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VOLUME 3 • ISSUE 1 • FALL 05
MDAdvantage Insurance Company of New Jersey
Navigating Drug Safety Issues:
The Physician’s Perspective
By Robert B. Goley and Janet S. Puro
Every day, there seems to be another
drug or medical device in the news with
safety issues. Popular antidepressants
might increase the risk of teen suicide.
Widely prescribed arthritis painkillers like
Vioxx and Celebrex appear to be linked
to heart attacks and strokes. The list goes
on and on (see insert for a list of some of
the most recent drug-related safety concerns). Many of these are drugs that you
as a physician may be currently prescribing, or even taking yourself. The situation
has left patients confused, drug companies defensive, and government officials
at odds over how to fix the problem.
tions. What should you be telling your patients? Do you
face any liability in prescribing these drugs?
This article, and its conclusion (set to appear in next
quarter’s MDAdvisor), will set out to explore these issues.
Surely, even the safest and most effective
drugs we use can have serious side
effects. Researchers will not know
everything about even the best
researched drug before it goes to market.
But how do we know when the risk to
patients is too high? Who bears the
ultimate responsibility for the decision?
Understanding the Role of the FDA
The Food and Drug Administration (FDA) approves
every drug that is sold in the United States. If the FDA
determines through review of research and testing
information that a particular drug is harmful or substandard, the manufacturer is notified and asked to remove
the drug from the market, either temporarily (drug recall)
or completely (drug withdrawal). A drug recall is mainly
requested if there is an error in the medication, including
contaminations, mislabeling, and dosage errors. A drug
withdrawal is issued if a multitude of serious side effects
or deaths are reported directly from patients taking the
medication. Most companies will voluntarily remove
their product from the market if flaws are detected.
However, unless the Secretary of the Department of
Health and Human Services declares an imminent
health risk, the FDA cannot force a drugmaker to
pull its medicine off the market.
And where do you as a physician fit in to
all of this confusion? With pharmaceutical
companies advertising their products
directly to consumers, patients are coming in to physician practices requesting,
and even demanding, specific medica-
In the early 1990s, at the height of the AIDS epidemic,
the FDA was criticized for being too slow about
approving potentially life-saving medicines. Now, the
FDA is being criticized for allowing drugs on the market
too quickly without focusing enough on whether the
benefits of new drugs truly outweigh their risks. The
Navigating Drug Safety
Issues: The Physician’s
Perspective (cont’d)
FDA has also been criticized because
many more resources are focused on
approving new drugs than monitoring the
safety of drugs already on the market.
Categories of
Drug Recall:
Class I
Dangerous/defective products that
imply possible
health problems
Class II
Implies temporary
health problems
and less serious
threats
Class III
Products unlikely to
cause problems,
but do not comply
with FDA standards
This year, the FDA unveiled a new vision
that will promote a culture of openness
and enhanced oversight within the
agency. As part of this vision, a new
independent Drug Safety Oversight Board
was created to oversee the management
of drug safety issues, and will provide
emerging information to health providers
and patients about the risks and benefits
of medicines. The Drug Safety Oversight
Board held its inaugural meeting on
June 17, 20051. Summaries of each board
meeting will be posted at www.fda.gov
approximately one week after each
meeting.
The most recent chapter in the FDA’s
crisis culminated in the resignation of its
Commissioner, Lester Crawford, on
September 23, 2005. Increasing criticism
and a particularly rocky final twelve
months marked his three-year tenure at
the FDA. So far, no candidate has publicly
surfaced as a permanent replacement for
Crawford, and any nominee will likely face
tough Senate scrutiny. President Bush
designated the National Cancer Institute’s
director, Dr. Andrew von Eschenbach, to
be the FDA’s acting commissioner in the
interim.
Do Physicians Receive Enough Information About
Drug Safety?
Despite the efforts of the FDA to ensure the safety
of prescription drugs and oversee the information
provided to physicians, there continues to be much
information about drug studies that goes undisclosed.
While often too complex for patients to understand,
clinical trial results are useful to doctors and academic
scientists, who use them to compare drugs and look for
clues to possible side effects. However, companies are
not required to disclose trial results to scientists or the
public. Calls for disclosure continue to grow stronger
with reports that drug manufacturers have failed to
publish important patient safety data.
Last year, the drug industry came under fire for failing
to disclose poor antidepressant study results. Then in
August 2004, GlaxoSmithKline agreed to pay $2.5
million to settle a suit by Eliot Spitzer, the New York
Attorney General, alleging that Glaxo had hidden
results from trials showing that its antidepressant Paxil
might increase suicidal thoughts in children and
teenagers2. Merck withdrew Vioxx from the market in
September of 2004 because a study had found that the
medicine doubled the risks of heart attacks and strokes.
In the weeks after the announcement, Pfizer insisted
that it had no evidence that its very similar drugs,
Celebrex and Bextra, caused heart problems. Pfizer has
since disclosed that it had, at the time of those statements, studies that indeed demonstrated heart problems among patients taking Celebrex or Bextra. In
December 2004, the National Institutes of Health
announced that a very large trial had found that high
doses of Celebrex more than tripled the risk of heart
problems3.
As a result of these investigations, major drug makers
have promised to provide more information about their
research on new medicines, yet crucial facts about many
clinical trials remain hidden. Within the drug industry,
companies are sharply divided about how much
information to reveal, both about new studies and
completed studies for drugs already on the market.
