BiDil for Heart Failure in Black Patients: Implications of the U.S. Food and Drug Administration Approval

In 2005, the U.S. Food and Drug Administration (FDA) approved BiDil (NitroMed, Lexington, Massachusetts), a combination of 2 generic medicationshydralazine hydrochloride and isosorbide dinitratein a single tablet, for treating heart failure in black patients. BiDil was approved for a specific racial groupwhich is a first for the FDA and is a clear departure from the FDA's long history of approving treatments for clinical conditions regardless of demographic classification (with the occasional exception of sex). One rationale for this departure was that the drug approval was important for addressing racial disparities in health (13). We argue that the FDA decision, although perhaps well-intentioned, may be a setback to scientific discourse on therapeutics and may be specifically deleterious to efforts aimed at addressing disparities in health and health care. Clinical Trials and Drug Approval Because many patient characteristics can influence variability in drug response, randomized, controlled trials have attempted to include a broad spectrum of the patient population, an approach specifically endorsed by the National Institutes of Health policy on the inclusion of women and minorities (4). Including a broad patient population assures that most information on variations in drug efficacy is available for patients who are affected by the same condition. It also allows for investigators to research explanatory factors that may underlie variability, from simple descriptions (for example, drug A is less effective in older individuals) to more complex explanations (for example, the lower efficacy of drug A in older individuals is partially explained by a higher burden of coronary disease). The merits of including broad patient populations in randomized, controlled trials are most clearly seen in studies in which this practice has not occurred, such as the trials of aspirin for the primary prevention of coronary disease. Although earlier trialsalmost exclusively in mendemonstrated the efficacy of aspirin (57), a recent trial in women did not show this benefit (8). Were the observed differences because of fundamental physiologic differences between men and women in their manifestation of coronary disease and their response to aspirin or because of the consequences of specific features of the trials (such as distinct dosing regimens, variations in inclusion criteria, or advances in other adjunctive therapies)? A trial that had included adequate numbers of both men and women would have answered many lingering questions despite data from well-done trials done in each population separately. In the past, trials have restricted enrollment to specific demographic groups. The African American Study of Kidney Disease and Hypertension (AASK) trial (9, 10) is a recent prominent example. This randomized, controlled trial of different antihypertensive treatments for hypertensive nephrosclerosis included only black participants. Black people are disproportionately affected by hypertension and kidney disease, and arguments both for efficiency and equity underlie the decision to explore treatments in this understudied patient population. However, the AASK investigators did not claim a race-specific effect of these therapies and reported instead on the general treatment effects for hypertensive nephrosclerosis (9, 10). A fundamental consistency in human biological responses is assumed in this type of trial reporting and in the FDA drug approval process, which has for years based approval of therapeutics for the general population on evidence from trials in mostly white, mostly male patient populations. Drugs are approved for treating clinical entities, not for treating specific demographic subgroups. Departures from this logic should require a compelling scientific argument with clear evidence of the biological mechanism underlying the differential response. Pharmacogenomic advances may, over time, provide that scientific argument, but such data are not available in most cases. The recent case of bucindolol offers some important insights. Scientific Implications of the FDA Approval of BiDil The FDA approval of BiDil was based on the results of the African American Heart Failure Trial (A-HeFT) (11), a randomized, controlled trial of BiDil added to standard therapy for self-identified black patients with heart failure. The makers of BiDil had initially sought approval for the drug in the general patient population (not just in black patients) on the basis of results of earlier trials of the generic combination (12, 13), but approval was denied because of statistical concerns that the earlier trials had failed to account for the multiple end points analyzed (14). In addition, the earlier trials did not address the important question of whether the hydralazine hydrochlorideisosorbide dinitrate combination confers benefit when added to standard heart failure therapy (including angiotensin-converting enzyme [ACE] inhibitors and -blockers). The A-HeFT evidence was clearBiDil, when added to standard therapy, reduced mortality in black patients with advanced heart failure. Faced with this evidence, the FDA had 2 choices: approve BiDil for the general populationa practice consistent with years of previous drug applicationsor approve BiDil only in black patients. In choosing the latter, the FDA chose the path with the most concerning scientific consequences both for heart failure treatments and for studies of medical therapies. 1. Drug approval for specific groups implies a differential drug response that has not been rigorously tested. The FDA approval of BiDil in black patients implies that the treatment is efficacious only in black people and not in other racial groups. Although a 1999 post hoc subgroup analysis of 2 earlier hydralazine hydrochlorideisosorbide dinitrate trials in black and white patients (Veterans Administration Cooperative Vasodilator Heart Failure Trial [V-HeFT] I [12] and II [13]) suggested that the response to treatment may differ among races (15), the evidence is insufficient to base the current FDA decision. First, because the V-HeFT II investigators included enalapril as an active treatment comparison group, the subgroup analysis could not determine whether the observed racial difference was due to an increased response to hydralazine hydrochlorideisosorbide dinitrate or a decreased response to enalapril among black participants. Second, these older trials do not provide evidence for differential response to hydralazine hydrochlorideisosorbide dinitrate among contemporary patients who are receiving other standard heart failure therapies. Finally, and perhaps most important, evidence from the subgroup analysis must be interpreted with the same caution as with other post hoc analyses of particular subgroups enrolled in clinical trials. Although such analyses are generally performed to determine whether response differs between groups, observed differences are far more likely to be in the degree of response (for example, drug A is more efficacious in diabetics than nondiabetics) than in the type of response (for example, drug X is efficacious only in diabetics and not in nondiabetics) (16). Reports of qualitatively different responses have not been consistently replicated and are particularly suspect when hypotheses have not been prespecified or appropriate adjustments have not been made for multiple hypothesis testing (16, 17) (which are both well-documented critiques of the analyses from V-HeFT I and II [1, 14]). Notably, the V-HeFT subgroup analysis did not prompt the major heart failure practice guidelines to recommended using these medications differently in black and white patients (18, 19). In studying only black patients, the recent A-HeFT trial could not address the lack of treatment efficacy in other racial groups. However, because the approval of BiDil for black patients implies a lack of treatment efficacy in other race groups, the FDA decision has important clinical and scientific implications. Clinically, the use of this effective medication in other demographic groups is now technically off-label (a paradox for BiDil because the use of the generic combination as an alternative to standard therapy is approved for all individuals). Scientifically, racial differences in response to hydralazine hydrochlorideisosorbide dinitrate (and perhaps other heart failure medications) may now be thought of as proven, although the statistical interaction on which such a conclusion is based has not explicitly been tested. In addition, untested assumptions about differential responses by race generally lend credence to other untested assumptions, including heart failure as a different disease entity in black patients. We should note that plausible biological mechanisms may explain a differential response of black patients to hydralazine hydrochlorideisosorbide nitrate, namely increased levels of nitric oxide in black people that are associated with adverse heart failure outcomes and may be reduced by hydralazine hydrochlorideisosorbide nitrate therapy (20). While such observations certainly merit further exploration, the association of a potential mediator of the differential drug response with a certain race group should not be the sole basis for drug approval exclusively in that race group. Recent data on racial differences in drug response to another heart failure drugbucindololoffer an important lesson in this regard. The negative results of the randomized, controlled trial of bucindolol (the Beta-Blocker Evaluation of Survival Trial [BEST] [21]) are in stark contrast to those of several trials of other -blockers that show mortality benefits in heart failure (2224). The BEST authors speculated that the reason for their negative results may have been the substantial numbers of black participants in the trial and a decreased response to -blocker therapy among them. In fact, subgroup analysis of the BEST results demonstrate