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ETHICAL ISSUES IN
PHARMACOGENOMICS
Mark A. Rothstein, J.D.
Herbert F. Boehl Chair of Law and Medicine
Director, Institute for Bioethics, Health Policy and Law
University of Louisville School of Medicine
© April 2009
WHY PHARMACOGENOMICS?
SAFETY
EFFICACY
ADVERSE EVENTS
FROM MEDICATIONS
• Annual deaths due to medical errors, 40-100K
mostly adverse drug reactions
(4th-6th leading cause of death)
• Annual cost of drug-related
problems in ambulatory care
$200B
• Percentage of in-patients
with serious adverse drug reactions
6.7%
• Percentage of in-patients
with fatal drug reactions
0.3%
SELECTED MEDICATION EFFICACY
RATES FOR COMMON CONDITIONS
Condition
Efficacy Rate (%)
Analgesics (Cox2)
80
Depression (SSRI)
62
Asthma
60
Cardiac arrythmias
60
Diabetes
57
SELECTED MEDICATION EFFICACY
RATES FOR COMMON CONDITIONS
Condition
Efficacy Rate (%)
Migraine (acute)
52
Migraine (prophylaxis)
50
HCV
47
Incontinence
40
Alzheimer's
30
Oncology
25
Source: Manasco & Arledge (2003)
The Promises of
Pharmacogenomics
More effective medications
Fewer side effects
Faster and cheaper clinical trials
“Rescue” drugs
DRUG
DEVELOPMENT
10-15 years
Up to $800,000,000 each
PROFESSIONAL
RESPONSIBILITIES
Physicians, Nurses, and Pharmacists
• Order genetic testing
• Interpret tests
• Provide counseling
MANUFACTURER
RESPONSIBILITIES
 Research and development
 Clinical trials
 Warnings
 Marketing
1. WARNINGS
Cassidy v. SmithKline Beecham
(C.P. Chester County, Pa., filed December 1999)
Class action lawsuit alleging that
manufacturer of vaccine for Lyme
disease (Lymerix) failed to warn that
some individuals, based on their
genotype (HLA-DR4+), would be
susceptible to “treatment-resistant Lyme
arthritis.”
How is the manufacturer supposed to
provide warnings to the consumer?
Are product labels, package inserts, or
other types of warnings sufficient?
Is there a danger in having
too many warnings?
2. LEARNED INTERMEDIARY
Can a manufacturer reasonably rely on
the prescribing physician or dispensing
pharmacist to supply warnings?
How “learned” are the intermediaries?
If it is foreseeable that the
intermediaries lack the needed
expertise, then the manufacturers may
not be able to escape liability.
3. DIRECT TO CONSUMER ADVERTISING
DTC advertising began in 1997 pursuant to
an FDA guidance. It has now grown to $4-5
billion per year.
It must be assumed that there would be
DTC advertising of pharmacogenomicallybased products.
Possible effects on liability: negligent
marketing.
4. OFF-LABEL USES
The FDA regulates drugs
and devices; it does not
regulate the practice of
medicine. A physician is
permitted to prescribe a
drug for any use that, in the
exercise of reasonable
medical judgment, is
appropriate.
If a physician prescribes a drug
approved for patients with a different
genotype, is the manufacturer liable
for adverse events?
It may depend on whether the off-label
uses were reasonably foreseeable,
whether the manufacturer failed to act
against potentially harmful off-label uses,
and whether the manufacturer encouraged
off-label uses, such as through advertising
or publications.
5. POST-MARKETING SURVEILLANCE
If drugs are marketed based on smaller,
genotype-matched trials, new responsibilities
may be placed on manufacturers to undertake
more vigilant post-marketing surveillance.
In theory, this should be easier to do with the
widespread adoption of electronic health
records and networks.
The failure to do adequate post-marketing
surveillance might be another basis of liability.
WARFARIN
• Blood thinner is prescribed more
than 30M times each year.
• It accounts for 43M ED visits each
year (second only to insulin).
• People with a variant of the genes
CYP2C9 or VKORC1 (vitamin K
epoxide reductase) break down the
drug more slowly, which means that
it stays in the body longer and
causes bleeding.
• In 2007, the FDA announced that a
new label is being required for
Warfarin, which states, under
"precautions": Certain variations in
two key genes may increase the need
for more frequent monitoring and the
use of lower doses.
• FDA projects that
widespread use of
genetic testing as
part of prescribing
could avoid 85,000
serious bleeding
events and 17,000
strokes, saving
about $1.1B
annually.
Woodcock J. and Lesko L. N Engl J Med 2009;360:811-813.
• The genetic test costs $300-$500.