Pharmaceutical companies can hide negative trial results
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by refusing to publish studies, or by highlighting the
most favorable data from studies they do publish. In
recent years, journal editors and academic scientists
have pressed big drug makers to release more information. Eli Lilly and some other companies have posted
hundreds of trial results to a registry on the Web
(www.clinicaltrials.gov). The registry is designed in part
to prevent companies from conducting several trials of
a drug, then publicizing only those trials with positive
results. But other drug makers, including Merck, Pfizer,
and GlaxoSmithKline, file only vague descriptions of
many studies, often failing even to name the drugs
under investigation. Drug names are helpful in tracking
how many times a drug has been studied. Merck, Pfizer
and Glaxo hold that disclosing too much information
about early-stage trials might reveal business or
scientific secrets4. As a result, doctors and patients lack
critical information about important drugs.
Understanding The Legal Environment
We have all read many news reports in the past year of
lawsuits brought against pharmaceutical companies for
drug-related patient issues. In order to understand one’s
own potential liability as a physician, it is necessary to
understand the legal environment for pharmaceutical
companies. There are two main types of suits brought
against pharmaceutical companies: mass tort suits and
class action suits.
of duplicative and inconsistent rulings, orders or
judgments, coordinates discovery, and promotes
efficient utilization of judicial resources. Although there
is centralized pretrial management, the cases will be
tried individually or in groups.
In cases filed in New Jersey Superior Court as part of a
mass tort, claimants typically filed individual complaints.
Although product manufacturers are most often the
primary defendants, in the past, treating physicians
prescribing or using the products have sometimes been
named in the suit as direct defendants or, more rarely,
brought into the suit as defendants in third party claims
filed against them by other defendants.
The Chief Justice of New Jersey has assigned four
Superior Court Judges to exclusively manage mass tort
cases. The cases are centralized and managed in three
vicinages: the Civil Division Part in Middlesex, Atlantic
and Bergen Counties. The County managing the mass
tort maintains a master docket number, which consolidates and centralizes management of the claims. Each
claimant may have separate counsel or more than one
counsel. Each counsel may represent more than one
claimant. A claimant can be an individual, group or
corporation. Out-of-state attorneys may be admitted
pro hac vice, which means they may be granted special
permission to participate in a particular case, even
though they are not licensed to practice in that state.
Mass tort suits are different than personal injury claims
related to acts of medical negligence or medical
malpractice affecting an individual patient. They involve
a large number of claims associated with a single
product, device or catastrophic event. Regardless of the
number of claimants, there is a “commonality” of facts
and recurrent issues of law. Synergy or interdependence
between the claims generally adds to their value.
Currently, there are five mass torts centralized in NJ
related to pharmaceutical products: Accutane, Diet
Drugs (such as PhenFen with settlement agreements
currently pending), HRT (Hormone Replacement
Therapy) PPA (Phenylpropanolamine) and Vioxx.
Currently an application is also pending to designate
Bextra as a mass tort.
To receive a designation of mass tort, an assignment
judge of any vicinage (or an attorney involved in one
or more of the cases) can apply to the New Jersey
Supreme Court if the appropriate “commonality” criteria
are met to warrant centralized case management.
Centralized case management avoids the risk
Class Action lawsuits are initiated when one or more
parties file a complaint on behalf of themselves and all
other people who may have a similar claim. When all of
the legal prerequisites to a class action are met and the
Court designates Class Certification, the suit covers all
members as claimants of a particular group.
➢
Navigating Drug Safety
Issues: The Physician’s
Perspective (cont’d)
By their very nature, however, tort suits for
personal injury claims are often considered
by the court as inappropriate for handling
as a class action. Although the members
of the proposed class may all allege that
their various claims arose as the result of
the same product, the court may conclude
that each plaintiff’s damages must be
determined on an individual basis. In such
cases, a sufficient community of interest is
lacking, and some courts have held that a
class action is therefore not available.
The basic requirements for class certification are “numerosity, commonality,
typicality and predominance.” In situations
involving class actions against a pharmaceutical company over a particular drug
(for example), “class certification” covers
all individuals who were prescribed the
drug – even if the individuals have not
brought suit themselves. All members of
a “class” are included in an ultimate jury
award or settlement – unless individuals
previously decided to opt out of the suit.
Class action suits may be filed in state or
federal court. Suits covering plaintiffs
residing in multiple states can be filed in
any of the state courts with jurisdiction
over some of the plaintiffs. When a high
profile or newsworthy event occurs
regarding a pharmaceutical product or a
medical device, typically more than one
class action suit or mass tort will be initiated – and the number of suits pending
against just one drug can be huge.
Plaintiff attorneys throughout the country
often file actions against manufacturers in
multiple venues based on identical issues
and overlapping classes of claimants. For
example, there are an estimated 5,000
suits pending against Merck in association
with the drug Vioxx5.
Laws governing class actions were intended to permit
fair and efficient resolution of legitimate claims of numerous parties by allowing the claims to be aggregated into
a single action against a defendant who has allegedly
caused harm. However, there have been significant
issues and problems with class action suits in the recent
past, including instances where class members have
been unfairly harmed or received little benefit for being
members of the class, instances where counsel for the
class were awarded excessively large fees, and instances
where bias was shown against out-of-state defendants.
In an attempt to improve the class action process and
achieve greater procedural uniformity, President Bush
signed the Class Action Fairness Act (“CAFA”) into law
on February 18, 2005. CAFA is intended to overcome
venue shopping, based on the perception that some
state courts are more “class action friendly,” leading
plaintiff attorneys to file cases in sympathetic jurisdictions. It also contains a Consumer Class Action Bill of
Rights that is intended to curb “coupon settlements,”
simplify explanations of rulings and settlements, and
control fees collected by attorneys acting as class counsel6.
