Specialized marketing needed for some drugs

In June, the Food and Drug Administration approved BiDil for use in black patients with severe congestive heart failure.

Reply:

The historic decision by the Food and Drug Administration to approve a medication for a specified racial or ethnic group ushers in a new era in the fight to end disparities in health care. The approval came on the heels of the African-American Heart Failure Trial, or A-HeFT.

A-HeFT showed that BiDil (a combination of hydralazine and isosorbide dinitrate) reduced death by 43% and hospitalization for heart failure by 39% when compared with placebo.

The decision also has raised some question about the message that marketing a drug to a specific minority population might send.

I believe that, given the disparities in health and health care between members of minority and majority populations, the decision is ethically sound and praiseworthy.

The Rev. Martin Luther King Jr. said, "Of all of the forms of inequality, injustice in health care is the most shocking and inhumane."

In 2002, the Institute of Medicine issued the report "Unequal Treatment: Confronting Ethnic and Racial Disparities in Health Care." The report documents that there is a difference between the quality of health care of minority and nonminority populations, even when those populations have equal access to services. The report highlighted the need to increase awareness of racial and ethnic disparities in health care among the general public and key stakeholders as well as among physicians and other health care professionals.

Yet many important disparities cannot be explained by differences in care -- they arise from other important determinants of health, including income, education and, in the end, biology. Genetics, for example, is an important determinant of the susceptibility to obesity, diabetes and cardiovascular disease when incidence among minority groups is compared with incidence in the white population of the United States.

Health disparities are documented in the National Health and Nutrition Examination Surveys for 1999-2002. NHANES is a stratified, multistage probability sample of the civilian, noninstitutionalized U.S. population.

Both the survey interview population of 7,000 U.S. adults 20 and older and the 5,000 respondents who completed the health examination in each year of the study included overrepresentations of low-income people, people age 60 and older, blacks and Mexican-Americans.

NHANES reports that, during 1999-2002, the age-adjusted prevalence of hypertension in the study population was 28.6%. The prevalence of hypertension increased with age and was higher among women than men. The age-adjusted prevalence was 40.5% among non-Hispanic blacks, 27.4% among non-Hispanic whites and 25.1% among Mexican-Americans.

The disparities in hypertension translate into disparities in the incidence of myocardial infarction, stroke and congestive heart failure. All these complications are more common in members of minority populations than in whites.

There are many treatment options for hypertension. Yet not all agents may be effective in particular populations. Medications such as ACE inhibitors and angiotensin-II receptor blockers, for example, might not be effective in black patients. Their labeling reflects this. The clinical trials for these agents highlight the need to have more representation by minority groups.

Until now, most clinical studies did not include minority patients in adequate numbers to assess the efficacy of an intervention based on race or ethnic background. This is largely due to the small proportion of minority and ethnic groups in the U.S. population. According to the last U.S. census, the American population is 12% black, 12% Hispanic, 1% Native American, 4% Asian or Pacific Islander, and 71%white. Unless a concerted effort is made to include minority patients in a study population, the population proportions do not allow enough power for subgroup analysis.

Participation in clinical research by minority groups has been hampered by mistrust in the medical establishment. The Tuskegee experiment -- in which black patients were deceived into thinking that they were being treated for syphilis when, in fact, they were part of a research project from 1932 to 1972 without their informed consent -- is at the root of much of this mistrust. It will take time to overcome these historical obstacles.

The efficacy of BiDil in other ethnic groups, and comparisons of its efficacy between groups, remain unknown. These will be the subject of future studies.

In the meantime, A-HeFT will remain a landmark study because of its design. It addresses a significant health disparity in the black minority group. The A-HeFT investigators were largely from this same group, creating a trustworthy relationship with study subjects. A-HeFT thus serves as a model of culturally appropriate clinical research.

In the years to come, we should expect more trials designed to test treatment effectiveness in specific minority groups. As part of this effort, we will need to increase the number of minority investigators and provide the funding required to achieve success in recruiting and retaining study subjects.

