Robert Temple, MD; Norman L. Stockbridge, MD, PhD
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Robert Temple, MD, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993-0002; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Temple and Stockbridge: U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993-0002.
Critics of the U.S. Food and Drug Administration (FDA) approval of the fixed combination of hydralazine hydrochloride, 37.5 mg, and isosorbide dinitrate, 20 mg, for treating heart failure in black patients have suggested that data were insufficient to distinguish treatment effects in black and white people; that distinctions based on race, rather than pathophysiology, were scientifically unreasonable; and that a “race-based” approval could be a commercial ploy to avoid a more expensive and prolonged full evaluation of a drug. The criticisms acknowledge that data supporting the approval came from a well-designed clinical trial in which self-identified black patients with heart failure who took hydralazine hydrochloride–isosorbide dinitrate with standard therapy experienced a statistically significant 43% (95% CI, 11% to 63%) reduction in mortality compared with those who took only the standard therapy. The criticisms do not always recognize that the decision to conduct the trial in only black patients reflected careful analyses of 2 previous trials in racially mixed patient populations that compared hydralazine hydrochloride–isosorbide dinitrate with placebo or with enalapril. Both trials showed little or no overall effect of hydralazine hydrochloride–isosorbide dinitrate in the mostly white patient population but hinted at a substantial effect in subsets of black patients. Perhaps most critically, the criticisms do not appreciate the urgency of strong scientific evidence of a substantial survival benefit in black patients. A serious attempt to avoid race-based approval by mandating study of a mixed population to identify a possible white patient–responder subset, particularly without a plausible hypothesis as to what that subset might be, would have required years of work, many thousands of patients, and wholly unreasonable delay in approval of a treatment whose effectiveness had been well-documented in the group for which it was intended.
Table 1. African American Heart Failure Trial Results*
Table 2. Vasodilator Heart Failure Trial I and II Results*
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Jonathan D. Kahn
Hamline University School of Law
January 5, 2007
BiDil: A Closer Look
At first glance, Robert Temple and Norman Stockbridge present an apparently reasonable rational for the FDA's approval of the heart failure drug, BiDil, with a race-specific label for use only in "self-identified black patients." Upon closer examination, however, their arguments fail to convince. Drs. Bobbins-Domingo and Fernandez clearly show the limits of the post-hoc sub-group analysis relied upon by the FDA to justify race- specific approval.[fn: Bobbins-Domingo K, Fernandez A. BiDil for Heart Failure in Black Patients: Implications of the Food and Drug Administration Approval. Ann. Intern Med. 2007;146:52-56.]
Beyond this, it is worth noting that since approval, NitroMed, BiDil's corporate marketer, has made much of a recent FDA announcement that the co-administration of the much cheaper generic components of BiDil are not bioequivalent to the patented BiDil single pill formulation.[fn NitroMed FDA Confirms No Drugs are Therapeutically Equivalent to BiDil(R) [press release] 4 May 2006. Accessed at http://phx.corporate- ir.net/phoenix.zhtml?c=130535&p=irol-newsArticle&ID=852400&highlight= on 4 January 2007.] If bioequivalence is such a significant issue as to warrant a separate FDA announcement, one wonders what Temple and Stockbridge make of the FDA's previous findings that the doses of H/I administered in V-HeFT I were not bioequivalent to those administered in V -HeFT II and that neither dose was bioequivalent to that administered in A -HeFT.[fn Center for Drug Evaluation and Research. Approval Package for: Application Number NDA 20-727 Administrative/Correspondence Reviews. n.d. Accessed at http://www.fda.gov/cder/foi/nda/2005/020727_S000_Bidil_AdminCorres.pdf on January 4 2007.] Again, the "very strong evidence" from "three well- controlled studies" seems here to weaken somewhat.
