Ethical Issues in Pharmacogenomics

Physicians, Nurses, and Pharmacists• Order genetic testing • Interpret tests • Provide counseling PROFESSIONAL RESPONSIBILITIES... If a physician prescribes a drug approved for patients

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,

mostly adverse drug reactions

(4th-6th leading cause of death)

• Annual cost of drug-related

problems in ambulatory care

SELECTED MEDICATION EFFICACY RATES

FOR COMMON CONDITIONS

SELECTED MEDICATION EFFICACY RATES

FOR COMMON CONDITIONS

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

Physicians, Nurses, and Pharmacists

• Order genetic testing

• Interpret tests

• Provide counseling

PROFESSIONAL RESPONSIBILITIES

 Research and development

 Clinical trials

 Warnings

 Marketing

MANUFACTURER RESPONSIBILITIES

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.”

1 WARNINGS

Cassidy v SmithKline Beecham

(C.P Chester County, Pa., filed December 1999)

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 pharmacogenomically-based

products

Possible effects on liability: negligent marketing

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

• 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

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"?

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?

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 end-stage

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

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 THOUGHTSOCIAL 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?