This new law is not retroactive and therefore does not
apply to class action suits currently pending. (The act
applies to any civil action commenced on or after
February 18, 2005). Going forward however, CAFA will in
effect transfer many major class action suits from state
courts to federal court. The Act provides federal district
courts with jurisdiction over any class action in which the
dispute exceeds $5 million (class members’ claims may
be aggregated to meet or total that amount and the
class must have a minimum of 100 members). If less than
one-third of the members are from the primary defendant’s state, then federal jurisdiction will prevail. When
greater than one-third but less than two-thirds of the
members and the primary defendants are from a single
state, the district courts have the option of declining
jurisdiction and remanding the case to the state courts.
If, however, greater than two-thirds of the class members
and at least one of the primary defendants are all from a
single state, and the principal injuries occurred in that
state, then jurisdiction remains with the state and not
the federal court.
The Class Action Fairness Act will allow redundant state
court actions to be removed to federal court, from which
they can be transferred and consolidated by the Judicial
Panel for Multidistrict Litigation (“MDL”). The Panel
(created by an act of Congress in 1968) consists of seven
federal judges (appointed by the Chief Justice of the
United States). The panel determines if civil actions
pending in different federal districts involve one or
more common questions of fact to warrant transfer to
one federal district for coordinated or consolidated
management. The centralization process efficiently
avoids duplication of discovery, prevents inconsistent
pretrial rulings, and conserves resources of the parties,
their counsel and the judiciary. Following completion of
the centralized pretrial management, the Panel usually
remands the cases back to their originating districts for
trial. The MDL Panel has also remained involved in mass
tort settlement programs as well.
Examples of federal suits that have been reviewed by
the MDL Panel in the past include fen/phen diet drugs
and hormone replacement therapy. Currently there are
multiple medical products liability suits pending review
with the Panel, including Orthopedic Screw Products,
Gammagard (IV Immunoglobulin), Diet Drugs, Rezulin
Products (settlement program), Propulsid (settlement
program), Silzone heart valve coating (settlement program), Sulzer Hip Prosthesis (settlement program), PPA
(settlement program), Baycol (settlement program),
Meridia, Paxil, Zyprexa, Ephedra, Accutane, and Vioxx.
Will the CAFA accomplish what was intended? There is
still some concern over the impact of large class action
suits with claimants from multiple states being forced
into federal court. There is also the potential that courts
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Honor Your Profession By Honoring Your Peers
CAFA also specifies a “mass action” category, which is
different than class certification. Mass actions are any
civil action in which the claims of 100 or more persons
are proposed to be tried jointly due to common
questions of fact or law. Only those individuals who
are claimants in the mass action suit are included in a
final settlement or jury award. Under the new law, mass
actions in state courts are subject to consolidation in
federal court following the same rules as the certified class.
MDAdvantage is currently accepting nominations
for the 2006 Edward J. Ill Awards. This annual event
honors physicians and healthcare professionals in
New Jersey who have shown exemplary competence,
leadership and commitment to their profession.
The award categories are as follows:
Edward J. Ill Award
Given to an eminent leader in his or her specialty.
Medical Educator Award
Given to an esteemed educator in academic medicine.
Medical Executive Award
Given to an outstanding medical executive.
Citizen’s Award
Given to a leading advocate for healthcare concerns
and public welfare.
Community Service Leader Award
Given to an outstanding organization dedicated to
improving the lives of those in need in New Jersey.
Nominations are open to all New Jersey physicians
and healthcare professionals and may be submitted to:
Joseph Reichman, MD
c/o MDAdvantage
Two Princess Road, Ste. 2
Lawrenceville, NJ 08648
Please forward the nominee’s name, along with a
description of qualifications and CV if available.
Written nominations will be accepted through
December 16, 2005.
Recent Drug Safety Issues
Recent Drug Safety Issues
Drugs
Purpose
Manufacturer
Safety Concerns
Accutane
Roche Laboratories
Treatment of a type of severe acne (nodular acne) that has
not been helped by other treatments, including antibiotics Aggressive and/or violent behaviors, birth defects
Adderall
Shire US Inc.
Controlled release amphetamine used to treat patients
with attention deficit hyperactivity disorder
Arava
Aventis Pharmaceuticals
Treatment of active rheumatoid arthritis
Avandia
GlaxoSmithKline
Baycol
Bayer
Fluid retention, potential for heart failure, hepatic failure
Oral agent for the treatment of type 2 diabetes
(with & without fatal outcome), edema
Cholesterol lowering medication belonging to the class of Reports of sometimes fatal rhabdomyolysis (a severe
muscle adverse reaction)
drugs known as statins
Bextra
Pfizer
Non-steroidal anti-inflammatory (NSAID)
Increased risk of heart problems; serious & potentially life
threatening skin reactions, including deaths
Celebrex
Pfizer
Cox-2 selective NSAID
A very large 3-year trial was halted after interim findings
suggested that high doses more than tripled the risk of
heart problems.
Crestor
AstraZeneca
Cytotec
Searle
Duragesic
Janssen Pharmaceutica;
Labtec (generic)
Elidel
Novartis
Enbrel
Immunex Corporation
Ephedra
Various
Fen-Phen
American Home Products
(fenfluramine); Various
(phentermine)
Sudden deaths reported in pediatric patients, particularly
those with underlying heart defects
Rare, serious hepatic injury, and severe infections,
including cases with fatal outcome
Status
Changes made to labeling in 2002. FDA continues to
assess reports of suicide or suicide attempts associated
with use. Announced in 8/05 that every person using the
drug will have to enroll in a national registry in an effort to
reduce birth defects.
Sale has been suspended in Canada based on U.S. postmarketing reports. Labeling for Adderall XR was changed
in U.S. FDA has not taken any other regulatory action to
date. In 6/05, the FDA announced it will be investigating all
attention deficit hyperactivity disorder drugs in response to
reports of serious psychiatric side effects in patients taking
Concerta & Ritalin.