NitroMed, has two patents on BiDil. The first covers use in the general population without regard to race. It expires in 2007. The second is race specific to Black patients. It does not expire until 2020. NitroMed therefore had a powerful financial incentive to obtain race- specific approval. The FDA's consent to a race-specific trial facilitated this goal.[ Kahn J. How a Drug Becomes "˜ethnic': law, commerce, and the production of racial categories in medicine. Yale J. Health Policy Law Ethics. 2004; 4:1-46. [PMID: 1052858]
Temple and Stockbridge also assert the difficulty of constructing a "reasonably powered study in white patients," which they estimate would "require about 16,000 patients." But this simply carries forward the fallacy of the relevance of race to assessing BiDil's efficacy. Far more relevant would be to calculate the numbers needed for a reasonably powered study in patients with relevant biological characteristics "“ such as non- ischemic vs. ischemic heart failure, or diabetes, or even, as one of the doctors on the FDA Advisory Panel noted, a history of alcohol abuse.[fn: Proceedings of the U.S. Food and Drug Administration Center for Drug Evaluation and Research Cardiovascular and Renal Drugs Advisory Committee [transcript]. 16 June 2005. Rockville, MD: U.S. Food and Drug Administration; 2005. Accessed at http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4183T1.pdf on 4 January 2007.]
Finally, the authors mischaracterize my arguments about when it is appropriate to use racial categories in biomedical research or regulatory approval. It is precisely because I found insufficient evidence of BiDil's race-specific efficacy that I, like representatives from the Association of Black Cardiologists and the International Society for Hypertension in Blacks, urged approval of BiDil without a race-specific indication.
The author testified at the FDA Advisory Committee Hearing on BiDil and urged it be approved without a race-specific label.
University of California, San Francisco
January 16, 2007
Bibbins-Domingo and Fernandez response to the FDA's perspective
We are surprised that the Food and Drug Administration's (FDA) defense of their position to approve BiDil for blacks with heart failure (1) extended beyond the evidence that this combination pill works in blacks to the assertion that this therapy does not work in whites. While the efficacy of the hydralazine/isosorbide dinitrate combination in blacks is clearly established given the results of the A-Heft trial, the lack of efficacy in whites is not. The FDA's contention is based on post-hoc subgroup analyses of two older, smaller trials that only studied this combination as primary treatment for heart failure and do not address the contemporary question of whether hydralazine/isosorbide dinitrate is effective as an adjunct to standard therapy in patients with refractory disease. In general, post-hoc subgroup analyses should be interpreted with caution and used primarily for generating hypotheses,(2) not for determining policy as appears to be the case here. The FDA position is not consistent with the AHA/ACC guidelines for this use of these medications (that have noted the particular benefit of this combination for black patients but have continued to list these medications as adjunctive therapies for all patients with refractory heart failure),(3) or even statements by the maker of BiDil and A-Heft researchers that BiDil is likely to be effective in whites and other groups.(4, 5)
Had the FDA felt that approval of these two generic medications in a single combination pill was warranted, the approval should have been granted for the general indication of treating patients with severe heart failure. Choosing instead to restrict the use to black patients does not make this medication more accessible to this target population (an apparent goal outlined in the FDA analysis);(1) certainly the cost implications that we describe in our critique (6) would argue that this therapy is now less accessible to many blacks with refractory heart failure. In addition, the FDA decision certainly makes this therapy less available to other racial groups and creates confusion for physicians treating a diverse population of patients. Imagine the physician faced with a hypertensive Asian patient with heart failure and refractory symptoms despite standard therapy. As a result of the FDA decision, use of the fixed hydralazine/isosorbide dinitrate combination in this patient is now "off-label" (and likely to pose issues for insurance reimbursement). Some might argue that this is appropriate, as this fixed combination has not been studied in Asians. However, it is difficult to accept that we know less about the efficacy of hydralazine/isosorbide dinitrate in this Asian patient (because its approval was based on a study exclusively in blacks) than we do about the efficacy of virtually every other medication that this patient might also be taking (that were likely approved based on studies performed mostly in whites). Had the FDA approved BiDil for general use, the valuable phase 4 observations that the FDA highlights in their discussion (1) would continue to inform the medical community about the appropriate use of these medications among the diverse patients we treat. With the restricted indication, these observations will no longer be forthcoming, and (for some) the question of efficacy of hydralazine/isosorbide dinitrate in non-Blacks will need to wait for future clinical trials.
