Timing of New Black Box Warnings and
Withdrawals for Prescription Medications
Karen
E. Lasser, MD, MPH; Paul D. Allen, MD, MPH; Steffie J. Woolhandler, MD, MPH;
David U. Himmelstein, MD; Sidney M. Wolfe, MD; David H. Bor, MD
Context Recently approved drugs may be more likely to have
unrecognized adverse drug reactions (ADRs) than established drugs, but no
recent studies have examined how frequently postmarketing surveillance
identifies important ADRs.
Objective To determine the frequency and timing of discovery of
new ADRs described in black box warnings or necessitating withdrawal of the
drug from the market.
Design and Setting Examination of the Physicians' Desk
Reference for all new chemical entities approved by the US Food and Drug
Administration between 1975 and 1999, and all drugs withdrawn from the
market between 1975 and 2000 (with or without a prior black box warning).
Main Outcome Measures Frequency of and time to a new black box
warning or drug withdrawal.
Results A total of 548 new chemical entities were approved in
1975-1999; 56 (10.2%) acquired a new black box warning or were withdrawn.
Forty-five drugs (8.2%) acquired 1 or more black box warnings and 16 (2.9%)
were withdrawn from the market. In Kaplan-Meier analyses, the estimated
probability of acquiring a new black box warning or being withdrawn from the
market over 25 years was 20%. Eighty-one major changes to drug labeling in
the Physicians' Desk Reference occurred including the addition of 1
or more black box warnings per drug, or drug withdrawal. In Kaplan-Meier
analyses, half of these changes occurred within 7 years of drug
introduction; half of the withdrawals occurred within 2 years.
Conclusions Serious ADRs commonly emerge after Food and Drug
Administration approval. The safety of new agents cannot be known with
certainty until a drug has been on the market for many years.
JAMA. 2002;287:2215-2220
Adverse drug reactions (ADRs) are believed to be a leading cause of death
in the United States.1
Prior to approval, drugs are studied in selected populations2,
3 for limited periods, possibly contributing to an
increased risk of ADRs after approval. Pharmaceutical companies frequently
market new drugs heavily to both patients and clinicians before the full
range of ADRs is ascertained. Inadequate clinician reporting may delay
detection of postmarketing ADRs; less than 10% of all ADRs are estimated to
be reported to MEDWATCH,4 the
Food and Drug Administration's (FDA's) voluntary postmarketing reporting
system.
Patient exposure to new drugs with unknown toxic effects may be
extensive. Nearly 20 million patients in the United States took at least 1
of the 5 drugs withdrawn from the market between September 1997 and
September 1998.5 Three of
these 5 drugs were new, having been on the market for less than 2 years.
Seven drugs approved since 1993 and subsequently withdrawn from the market
have been reported as possibly contributing to 1002 deaths.6
For example, cisapride was approved for the treatment of a benign condition,
nocturnal gastroesophageal reflux in adults. After its introduction, many
pediatricians prescribed the drug to infants with gastric reflux, 24 of whom
were reported to have died.6
Should clinicians hesitate to prescribe newly approved drugs? Few data
are available on how frequently serious ADRs are discovered after drug
introduction. Previous studies examining drug labeling changes have found
high rates of undetected postapproval risks7
with low rates of subsequent drug withdrawal.8,
9 However, no study has analyzed changes in the
Physicians' Desk Reference,10-35
the most commonly used source of labeling information.36
We analyzed the incidence of new black box warnings in the Physicians'
Desk Reference from 1975 to 2000, a marker of the most serious ADRs, and
used survival analyses to determine the course of their discovery. We also
calculated the frequency and timing of drug withdrawals over this period.
METHODS
Data Sources and Definitions
We chose the study period 1975-2000 because it corresponds with the FDA's
modern era of drug surveillance.37,
38 We obtained a list of drugs approved from
1975-1999 from the Tufts Center for the Study of Drug Development.39
(Drugs approved in 2000 were excluded because none appear in the other data
source for the study, the year 2000 Physicians' Desk Reference,34
which was released in November 1999.) We used the drug approval date to
approximate the date the drug was first marketed. We compiled a list of
drugs withdrawn for safety reasons from a Federal Register notice40
published in 1998 and from information on the FDA Web site about drug
withdrawals between 1998 and 2000.41-43
We defined a drug as "withdrawn for safety reasons" if the drug removal was
initiated by the FDA for safety reasons or if the manufacturer voluntarily
withdrew it from the market following the identification of life-threatening
ADRs.
We included all drugs that the FDA defined as new molecular entities (ie,
an active ingredient that had never been marketed in the United States).44
We excluded over-the-counter medications, diagnostic agents, and biologics
(defined as any drug approved through the FDA's Center for Biologics
Evaluation and Research45).
We included drugs initially available by prescription that subsequently
became available over-the-counter (eg, cimetidine).