The prescribing information & monitoring
recommendations were updated in 10/03.
Product labeling has been updated to reflect the postmarketing experience of the product since its launch in
6/99.
Bayer Pharmaceutical Division voluntarily withdrew the
drug from the U.S. market in 8/01.
FDA asked Pfizer to voluntarily withdraw the drug from the
market on 4/7/05. Pfizer agreed to suspend sales and
marketing of Bextra in U.S., pending further discussions
with FDA.
Still on market, but sales have dropped significantly. FDA
has concluded that the benefits outweight the potential
risks in properly selected & informed patients. FDA asked
for revised labeling, including a boxed warning and a
Medication Guide. Physicians are encouraged to use the
lowest effective dose.
FDA required a 5-mg. dose be made available. FDA is
evaluating reports of adverse muscle effects with regard to
clinical severity & apparent relationship to the drug.
Cholesterol lowering medication belonging to the class of Increased risk of myopathy; reports of sometimes fatal
drugs known as statins
rhabdomyolysis (a severe muscle adverse reaction)
A major adverse effect of the obstetrical use is
hyperstimulation of the uterus which may progress to
Used to reduce the risk of non-steroidal anti-inflammatory uterine tetany with marked impairment of uteroplacental
drug-induced stomach ulcers; the drug is also used offblood flow, uterine rupture, or amniotic fluid embolism.
Major changes were made to Cytotec labeling in 4/02,
label to induce labor and delivery; used as part of the FDA- Pelvic pain, retained placenta, severe genital bleeding,
shock, fetal bradycardia, and fetal and maternal death have including the creation of a new labor & delivery section
approved regimen for use with mifepristone to induce
that provides safety information related to those issues.
been reported.
abortion in pregnancies of 49 days or less
FDA is investigating reports of death & serious side effects.
Deaths & overdoses in patients using both the brand name In 6/05, the Duragesic product label was updated to add
Pain control (fentanyl transdermal system)
Duragesic and the generic product
new safety information in several areas.
FDA required labeling changes, including the placement of
a boxed warning about the potential cancer risk. Because
the risks are uncertain, FDA advises drug should be used
only as labeled for patients after other prescription
Second-line agent for short-term & intermittent treatment
treatments have failed to work or cannot be tolerated.
of atopic dermatitis
The Warnings, Precautions, and Adverse Events sections of
Treatment for moderate to severe rheumatoid arthritis
the labeling have been revised.
FDA has determined that ephedra presents an
unreasonable risk of illness or injury. On 4/12/04, a final rule
Ephedra products extensively promoted to aid weight loss, Significant adverse health effects, including heart attack & went into effect prohibiting the sale of dietary supplements
stroke
containing ephedrine alkaloids (ephedra).
enhance sports performance, and increase energy
In 1997, the manufacturers agreed to withdraw
fenfluramine from the market & FDA recommended that
patients stop taking the drugs. Phentermine was not taken
off the market, as there has been no identified problem
with taking this drug alone. A number of lawsuits have
been filed against the manufacturers of both drugs. On
A combination of drugs (fenfluramine & phentermine)
August 28, 2000, the U.S. District Court in Philadelphia
commonly used to treat obesity; the combination of the
approved the settlement reached with AHP in a nationwide
two drugs is considered off label as they were not
fen-phen class action suit.
approved by the FDA for use together
Heart valve disease
FDA has issued a public health advisory about a potential
cancer risk from use. This concern is based on information
from animal studies, case reports in a small no. of patients,
and knowledge of how drugs in this class work.
Serious infections and sepsis, including fatalities;
lymphoma
Meridia
Abbott Laboratories
Treatment of obesity
Mifeprex (RU-486)
Danco Laboratories
Medical abortion
Naproxen
Bayer (Aleve), Naprosyn
(Roche), generic
OTC NSAID
Natrecor
Johnson & Johnson (Scios
Inc.)
Treatment of patients with acutely decompensated
congestive heart failure
Neurontin
Pfizer (originally ParkeDavis)
Epilepsy; also used for many other off-label uses
Viramune
Boehringer Ingelheim
Non-nucleoside reverse transcriptase inhibitor (NNRTI)
used in triple antiretroviral regimens to reduce AIDS
morbidity & mortality
Oxycontin
Purdue Pharma
Management of moderate to severe pain for an extended
period of time
Palladone
Purdue Pharma
Treatment of moderate to severe chronic pain in opiatetolerant patients (extended release capsules)
Paxil
GlaxoSmithKline
Antidepressant (SSRI); also used to treat anxiety, panic,
obsessive compulsive disorder, & post-traumatic stress
disorder. Use of antidepressants for patients under 18
years has not been approved by FDA (with the exception
of Prozac). Use in children & teenagers considered offlabel.
Permax
Eli Lilly & Co.
Management of the signs & symptoms of Parkinson's
disease
New labeling changes were approved by the FDA in 7/05
to incorporate additional information for patients with renal
impairment or renal insufficiency. Lawsuits have been filed
Primary pulmonary hypertension (PPH), heart valve disease, against manufacturer alleging it should have known and
warned of the serious adverse effects Meridia can cause.
mortality
FDA is investigating recently reported serious adverse
events. A public health advisory was issued in 7/05. Danco
Five reported deaths from sepsis or serious bacterial
is updating labeling, Medication Guide and Patient
infection following treatment
Agreement.
FDA asked manufacturers of all OTC NSAIDs to revise their
labels to include more specific information about potential
Increased risk of cardiovascular and cerebrovascular
risks. FDA will be analyzing all available information from
events (based on emerging information from a long-term studies to determine if further additional regulatory action
prevention trial)
is needed.
