Targeting RaceBiomedical Interventions

John R. Stone, MD,PhDJuly 2005

Tuskegee University National Center for Bioethics in Research and Health Care

jrstone15366@gmail.com

Acknowledgements

• Harold Kincaid• Mona Fouad• Isaac Mwase• Ann Smith

June 2005

FDA approves Bidil for treatment of

congestive heart failure in

African Americans

FDA Approval of BiDil

•Much hype•Good idea?•Bad idea?

Ethical Issues/BiDilBenefit PotentialBenefit Potential• Better CV health for

AA-perhaps• Better health in in

generalgeneral for AA—unknown

• Particularized care• More efficiency

Harm PotentialHarm Potential• Impersonal care• More stigma• More stereotypes• Reify race/biol • Reify race/genetics• Ignore social• Sustain, increase

injustices

Talking about race

• Uncommon in racially mixed groups

• Uncommon in public• Loaded• Scary territory• Opportunity for constructive

dialogue

Troy Duster, Buried alive: the concept of race in science. The Chronicle Of Higher Education. 2001;48(3):B11 (emphasis added)

• “The major task for Americans is to analyze how and under what circumstances we use the concept of race.”

• “It is a mistake to discard race just because racial categories do not map exactly onto biological processes. But it is also a mistake to uncritically accept old racial classifications when we study medical treatments.”

Troy Duster, Buried alive: the concept of race in science. The Chronicle Of Higher Education. 2001;48(3):B11 (emphasis added)

• “The task is to determine how the social meaning of race can affect biological outcomes like varying rates of cancer and heart failure. Burying the concept of race can seem very appealing in the short term. But in practical applications, race remains very much alive.”

Jonathan Kahn. How a Drug Becomes “Ethnic”: Law, Commerce, and the Production of Racial Categories in Medicine. Yale Journal Of Health Policy, Law, And Ethics IV:1 (2004), p. 3 (emphasis added)

• “At the most basic level, it turns out that BiDil became an ethnic drug through the interventions of law and commerce as much as through medical understanding of biological differences that correlate with racial groups.” (p. 3)

MG Bloche. Race-Based Therapeutics. NEJM 2004;351:2035-2037 (p. 2037) (emphasis added)

• “Race is at best a placeholder for other predispositions, and not a biologic verity.”

Possible legitimate reasons to target groups in medical care• Enhance benefit (life, quality)

• “Particularize” or “personalize” care (groups ≠ individuals)

• Reduce harms (death, suffering)• Enhance efficiency

• Facilitate identification of important factors (motive for pharmacogenetics)

Questions

• Do investigator economic interests matter in the BiDil case?

• Do their conflicts of interest undermine scientific validity?

Questions

• Should the FDA approve race-targeted biomedical interventions?• Never/always/sometimes• What guidelines?• What processes?

• Safeguards?• Harms?• Benefits? • What after market monitoring and

safeguards?

BackgroundCongestive Heart Failure (CHF)• Early death• Sustained, progressive suffering• Huge problem• Causes (Europe/North America)

• Hypertension• Coronary artery disease• Valvular heart disease• Cardiomyopathies• Miscellaneous diseases

Background: Earlier CHF Therapy• Pathophysiology: peripheral vascular

constriction as CHF progresses• Digoxin• Diuretics• Sodium restriction• Blood pressure control• Weight loss• Cardiac surgery (mainly valvular)

CHF Outcomes

• Deaths AA/W reported >2:1

Jonathan Kahn. How a Drug Becomes “Ethnic”: Law, Commerce, and the Production of Racial Categories in Medicine. Yale Journal Of Health Policy, Law, And Ethics IV:1 (2004);1-46.

CHF Clinical Trials

• Promote peripheral vasodilation• Arterial• Venous

• Hydralazine plus nitrates• ACE Inhibitors• ACE Receptor-blockers (much

later)

CHF Trials: Isosorbide Dinitrate + Hydralazine

• Limited effectiveness of I + H• ACE inhibitors

• More potent (better & longer lives)• Less potent in AA-space for BiDil (Kahn)• Better tolerated

• ACE inhibitors standard of care• CHF• Myocardial Infarction

• ACE receptor blockers as alternative

BiDil Story: CHF

• I/H: Isosorbide dinitrate + hydralazine• 1980-1985: V-HeFT I, VA, , I/H

marginally > placebo, not Prazosin (mortality)

• 1986-1991 V-HeFT II, ACE inhib > I/H, ACE inhibfrontline, I/H backup if intoler (mortality)

• 1987 Jay Cohn patent app I/H combo, approv 1989, CHF (no race mention)

Jonathan Kahn. How a Drug Becomes “Ethnic”: Law, Commerce, and the Production of Racial Categories in Medicine. Yale Journal Of Health Policy, Law, And Ethics IV:1 (2004);1-46.

BiDil Story• 1992 BiDil Trademark• 1995 Medco intell prop rts f J Cohn • 1996 Medco NDA-FDA-denied

• Cohn et al. arg f BiDil and Medco• Advisory committee votes against • Cohn+ arg f I/H’s efficacy (no race focus)• Biostatisticians, FDA Advis Com, argue V-

HeFT uncertainties about I/H efficacy• MedCo returns intell prop rts to Cohn

Jonathan Kahn. How a Drug Becomes “Ethnic”: Law, Commerce, and the Production of Racial Categories in Medicine. Yale Journal Of Health Policy, Law, And Ethics IV:1 (2004);1-46.