We identified black box warnings through a manual search of all 26 annual
volumes of the Physicians' Desk Reference between 1975 and 2000.10-35
The Physicians' Desk Reference, an annual compendium of the
FDA-approved professional product labeling for selected drugs, is released
in November of the year before its cover date. Black box warnings are
prominently displayed in the Physicians' Desk Reference to alert
practitioners to serious risks.46
According to the Federal Register,
Special problems, particularly those that may lead to death or serious
injury, may be required by the Food and Drug Administration to be placed
in a prominently displayed box. The boxed warning ordinarily shall be
based on clinical data, but serious animal toxicity may also be the basis
of a boxed warning in the absence of clinical data.47
We excluded black box warnings that were present when a drug first
appeared in the Physicians' Desk Reference. We also excluded black
box warnings that a drug should be administered by a qualified physician, as
this warning may not indicate a new ADR. We defined a Physicians' Desk
Reference change as either the addition of 1 or more black box warnings
per drug or the withdrawal of a drug.
Analysis
For drugs that had a black box warning in the 2000 Physicians' Desk
Reference, we examined earlier editions of the Physicians' Desk
Reference to determine when the black box warning first appeared. If a
drug did not have a black box warning in the Physicians' Desk Reference
in which it first appeared, we measured the time (rounded to the nearest
month) that elapsed between the approval date and the year of the first
Physicians' Desk Reference in which a black box warning appeared. We
approximated the exact date of the Physicians' Desk Reference year as
January 1 of its cover year. We similarly measured the time from approval to
withdrawal for drugs withdrawn for safety reasons.
We calculated the proportion of all new drugs that acquired a new black
box warning or withdrawal from the market for safety reasons. For drugs that
acquired multiple black box warnings, we counted each warning as a separate
event. For withdrawn drugs that had a black box warning prior to withdrawal,
we counted 2 separate events in the analysis of Physicians' Desk
Reference changes, and counted only the withdrawal date in the analysis
of time until withdrawal. We calculated the time that elapsed before 50% of
eventual drug withdrawals took place, and the time that elapsed before 50%
of all Physicians' Desk Reference changes were made. We also analyzed
the content of the black box warnings and the reasons for withdrawal
according to the type of toxicity.
Statistical Methods
We used the SAS statistical package (Version 8; SAS Institute, Cary, NC) for
frequency analysis, and the Lifetest procedure to calculate Kaplan-Meier
survival curves for censored failure-time data. We used Kaplan-Meier
survival curves to estimate a drug's "survival" (without reaching the end
point of a new black box warning and/or withdrawal from the market) over the
study period, taking into account the fact that drugs are on the market for
varying periods (some briefly). We censored those drugs that had not reached
the end point in question at the time of the analysis.
RESULTS
Five hundred forty-eight new chemical entities were approved from
1975-1999. Of these, 56 (10.2%) drugs acquired a new black box warning or
were withdrawn from the market. In Kaplan-Meier analyses, the estimated
probability of a new drug acquiring black box warnings or being withdrawn
from the market over 25 years was 20% (Figure
1).
Forty-five drugs (8.2%) acquired 1 or more black box warnings that were
not present when the drug was approved (Table
1). Sixteen drugs (2.9%) approved between 1975 and 2000 were withdrawn
from the market between 1975 and 2000; 5 had acquired a black box warning
prior to withdrawal (Table
2). In Kaplan-Meier analyses, new drugs had a 4% probability of being
withdrawn from the market over the study period. Half of withdrawals
occurred within 2 years following the drug's introduction. There were 81
changes in the Physicians' Desk Refer ence during the study period.
In Kaplan-Meier analyses, 50% of these changes occurred within 7 years
following drug introduction. Physicians' Desk Reference changes were
most commonly made for hepatic toxicity (n = 15 [19%]), hematologic toxicity
(n = 13 [16%]), cardiovascular toxicity (n = 17 [21%]), and risk in
pregnancy (n = 9 [11%]).
We noted several inconsistencies among Physicians' Desk Reference
safety warnings. The Physicians' Desk Reference entries for the
-blockers timolol
maleate, atenolol, and metoprolol contained black box warnings indicating
that abrupt discontinuation of the drug could exacerbate coronary artery
disease. However, the entries for the
-blockers carteolol
hydrochloride, penbutolol sulfate, and bisoprolol fumarate had no such
warning. We also observed asynchronous appearances of black box warnings
among drugs of the same class. Timolol obtained a black box warning in 1983,
while metoprolol and atenolol obtained the same warning in 1985 and 1987,
respectively. Similarly, the combination drug triamterene-hydrochlorothiazide
obtained a black box warning for hyperkalemia in 1989, while triamterene
obtained this warning in 1991. Finally, ketoconazole obtained a black box
warning for a life-threatening drug interaction with terfenadine in the 1993
Physicians' Desk Reference, while terfenadine did not have a
comparable warning until 1994.