Clinical trials are ongoing to assess further the benefits &
risks. Manufacturer states it is proactively educating
physicians regarding the conditions and circumstances in
which the drug should be used. Package insert was
updated, but manufacturer has recently been accused of
Renal dysfunction, mortality
promoting off-label use.
In 5/04, Pfizer's Warner-Lambert division pleaded guilty to
illegally marketing the drug to treat ailments for which it
was not approved. Pfizer, which did not own WarnerLambert when the government said the wrongdoing
happened, paid a $430 million fine to settle charges that
included defrauding Medicaid. The drug continues to be a
top seller.
Risk of suicide
The labeling has been revised several times to include
more information on liver toxicity. Health care providers
should weigh the benefits and risks associated with
nevirapine use before prescribing nevirapine for the
treatment of their HIV-infected patients.
Liver toxicity associated with long-term use
The DEA has asked Purdue Pharma to change its strategy
regarding Oxycontin. In 7/01, at the urging of the FDA,
Abuse liability similar to morphine
Purdue added a black box warning to drug labels.
Purdue Pharma agreed to suspend sales and marketing in
7/05. Prior to that, Palladone had been sold in the U.S.
Potential for severe side effects if taken with alcohol due to since 1/05 and has been used by only a small number of
time release formulation
patients.
In 3/04, FDA issued a Public Health Advisory cautioning
physicians about the need to closely monitor all patients
being treated with antidepressants. The FDA proposed
labeling changes, including a 'black box' warning, for 10
antidepressants (Paxil, Prozac, Zoloft, Luvox, Celexa,
Serzone, Effexor, Remeron, & Wellbutrin). In 8/04, Glaxo
agreed to pay $2.5M to settle a suit by Eliot Spitzer (NY
Atty. General) alleging that Glaxo had hidden results from
trials. In 9/05, Glaxo changed the Pregnancy subsection of
the Precautions labeling sections indicating an increase in
Use may increase suicidal thoughts in children & teenagers; the risk of congenital malformations during the first
trimester.
significant withdrawal symptoms; risk of birth defects
During postmarketing surveillance, a small number of
individuals have been identified as developing cardiac
In 2003, the warnings section of the U.S. Package Insert was
valvulopathy involving one or more valves
modified.
Drugs
Pur ose
Manufacturer
Safet Concerns
Nasal decongestant (prescription & OTC); weight control
(OTC)
Phenylpropanolamine (PPA) Various
Increased risk of hemorrhagic stroke in women, and
possibly also men.
Recent Drug Safety Issues
Status
FDA requeste t at a rug compa
marketing products containing PPA
products in 11/00.
New labeling adopted in 1/03, inclu
states that therapies should not be
of cardiovascular disease. Also, estr
Hormone replacement therapy used to treat symptoms of
of endometrial cancer when used w
menopause
Premarin
Wyeth Pharmaceuticals
New a e ing a opte in 1 , inc u
Recent Drug Safety Issues
Hormone replacement therapy used to treat symptoms of Long-term use significantly increases risk of stroke, blood states that therapies should not be
menopause
clots, heart attacks & breast cancer.
of cardiovascular disease.
Prempro
Wyeth Pharmaceuticals
Janssen cease mar eting Propu si
7/14/00. On 2/4/04, Janssen and the
Drugs
Safety Concerns
Status Committee, through lead counsel,
Manufacturer
Purpose
FDA requested that all drug companies
discontinue
reached
an agreement in principle t
marketing products containing PPAlawsuits
& remove
PPA from
related
toall
the product Prop
Johnson & Johnson Nasal decongestant (prescription & OTC); weight control Increased risk of hemorrhagic stroke in women, and
(OTC)
possibly also men.
products in 11/00.
Phenylpropanolamine (PPA) Various
(Janssen
Pharmaceutica)
Treatment
of
severe
nighttime
heartburn
in
adults
Heart
rhythm
abnormalities
Propulsid
(cont’d)
Premarin
Protopic
Prempro
Raptiva
Propulsid
Redux (dexfenfluramine)
Remicade
Protopic
Rezulin
Raptiva
Redux (dexfenfluramine)
Remicade
Risperdal
Rezulin
Serzone
Risperdal
Serzone
Strattera
Thimerosal
Strattera
Tysabri
Thimerosal
Viagra
Tysabri
Viagra
Vioxx
Vioxx
Zyprexa
Zyprexa
NIH stopped a trial after finding the pills not only failed to
reduce the risk of heart disease, but raised the possibility
of a stroke. Other risks include ovarian cancer, lupus,
scleroderma, gallbladder cancer.
NIH stopped a trial after finding the pills not only failed to New labeling adopted in 1/03, including a boxed warning,
used required
for the prevention
reduce the risk of heart disease, but raised the possibility states that therapies should not beFDA
labeling changes, inc
of a stroke. Other risks FDA
include
ovarian
cancer,
lupus,health of
cardiovascular
Also, estrogens
increase
the risk
a boxed
warning
about the potentia
has
issued
a public
advisory
aboutdisease.
a potential
scleroderma, gallbladder cancer.
of endometrial cancer when used without a progestin.
Wyeth Pharmaceuticals
cancer risk from use. This concern
is based on information the risks are uncertain, FDA advises
New labeling adopted in 1/03, including a boxed warning,
for patients after ot
fromincreases
animal risk
studies,
case
reports
in athat
small
no. ofshould
patients,
Second-line
agentused
for to
short-term
& intermittent
treatment
therapy
treat symptoms
of Long-term
use significantly
of stroke,
blood
Hormone replacement
states
therapies
not beonly
used as
for labeled,
the prevention
treatments have failed to work or ca
and knowledge
of how drugs inofthis
class work.disease.