J. Michael Gonzalez-Campoy, MD, PhD, medical director and CEO, Minnesota Center for Obesity, Metabolism, and Endocrinology (MNCOME); Minority Affairs Consortium Delegate to the AMA House of Delegates

Reply:

I agree with the marketing of BiDil for use with African-American patients, a practice which some have termed "race-based" medicine. I believe, however, that we must be careful about how broadly we use this practice. First some background.

To critique this practice, we need to understand how the term "race" is defined and used. In the United States, Canada and other Western countries, race is defined as a combination of anthropologic origin and social description of human groups used historically to divide and subjugate, but now used for ethnic clustering and empowerment of all groups.

Self-identified membership in a social group is the more appropriate definition of race for many purposes, but in medicine, some weight may be given to anthropological origins. The medical practice of sensitivity to differences in segments of the population based on the anthropological origin of that segment has been termed race-based medicine.

Historically, data on whether and how different anthropological segments of the population might respond to drugs has been sorely missing.

In the large multicenter chronic-disease drug studies of the 1970s and 1980s, the study subjects' racial composition was overwhelmingly Caucasian. There are two reasons for this. First, there was a lack of effort by trial coordinators to enroll minority subjects. Second, there was (and still is, to a certain extent) a lack of trust in the clinical-trials process rooted in part in knowledge of previous exploitative trials such as the Tuskegee syphilis study of African-American men and experiments performed by Nazi Germany on Jews during the Holocaust. Because studies from this era were so one-sided, physicians were unclear on how to apply the acquired data to their more diverse patient population. This was de facto race-based medicine of a different sort.

Fortunately, drug studies of the '90s began to be more inclusive. Some of this change may be economically driven -- the country is becoming more diverse, and non-Caucasian groups are slowly developing more purchasing power for drugs. Institutional review boards at university-based research institutions require that studies encourage equitable enrollment. And there is a trend toward involving community physicians who have high numbers of non-Caucasian patients.

Before the introduction of angiotensin-converting-enzyme inhibitors, the main oral medications approved for congestive heart failure were diuretics and digoxin, which didn't improve mortality. ACE inhibitors work better in people who have higher levels of renin, which increases the levels of angiotensin I. Because some African-American patients have lower levels of renin, it was widely thought that they would not benefit from ACE inhibitor therapy. When these ACE inhibitors were compared with isosorbide dinitrate-hydralazine and a placebo in two important multicenter trials, two conclusions were reached: The combination of isosorbide dinitrate and hydralazine lowered mortality compared with placebo, and the long-acting ACE inhibitor enalapril lowered mortality compared to isosorbide dinitrate-hydralazine. But there was little diversity among the subjects for these studies.

The company that developed BiDil wisely designed a study to test isosorbide dinitrate-hydralazine among a group of subjects that had been neglected in the past: African-Americans. When this drug improved mortality among the trial subjects, its developers sought and received FDA approval to market the drug for use among that African-American population. Is this "race-based medicine?" Perhaps, but I doubt that its specialized marketing represents a threat to the health care system. It is important that we continue to make all clinical trials equitable and that the number of branded, chronic disease medications that were originally studied among nondiverse populations gets smaller with each passing year.

Since most people in the United States do not have a pure gene pool, the differences found in clinical trials among ethnic groups might be secondary to socioeconomic or environmental factors. During my residency training and clinical practice, I have treated a Caucasian woman with sickle trait and an African-American man with cystic fibrosis.

If we are to eliminate health care disparities in the United States, we must have access to all appropriate data, whether some group of critics believes the data are race-based or not. The consequence is too important to our patients and the physicians who serve them.

Kevin McKinney, MD, associate professor of internal medicine, University of Texas Medical Branch in Galveston; member of the AMA Minority Affairs Consortium and the Commission to End Health Care Disparities; president, Galveston County Medical Society and Houston Medical Forum