the report included:
•
labeling requirements and advertising
limits for new medications
•
clarified authority and additional
enforcement tools for the agency
•
clarification of FDA’s role in gathering and
communicating additional information on
marketed products’ risks and benefits
•
mandatory registration of clinical trial
results to facilitate public access to drug
safety information
•
increased role for FDA’s drug safety staff
•
large boost in funding and staffing for the
agency
(Available at www.iom.edu/
CMS/3793/26341/37329.aspx)
the last decade,25 and 21 NME drug applications
in 2008,26 many of which were for narrow indications or rare diseases. Many recent approvable
and not-approvable decisions from FDA suggest
that the number of approvals, particularly firstaction approvals, is unlikely to increase markedly
in the near future. Sponsors should continue to
prepare complete NDAs based on development
plans that capitalize on the lessons from scrutiny
of the COX-2 inhibitors.
References
1.
Celebrex Label, approved 5 January 1999. Available
at www.accessdata.fda.gov/drugsatfda_docs/
label/1998/20998lbl.pdf.
2.
Vioxx Label, approved 20 May 1999. Available
at www.accessdata.fda.gov/drugsatfda_docs/
label/1999/21042lbl.pdf.
3.
Bextra Label, approved 16 November 2001. Available
at www.accessdata.fda.gov/drugsatfda_docs/
label/2001/21341lbl.pdf.
4.
Vioxx Label, approved 11 April 2002. Available
at www.accessdata.fda.gov/drugsatfda_docs/
label/2002/21042s7lbl.pdf.
5.
“Novartis Is Confident In Prexige’s Prospects Despite
Arcoxia AC Debacle,” The Pink Sheet,30 April 2007.
6.
“Novartis to Resubmit Prexige NDA in 2007,” The Pink
Sheet, 11 November 2006. Available at www.fdaweb.com/
login.php?sa=v&aid=D5104187&cate=&stid=%241%248
e..vX1.%24DgUD5yAS16wox34RJb.FW.
7.
Official Journal of the European Union, c104. Available at
http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri
=OJ:C:2008:104:0012:0022:EN:PDF.
8.
EMEA decision about Prexige. Available at www.
emea.europa.eu/pdfs/human/press/pr/QA_
Lumiracoxib_53636307en.pdf.
Regulatory Focus
23
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
24
The Pink Sheet, 30 August 2004, page 6.
FDA’s Drug Safety Initiative. Available at www.fda.gov/
cder/drugSafety.htm.
FDA’s Drug Safety Oversight Board MAPP.
Available at www.fda.gov/downloads/AboutFDA/
ReportsManualsForms/StaffPoliciesandProcedures/
ucm073564.pdf.
Memorandum by John K. Jenkins and Paul K. Seligman
regarding “Analysis and recommendations for Agency
action regarding non-steroidal anti-inflammatory drugs
and cardiovascular risk.” Available at www.fda.gov/
ohrms/dockets/ac/06/briefing/2006-4202B1_09_FDATab09.pdf.
FDA’s NSAID Medication Guide. Available at www.fda.
gov/downloads/Drugs/DrugSafety/UCM088567.pdf.
www.fda.gov/bbs/topics/NEWS/2007/NEW01551.html.
FDA’s Critical Path Initiative. Available at www.fda.gov/
ScienceResearch/SpecialTopics/CriticalPathInitiative/
ucm076689.htm.
FDA’s Postmarketing Study Commitments Database.
Available at www.accessdata.fda.gov/scripts/cder/pmc/
index.cfm.
FDA, Guidance for Industry: Reports on the
Status of Postmarketing Study Commitments—
Implementation of Section 130 of the Food and
Drug Administration Modernization Act of 1997.
Available at www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/
UCM080569.pdf.
“The REMS Effect: Delays From FDA REMS Reviews
Becoming Clearer,” The Pink Sheet. 12 January 2009.
List of approved REMS. Available at www.fda.
gov/Drugs/DrugSafety/PostmarketDrugSafety
InformationforPatientsandProviders/ucm111350.htm.
“New Law Boosts Safety Strategies in New Approvals:
Dal Pan,” FDAWebview, 23 April 2009. Available at
www.fdaweb.com/login.php?sa=v&aid=D5111483&cate=
&stid=%241%24OL4.9c5.%24RwXd2kDu2saL9ZFjkmxwe.
December 2009
21.
22.
23.
24.
25.
26.
“Negative Arcoxia Review May Reflect Increasingly High
Hurdle for Me-Toos,” The Pink Sheet, 23 April 2007.
www.hhs.gov/asl/testify/2008/02/t20080227e.html.
McClellan M. “Drug Safety Reform at the FDA—
Pendulum Swing or Systematic Improvement?” NEJM,
26 April 2007. Available at http://content.nejm.org/cgi/
content/full/NEJMp078057.
“NME and NDA Approvals Decline in 2007,”
FDAWebview, 7 January 2008. Available at www.fdaweb.
com/login.php?sa=v&aid=D5107610&cate=&stid=%241%
24Ld..2Z%2F.%24mT9g3UXpjAzG5cMpnJwED%2F.
Scott Gottlieb, MD, deputy commissioner for medical and
scientific affairs, Food and Drug Administration, remarks
at Seventeenth Annual Cancer Progress Conference, New
York, NY; 6 March 2007. Available at www.fda.gov/
NewsEvents/Speeches/ucm052340.htm.
FDA Drug Approval Reports. Available at www.fda.gov/
cder/rdmt/default.htm.
Acknowledgements
The author is grateful to Olivia Pinkett and Anne Stokley of
GlaxoSmithKline for their constructive contributions to this
manuscript.
Author
Julia S. Rivers, MA, is a program manager in policy,
intelligence and education in US regulatory affairs at
GlaxoSmithKline. Originally a music teacher by training,
she has worked in the pharmaceutical industry for 18 years,
specializing in the development and delivery of regulatory
training and awareness sessions and eLearning modules, IT
and communications skills training, process improvement,
and project management. Rivers holds an MA in international
peace and conflict resolution from Arcadia University and currently is completing an MS in quality assurance/regulatory
affairs at Temple University.