Fujisawa
Healthcaremenopauseof atopic dermatitis
cancer.
clots, heart attacks & breast
cardiovascular
Wyeth
Pharmaceuticals
Treatment o a u t patients wit c ronic mo erate to
New
ytic
Janssen ceased marketing Propulsid
in theemo
U.S. as
of anemia warning a
7/14/00. On 2/4/04, Janssen and the
Plaintiffs Steering
severe plaque psoriasis
Hemolytic anemia
information
in 7/05.
Genentech
Committee, through lead counsel, announced they had
In 1 7, t e manu acturers agree t
reached an agreement in principle to resolve all federal
American
the
Home
Products
market.
A
Nationwide Class Act
lawsuits related to the product Propulsid.
Johnson & Johnson
(fenfluramine);
Various
Agreement received Final Judicial A
(Janssen
Pharmaceutica)
Treatment of severe nighttime heartburn in adults
Heart rhythm abnormalities
Hormone replacement therapy used to treat symptoms of
menopause
(phentermine)
Treatment of obesity
Heart valve disease
2002.
required
labeling changes, including the placement of
Acute iver ai ure, jaun ice c oFDA
Jo nson Jo nson
Treatment o r eumatoi art ritis, ro n's isease,
estasis,
epatitis,
FDA has issued a public health advisory about a potential a boxed warning about the potential cancer risk. Because
ankylosing spondylitis
(Centocor)
lymphoma
Warning
on hepatotoxicity added to
cancer risk from use. This concern is based on information the risks are uncertain, FDA advises drug should be used
Par e-Davis Warner-Second-line agent for short-term & intermittent treatment from animal studies, case reports in a small no. of patients, only as labeled, for patients after other prescription
treatments have failed to work or cannot
be tolerated.
of atopic dermatitis
drugs inliver
this class
work.
Lambert
Treatment of Type II diabetes mellitus and knowledge of howSevere
toxicity
Product
removed from market in 3/
Fujisawa
Healthcare
Treatment of adult patients with chronic moderate to
New hemolytic anemia warning added
n to the
, prescribing
sent warn ng etters to
severe plaque psoriasis
Hemolytic anemia
information in 7/05.
Genentech
drug's elevated risk of stroke in elde
In 1997, the manufacturers agreed to withdraw Redux from
FDA announced that older patients
the market. A Nationwide Class Action Settlement
American Home Products
antipsychotic
Agreement received Final Judicial given
Approval
on January 3, medicines are m
(fenfluramine); Various
prematurely, & now requires black b
(phentermine)
Treatment of obesity
Heart valve disease
2002.
Acute liver failure, jaundice/cholestasis,
& Johnson
hepatitis,
Johnson
medicines (Zyprexa, Symbyax, Seroq
Johnson
Increased risk of
& Johnson Treatment of rheumatoid arthritis, Crohn's disease, &
diabetes, neuroleptic malignant
ankylosingTreatment
spondylitis of schizophrenia
(Centocor)
lymphoma
Warning on hepatotoxicity added to
labeling in 12/04.
Geodon).
(Janssen Pharmaceutica)
syndrome, stroke, tardive dyskinesia
Parke-Davis/Warnern 5 1 4 Bristo Myers qui an
Lambert
Treatment of Type II diabetes mellitus
Severe liver toxicity
Product removed from market in 3/00.
Serzone
in the
U.S. This follows a
In 4/03, J&J sent warning letters toselling
U.S. physicians
citng
Antidepressant
Liver damage
2001.
Bristol Myers Squibb
patients. In 4/05,
drug's elevated risk of stroke in elderly
FDA announced that older patientsnwith dementia
, a ewho
ng are
was up ate to n
given antipsychotic medicines are more
likely
die the FDA announced
effects.
Into6/05,
prematurely, & now requires black all
boxattention
warnings on
related
deficit
hyperactivity dis
medicines (Zyprexa, Symbyax, Seroquel, Abilify, Clozaril,
Johnson & Johnson
Increased risk of diabetes, neuroleptic malignant
to reports of serious psychiatric side
(Janssen Pharmaceutica)
Treatment of schizophrenia
syndrome, stroke, tardive dyskinesia
Geodon).
taking Concerta
& Ritalin. On 9/29/0
On 5/19/04 Bristol Myers Squibb announced
it would stop
Advisory
Severe drug related liver injury; selling
reports
of suicidal
thinking
Serzone
in U.S. This
follows Health
a black box
warningto
in alert physicians o
Antidepressant
2001.
Bristol
thinking in children & adolescents.
Treatment of attention deficit disorder Liver damage
in children & adolescents
EliMyers
Lilly Squibb
& Co.
In
12/04,
labeling
was
updated
to
include
serious
liver
side
A mercury-containing organic compoun an
FDA as wor e wit , an continue
effects. In 6/05, the FDA announced it will be investigating
organomercurial); the most common preservative used in Theoretical potential for neurotoxicity
manufacturers
of even
levels ofdisorder
to reduce or eliminat
deficitlow
hyperactivity
drugs in response
all attention
vaccines & biologics that are marketed in the U.S.
organomercurials
vaccines.
