ETHICAL ISSUES IN PHARMACOGENOMICS

Mark A. Rothstein, J.D.Herbert F. Boehl Chair of Law and Medicine

Director, Institute for Bioethics, Health Policy and LawUniversity 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-relatedproblems in ambulatory care

• Percentage of in-patientswith serious adverse drug reactions

• Percentage of in-patientswith fatal drug reactions

40-100K

$200B

6.7%

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 25Source: Manasco & Arledge (2003)

The Promises of Pharmacogenomics

More effective medications

Fewer side effects

Faster and cheaper clinical trials

“Rescue” drugs

DRUGDEVELOPMENT

10-15 years

Up to $800,000,000 each

Physicians, Nurses, and Pharmacists

• Order genetic testing

• Interpret tests

• Provide counseling

PROFESSIONALRESPONSIBILITIES

Research and development

Clinical trials

Warnings

Marketing

MANUFACTURERRESPONSIBILITIES

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. WARNINGSCassidy 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 havingtoo 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.

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 SURVEILLANCEIf 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 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 armof the trial.

Results:

43% improvement in survival

and

33% reduction in first hospitalization.

A patent was issued for BiDilon 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?