COMMENT
Many serious ADRs are discovered only after a drug has been on the market
for years. Only half of newly discovered serious ADRs are detected and
documented in the Physicians' Desk Reference within 7 years after
drug approval. Our definition of a serious ADR was conservative, since it
was limited to Physicians' Desk Reference black box warnings. We did
not consider other labeling changes such as bolded warnings without boxes,
"Dear Health Care Professional" letters, or case reports in the medical
literature. Our finding that half of all drug withdrawals occurred within 2
years is consistent with previous research,9 as
is our documentation of potentially dangerous inconsistencies in the
Physicians' Desk Reference.48-50
Why are so many ADRs brought to light only after drug approval?
Premarketing drug trials are often underpowered to detect ADRs,2,
51 and have limited follow-up. In some cases, drugs
are approved despite identification of serious ADRs in premarketing trials.52
For instance, alosetron hydrochloride was reported to be associated with
ischemic colitis prior to its approval, and grepafloxacin hydrochloride was
approved despite reports of QT prolongation and 2 possible deaths.6
Both were subsequently withdrawn from the market because of these adverse
events. Some drugs represent a significant advance over existing drugs in
the reduction of morbidity and mortality and warrant use despite limited
experience. However, the drugs that do not represent a significant advance
should be considered second-line drugs until their safety profile is better
known.
Despite limited knowledge about the safety of new drugs, their market
uptake and sales volume may be explosive. The pharmaceutical industry
promotes the early use of new drugs, and influences physicians' adoption of
such drugs.53-55
Direct-to-consumer drug advertising also generates a high volume of new drug
prescriptions.56 Drug firms
may rush new drugs to market because of concerns about patent life, a desire
to mold prescribing habits prior to the market entry of competitors, and
hopes for a fast "ramp-up" in sales that will encourage investors and
increase stock prices.57-59
New drug safety may be further compromised by the apparent failure by drug
companies to conduct postmarketing (phase 4) studies, which are required by
the FDA when a safety question arises during the preapproval period.6,
60
Given the frequent introduction of drugs for which new serious adverse
events are discovered, the FDA should consider raising its threshold for
approving new drugs when safe, effective therapies already exist, or when
the new drug treats a benign condition. Postmarketing surveillance should be
completed, analyzed, and disseminated to physicians. The date of drug
approval should be prominently included in drug labeling, and changes in
labeling should be highlighted and dated. Furthermore, when a serious ADR is
discovered, labeling of all drugs in the same class should be reviewed if a
class effect is suspected.
Based on our results and those of others,7
clinicians should avoid using new drugs when older, similarly efficacious
agents are available. Patients who must use new drugs should be informed of
the drug's limited experience and safety record, and be observed for
possible hepatic, hematologic, or cardiac toxicity. Clinicians should report
ADRs to MEDWATCH, the voluntary reporting system. Given the inadequacy of
clinician reporting of ADRs, other reporting methods such as
patient-initiated reporting should be explored. Innovative new therapies are
important, but when safe and effective therapies already exist, any new drug
should be considered a black box.
Author/Article Information
Author Affiliations: Department of Medicine, Cambridge Hospital and
Harvard Medical School, Cambridge, Mass (Drs Lasser, Allen, Woolhandler,
Himmelstein, and Bor); and Public Citizen Health Research Group, Washington,
DC (Dr Wolfe).
Corresponding Author and Reprints: Karen E. Lasser, MD, MPH, Macht
4th Floor, Cambridge Hospital, 1493 Cambridge St, Cambridge, MA 02139
(e-mail: klasser@challiance.org).
Author Contributions: Study concept and design: Lasser,
Allen, Woolhandler, Himmelstein, Wolfe, Bor.
Acquisition of data: Lasser, Allen, Woolhandler, Himmelstein,
Wolfe, Bor.
Analysis and interpretation of data: Lasser, Woolhandler,
Himmelstein.
Drafting of the manuscript: Lasser.
Critical revision of the manuscript for important intellectual
content: Lasser, Allen, Woolhandler, Himmelstein, Wolfe, Bor.
Statistical expertise: Lasser, Woolhandler, Himmelstein, Wolfe.
Obtained funding: Bor.
Administrative, technical, or material support: Bor.
Study supervision: Woolhandler, Himmelstein, Bor.
Funding/Support: Dr Lasser's work was supported by National
Research Service Award grant 5T32PE11001-12, and Drs Woolhandler and
Himmelstein's work was supported in part by a grant from the Open Society
Institute.
Acknowledgment: Sidney S. Atwood, BA, provided assistance in
programming and data management; Peg Hewitt, research librarian, and the
Tufts Center for the Study of Drug Development made their data on drugs
approved in the United States available to us; John Orav, PhD, helped with
statistical analyses; Larry D. Sasich, PharmD, MPH, provided us with
additional information on specific drugs; and Maxim D. Shrayer, PhD,
commented on earlier drafts of the manuscript.
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