Various
to reports of serious psychiatric side
effects in patients
Ritalin. On 9/29/05, FDA issued a Public
A patient in a ong-term c inica taking
tria Concerta
ie rom& progressive
Advisory
alert physicians Biogen-IDEC
of reports of suicidal
Severe drug related liver
injury; reports
of suicidal thinking Health
has suspended marke
multifocal
leukoencephalopathy
(PML),
a raretoneurologic
in children & adolescents.
in children & adolescents
Eli Lilly
& Co. Idec & Elan Treatment of attention deficit disorder
Biogen
disease; a second patient in thethinking
same trial
had a confirmed dosing of patients in on-going clinic
A mercury-containing organic compound (an
FDA has worked with, and continues to work with, vaccine
diagnosis
of PML.
concurs
withfrom
this decision
Pharmaceuticals
Treatment
for common
relapsing
forms of used
multiple
sclerosis potential for
organomercurial);
the most
preservative
in Theoretical
neurotoxicity
of even low levels of manufacturers to reduce or eliminate
thimerosal
vaccines & biologics that are marketed in the U.S.
Various
Pfizer
Biogen Idec & Elan
Pharmaceuticals
Pfizer
Erectile dysfunction
from the
market.
There
A small number of post-marketing reports of sudden vision In 7/05, FDA approved updated labeling
for Viagra,
Cialis
loss, attributed to non-arteritic ischemic optic neuropathy & Levitra to reflect the rare ocular occurrences.
pending against Merck
Cox-2 selective NSAID
Merck
Merck
Eli&Lilly
Eli Lilly
Co. &
Treatment for relapsing forms of multiple sclerosis
organomercurials
vaccines.
A patient in a long-term
died from
progressive
Aclinical
small trial
number
of post-marketing
reports of sudden vision In 7/05, FDA approved updated lab
has neuropathy
suspended marketing
and allto
further
Biogen-IDEC
multifocal leukoencephalopathy
(PML), a rare
neurologic
& Levitra
reflect the rare ocular o
loss, attributed
to non-arteritic
ischemic
optic
disease; a second patient in the same trial had a confirmed dosing of patients in on-going clinical trials. The FDA
concurs with this decision
diagnosis of PML.
Erectile dysfunction
Co.
Merck announced in 9/04 that it was
are an estim
in associatio
In the first Vioxx trial, a Texas jury or
Merck announced in 9/04 that it was
withdrawing
drug
stunning
$253
million to a widow wh
from the market. There are an estimated 5,000 suits
heart
after taking the me
pending against Merck in association
witharrhythmia
the drug Vioxx.
vowed
to
appeal
In the first Vioxx trial, a Texas jury ordered Merck to paythe
a case, which wi
$26 million
stunning $253 million to a widow whose
husbanddue
diedto
of caps on punitive
heart
arrhythmia
after
taking
the
medication.
Merck
has
second Vioxx trial is currently under
Increased risk for heart attacks & strokes
vowed to appeal the case, which will likely be cut to about
$26 million due to caps on punitive damages in Texas. The
Labeling
changes
made
second Vioxx trial is currently underway
in Atlantic
City, NJ.
in 3/04 re: m
atypical antipsychotics with an estab
Cox-2 selective NSAID
Increased risk for heart attacks & strokes
Atypical antipsychotic
Atypical antipsychotic
forpatients
diabetes
Labeling changes made in 3/04 re: factors
monitoring
on mellitus and mo
atypical antipsychotics with an established
diagnosis
or risk
symptoms
of hyperglycemia.
In 4/05
factors for diabetes mellitus and monitoring
all
patients
older patients withfordementia who a
symptoms of hyperglycemia. In 4/05, FDA announced that
medicines
are
more
likely
to
die
pre
older patients with dementia who are given antipsychotic
requires black
medicines are more likely to die prematurely,
& now box warnings on rela
(Risperdal,
Symbyax, Seroquel, Abil
requires black box warnings on related
medicines
(Risperdal, Symbyax, Seroquel, Abilify,
Clozaril,
Geodon). in 6/05 that it ha
Eli Lilly
announced
Lillydiabetes
announced
6/05 that it has
entered intoinanprinciple to settle abo
agreement
Increased risk of hyperglycemiaEli
and
ininpatients
agreement in principle to settle about 8,000 (75%) of claims
Increased risk of hyperglycemia and diabetes in patients
against the company related to Zyp
takingmedications
atypical antipsychotic medications
against the company related to Zyprexa.
taking atypical antipsychotic
Note: For
purposes
only. This
table
lists
somelists
of the
mostof
notable
recentnotable
drug safety
concerns,
is notconcerns,
meant or intended
to be
an exhaustive
or wholly
Note:
Forrepresentative
representative
purposes
only.
This
table
some
the most
recent
drugand
safety
and is not
meant
or intended
to be an exhaustive or wholly
accurate list. Information in this table does not constitute medical advice and it serves no other purpose than to provide additional background material. Further
accurate
list. Information in this table does not constitute medical advice and it serves no other purpose than to provide additional background material. Further
information on a particular drug can be found either from the FDA (www.fda.gov) or the drug manufacturer.
information on a particular drug can be found either from the FDA (www.fda.gov) or the drug manufacturer.
Navigating Drug Safety
Issues: The Physician’s
Perspective (cont’d)
could become overburdened and take
longer to reach trial. Additionally, the federal court takes a conservative approach
and may tend to deny class certification.
Pursuit of Damages: the Collectible Claim
The first hurdle for a claimant to overcome
in establishing a claim is the statute of limitations, which is the time limit or deadline
that the injured party has to file his or her
claim. (Each state has its own variation of
the statute of limitations.) The individual
actions which have been filed may then
be qualified as part of a mass tort. In New
Jersey, the statute of limitations is two
years from the date the cause of action
accrued. Often the date the cause of
action ”accrued” is different than the date
of treatment. The so-called discovery
doctrine provides that statute does not
start to run until the patient becomes
aware of the injury and is aware that the
injury is due to the fault of an identifiable
party. This can allow a claimant significant
extensions of time to initiate a lawsuit
when there is a delayed manifestation of
injury or the issue of fault is not self-evident.