BiDil Story• 1999: Peter Carson, Susan Zeische,

Gary Johnson, Jay Cohn., retrospective analysis (J Cardiac Failure, v. 178):• V-HeFT I: AA but not W ↓ mortality w/ I/H (P

= .04)• V-HeFT I: Signif AA / W diffs, e.g. CHD • V-HeFT II: only W ↓ mortality (P = .02),

• V-I: 180B/450W; V-II:215B/574W

Jonathan Kahn. How a Drug Becomes “Ethnic”: Law, Commerce, and the Production of Racial Categories in Medicine. Yale Journal Of Health Policy, Law, And Ethics IV:1 (2004);1-46.

BiDil Story• 1999: NitroMed intell prop rts f J Cohn• 1999: J Cohn, P Carson app patent I/H f AA w/

CHF, transfer rts to NitroMed• 1999 P Carson, colleague publish review, of LV

dysf outcomes• reconfirm 2:1 B/W mortality (older studies)• assume underlying hypertension basically biological

because supposedly not based on SES. • CHF death rates 35-74, most W > age 74, B < 74• most B CHF deaths < 74, so ignoring much data; • unsophisticated SES analysis• ignore recent stats sugg B/W mortal rates ~ 1.1:1

Jonathan Kahn. How a Drug Becomes “Ethnic”: Law, Commerce, and the Production of Racial Categories in Medicine. Yale Journal Of Health Policy, Law, And Ethics IV:1 (2004);1-46.

BiDil Story• 2001: Jay Cohn et al., NEJM, ACE inhib

less effective in blacks (NitroMed’s V-HeFT underway)

• 2001 NitroMed gets support of ABC (Assoc Black Cardiol) and Congressional Black Caucus

• 2001 NitroMed raises $31 million vent capital funds for A-HeFT

Jonathan Kahn. How a Drug Becomes “Ethnic”: Law, Commerce, and the Production of Racial Categories in Medicine. Yale Journal Of Health Policy, Law, And Ethics IV:1 (2004);1-46.

BiDil Story

• 2004 (Nov) NEJM A-HeFT trial• 1050 African Americans (self-

identified), randomized• (I/H + best) or bestrandomized• Early termination (deaths)• 43% death reduct (10.2%6.2%)

Anne L. Taylor, et al. Combination of Isosorbide Dinitrate and Hydralazine in blacks with heart failure NEJM 2004;351:2049-2057

June 2005

FDA approves Bidil for treatment of

congestive heart failure in

African Americans

Questions

• Do investigator economic interests matter in the BiDil case?

• Do their conflicts of interest undermine scientific validity?

Questions

• Should the FDA approve race-targeted biomedical interventions?• Never/always/sometimes• What guidelines?• What processes?

• Safeguards?• Harms?• Benefits? • What after market monitoring and

safeguards?

Bidil & Race-targeting Burdens/Harms?• ▲ Injustices and Harms?

• ▲Stereotypes, bias, prejudice• ▼Focus on health & healthcare ≠• ▼Treatment for expensive minority

conditions?

• ▼ Genetics-based research?• Race poor marker• Group diff: only some genetic

Harms/BiDil Example

• Reinforces alleged connection of race to biology & genetics,

• Pharmacogenetics focus diverts attention from social factors in health inequalities

Jonathan Kahn. How a Drug Becomes “Ethnic”: Law, Commerce, and the Production of Racial Categories in Medicine. Yale Journal Of Health Policy, Law, And Ethics IV:1 (2004);1-46.

Bidil & Race-targeting Benefits?

• ▲ Greater market motivation?• ▲ Minority niche focus? • ▲ Treatment for minority health

conditions?• ▲ Opportunity for increased

minority input into treatment development?

Race-targeting: Checks & Balances• Fair involvement of targeted populations in

FDA approval processes, including enhanced representation on advisory panels and approval boards.

• Fair selection of panel and board members.• Enhanced public input opportunities.• Push after-market monitoring and national

registry• Revise our health-care system and

relationships with industry (e.g., see Marcia Angell-reference)

Ethical Issues/BiDilBenefit PotentialBenefit Potential• Better CV health for

AA-perhaps• Better health in in

generalgeneral for AA—unknown

• Particularized care• More efficiency

Harm PotentialHarm Potential• Impersonal care• More stigma• More stereotypes• Reify race/biol • Reify race/genetics• Ignore social• Sustain, increase

injustices

References

Marcia Angell, The Truth about the Drug Companies: How They Deceive Us and What to Do About It. New York: Random House, 2004.

MG Bloche. Race-Based Therapeutics. NEJM 2004;351:2035-2037.

Troy Duster, Buried alive: the concept of race in science. The Chronicle Of Higher Education. 2001;48(3):B11.

Jonathan Kahn. How a Drug Becomes “Ethnic”: Law, Commerce, and the Production of Racial Categories in Medicine. Yale Journal Of Health Policy, Law, And Ethics. 2004;IV:1:1-46