• Turnaround time for tests can be
as much as 10 days.
• On May 4, 2009, CMS announced
it will not pay for the tests because
of a lack of evidence of clinical
utility.
Ethical Issues
Example: Selecting Drug Targets
Before spending tens or hundreds of
millions of dollars on a new drug for a
particular allele, any biotech or
pharmaceutical executive would want to
know the allele frequency as well as the
demographic characteristics of the
population with the allele.
Commercial entities
are not going to
spend vast sums of
money to develop
improved therapies
where the genetic
variation addressed
by the drug is found
mainly in poor people
in developing
countries.
Orphan Genotypes
If a condition is sufficiently rare, it
would not make economic sense for a
manufacturer to invest in developing a
targeted therapeutic.
The Orphan Drug Act of 1983 defines
an "orphan drug" as one affecting
fewer than 200,000 persons in the
U.S., and it gives incentives (e.g. tax
incentives) to companies to develop
drugs for these diseases.
Should there be comparable
legislation for "orphan genotypes"?
Access
New pharmacogenomic-based drugs
are likely to be more expensive than
other medications – certainly more than
off-patent generic drugs. Who will have
access to these products?
Will managed care organizations include
these new drugs on their formularies?
Would physicians have an ethical
obligation to advise patients that these
drugs are available, even though the
patient would have to pay in cash?
Privacy
Pharmacogenomics will result in an increase
in genetic information at a time when
electronic data exchange increases the
possible scope of disclosures.
Will the information be adequately protected?
Will there be adequate protections against the
discriminatory use of the information by
employers and insurers?
Race-Based Medications
Ethical Issues Raised by BiDil
BiDil is a combination of 2 drugs that
have been available in generic form for
decades: hydralazine and isosorbide
(nitroglycerin).
It was postulated that this combination of
drugs would benefit individuals with endstage cardiovascular disease.
In 1997, the FDA rejected the drug after
a trial in a mixed race group, although a
subgroup of African American subjects
appeared to show benefit.
Medco then sold its rights to BiDil to
Nitromed, Inc.
African Americans are more likely to have
decreased levels of nitric oxide, and BiDil
is a nitric oxide enhancer.
This was the biological hypothesis for an
improved outcome in this subpopulation.
Nitromed joined with the Association of
Black Cardiologists to sponsor the
African American Heart Failure Trial,
which involved 1,000 patients at 170
sites.
On July 19, 2004, the trial was halted
because of the significant success of
patients enrolled in the treatment arm
of the trial.
Results:
43% improvement in survival
and
33% reduction in first hospitalization.
A patent was issued for BiDil
on August 31, 2004.
On December 23, 2004, a new drug
application was submitted to the FDA in
which approval was sought only for
African American patients.
Approval was granted, June 23, 2005.
Stock Price of Nitromed, Inc.
On February 2, 2009, Deerfield
Capital (a private equity firm)
agreed to buy Nitromed, Inc. for
$0.80 per share
Why has BiDil been a commercial failure?
• Substitution by physicians?
• Rejection by patients?
Research on Vulnerable Populations
Individual genetic variations are not
distributed equally throughout the
population because of endogamy,
migration, geographic isolation,
founder effect, genetic drift, and other
principles of population genetics.
Some genetic traits
have a higher
frequency among
subpopulations
socially defined by
race or ethnicity.
There is a great potential for discrimination
and stigma when an increased risk of an
undesirable health condition is associated
with a particular population group,
especially when the group is a racial or
ethnic minority in a society.
These groups are said to be “vulnerable.”
Because of the social risks of genetic
research, special efforts are needed to:
1. Consult with leaders and members of affected
subpopulations at all stages of the research.
2. Be careful about inclusion and exclusion criteria
for studies as well as the use of convenience
sampling.
3. Make special efforts to ensure that informed
consent documents and other aspects of the
study (e.g., recruitment, medical exams, return
of biological specimens) are developed with due
regard for social sensitivities.
4. In publications and public pronouncements, be
careful not to overgeneralize about the
findings or place undue emphasis on the study
group.
5. Provide for health screening or interventions,
where appropriate, for vulnerable individuals
identified in the study.
6. Consider benefit-sharing or similar measures
for commercially valuable research findings.
FINAL THOUGHT
SOCIAL JUSTICE
Is it ethical for society (public and private
sectors) to spend substantial resources on
developing expensive new therapies that
may be only slightly safer or slightly more
effective than existing medications –
 -- when tens of millions of people even
in some developed countries (e.g., USA)
lack access to health care?
 -- when hundreds of millions of
people in developing countries lack
basic sanitation, clean drinking
water, immunization, and preventive
health services?