The situation is different for the individual
patient who may be part of a “class.” In
class action suits, one or more members
of a class may sue on behalf of all members of the class. Therefore, the individual
patients are covered as members of the
class without actually filing suit themselves.
The filing of the complaint seeking class
action certification tolls the statute of
limitations for the benefit of all members
of the potential class.
After the statute question has been
answered and a claimant has determined
if the basis of a suit is truly product liability
or an act of medical negligence on the part of a health
care provider (medical malpractice), there are other
major obstacles to overcome – both in mass tort litigation and class action suits. In pursuit of a product liability
claim, it is the job of the plaintiff attorney to establish
causation, which may be difficult for “latent injuries”
which may not yet be evident.
In their pursuit of money as compensation for damages
they have suffered or will incur in the future, plaintiffs
are usually seeking to collect both compensatory and
punitive damages from the defendants. The term
“compensatory damages” covers a number of categories
of loss, both economic and non-economic. Economic
damages include lost wages, decreased earning capacity
and other items of pecuniary loss. Non-economic damages (often the subject of discussion and debate on the
topic of damage caps and tort reform) include elements
of pain and suffering, physical impairment, disfigurement, loss of enjoyment of life and other non-pecuniary
damages.
The big ticket item in terms of jury awards is punitive
damages (damages awarded separately and in addition
to compensatory damages as punishment for the
wrongdoer). In the first Vioxx trial in Texas, the major
portion of the $253 million award was $229 million in
punitive damages. Many states, including Texas and
New Jersey, have some type of cap on punitive damage
awards. In the Vioxx trial, total awards are likely to be
cut to about $26 million as a result of a cap on punitive
damages in Texas7.
The Less Vulnerable Physician?
Physicians, from a practical standpoint, are not named
in large class action suits. As demonstrated however in
many of the past product liability suits, individual physicians have been named as direct defendants or third
party defendants in individual or mass tort suits. In many
of these actions (such as breast implant and diet drugs),
manufacturers waged their own defense by arguing that
physicians had adequate information about the risks of
utilizing or prescribing their products. Physicians also
888-355-5551 • www.MDAdvantageonline.com
became vulnerable to lawsuits which began as mass tort
product liability suits but diverged into concurrent or
subsequent medical malpractice claims.
The relationship between physicians and product manufacturers remains strained and uncertain. However, the
tactics that plaintiff attorneys appear to be taking in the
latest high profile or newsworthy product liability cases
are “cautiously encouraging” for physicians. Trends are
showing that physicians are not being named in more
recent mass tort litigation, such as in the case of Vioxx.
Strategically, the cases are being geared exclusively
toward the large manufacturers. Plaintiffs are taking the
stance that patients and their physicians were not adequately warned of the risk of the products. Large manufacturers have been avoiding filing third party claims
against physicians (their customers) for inappropriate
use of the product or device.
The first of the mass tort trials for a particular drug, class
of drugs, or device is strategically critical for both plaintiffs and the defense. Although physicians generally are
not being named as defendants in these newest cases,
the trend can of course change in the future based on
the outcomes of the initial trials. For example, the first
Vioxx case has been closely analyzed. Merck has vowed
to fight each Vioxx case one by one and says it has a
strong case on appeal in the recently completed Texas
trial. In the second Vioxx trial, which is underway in
Atlantic City, and the first federal Vioxx case, expected
in November, the opposing sides will plan strategically
from lessons learned in the first trial. Monitoring the
progress of these trials will enable physicians to gather
information on what, if any, potential liability issues may
be brought up in the future.
The conclusion of this article will be published in the
Winter Edition of MDAdvisor. Topics covered will include
an overview of how physicians are responding to drug
safety issues and guidelines for minimizing liability and
ensuring safe and effective care to patients. The article
will also include a summary of recent interviews with relevant parties such as physicians and a claimant attorney.
If you are a physician interested in providing comments
on this article or would like to share how your practice
is handling these drug safety issues, please contact
Janet Puro at [email protected] or (888) 355-5551
x1197. Comments may also be mailed to
MDAdvantage, Two Princess Road, Suite 2,
Lawrenceville, NJ 08648.
References
1
Press Statement, Food & Drug Administration, Statement on First
Meeting of FDA’s Drug Safety Oversight Board. (2005, June 17).
2,4
Berenson, Alex. (2005, May 31). Despite Vow, Drug Makers Still
Withhold Data. The New York Times.
3
Harris, Gardiner. (2005, February 17). Medical Panel Poses Pointed
Questions to Drug Makers Over Risks of Painkillers. The New York
Times.
5,7
Business: The Week Ahead. (2005, September 15). Merck’s Vioxx
Drama Moves to New Jersey Venue. The Star-Ledger, p. 24.
6
Amoresano, Guy V. and Michael R. McDonald. (2005, April 25).
Class Litigants Face Tougher Forum. New Jersey Law Journal.
Robert B. Goley is the Vice President of Claims Administration
at MDAdvantage. He and Ms. Puro, Project Specialist, have been
frequent authors on tort reform and other issues affecting New
Jersey physicians.
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Risk Management Seminars
Mark Your Calendar!
MDAdvantage will be presenting the following risk management seminars.
November 9, 2005
Come visit the MDAdvantage Exhibit Booth at the New Jersey Physician’s Expo!
We will also be presenting a one-hour seminar,
The Most Vulnerable Physician: A Review of the Top Reasons Doctors are Sued
Meadowlands Expo Center, Secaucus
November 12, 2005
Effects of Malpractice on Physicians
Barry Brown Health Education Center, Voorhees
Please keep an eye on your mail for other future risk management seminars!
You can also find details, as they become available, in our Events section of
www.MDAvantageonline.com.
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