We respect the FDA's interest in approving any therapeutic (including BiDil) that may benefit the 5 million Americans with heart failure, including blacks that develop this devastating illness at disproportionately high rates. However, we find the assertion that urgency to approve a combination formulation of two already widely available generic medications justifies a departure from the FDA's history of approving treatments of disease entities, not specific demographic groups, far less compelling. By restricting the indication for this therapy to a single race, the FDA decision distorts the clinical discussion on how we manage patients with refractory heart failure, the scientific discourse on how to appropriately study therapeutic efficacy in subgroups, and the larger political and societal debate on race and medicine.
1. Temple R, Stockbridge NL. BiDil for heart failure in black patients: The U.S. Food and Drug Administration perspective. Ann Intern Med. 2007;146(1):57-62.
2. Yusuf S, Wittes J, Probstfield J, Tyroler HA. Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials. Jama. 1991;266(1):93-8.
3. Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005;112(12):e154-235.
4. Paine J. A Cure for Race? washingtonpost.com 2004 November 16, 2004.
5. Saul S. U.S. to Review Heart Drug Intended for One Race. The New York Times 2005 June 13, 2005.
6. Bibbins-Domingo K, Fernandez A. BiDil for heart failure in black patients: implications of the U.S. Food and Drug Administration approval. Ann Intern Med. 2007;146(1):52-6.
Robert J Temple
Food and Drug Administration
February 16, 2007
Response to Letters
Critics of FDA's approval of BiDil for the treatment of heart failure in self-identified blacks have taken two positions: 1) Approval for blacks was premature; before approval there should have been further testing to discover what characteristics in blacks and whites might predict responses.1,2 2) FDA should have approved BiDil, but for the broader population.3 We note that Dr. Kahn, in his letter, says this is what he meant, not that there should have been no approval.
Our Annals paper focused on why delaying approval would have been intolerable, given the dramatic effect shown in the black population and the extreme difficulty of assessing effects further in whites or discovering clinical predictors of response. But approval for the black population alone was not based, as Bibbins-Domingo and Fernandez assert2, on the argument that BiDil's approval was urgently needed to address racial disparities in health. Approval for all patients would have accomplished that end equally well. We approved the drug for the black population because the evidence did not support broader approval, a conclusion also reached by 7 of 9 Cardio-Renal Advisory Members.
We are entirely aware of the risks of subset analysis and have regularly endorsed Yusuf's warnings about such analyses.4 But a replicated subset finding is not the same as a single subset finding and the findings in V-HeFT I and II quite powerfully in indicate a differential effect in blacks and whites. We clearly did not assert that the absence of an effect in whites has been proved, only that there is good evidence of a differential effect and that the effect in whites is far smaller if there is one. Bibbins-Domingo and Fernandez argue that the findings in V-HeFT II, essentially identical outcomes with enalapril and hydralazine-isosorbide dinitrate in blacks, could have reflected a poor response to enalapril (another racial difference in response?), but that hypothesis doesn't support their view. What was striking in V-HeFT II was the evidence of no effect of hydralazine-isosorbide dinitrate in whites, in whom the enalapril was known to work. Moreover, the possibility that the equal effect of the treatments in blacks represented no effect of either drug is thoroughly rebutted by A-HeFT. V-HeFT I, a placebo- controlled trial, also showed a strong difference in effect, with a nominally significant effect vs placebo in the black population, an effect similar in size to that seen in blacks in A-HeFT.
It is hard to follow the postulated adverse consequences of our approval alleged by Bibbins-Domingo and Fernandez. Whether physicians should try the combination in white patients is not for us to say. Certainly there is no legal bar to such off-label use and labeling does not contraindicate such use. Although it seems likely that some subset of the white population may prove to respond, in the absence of any evidence of this in studies that were able to detect drug effects in a responsive population, we don't believe labeling should recommend it.
Our threshold for making subset distinctions is high because of the potential for error, despite the current great interest in meaningful individualization of therapy. But errors can have two directions. When evidence of a difference is strong it seems irresponsible to dodge its implications. The LIFE study5 illustrates this. On the basis that study, losartan (which was superior overall to atenolol in reducing stroke), was given a specific labeling claim for reduction of stroke. Because the finding was reversed in blacks, with atenolol nominally significantly superior to losartan, labeling notes that "the LIFE study provides no evidence that the benefits of losartan apply to Black patients."
Dr. Kahn's letter focuses mainly on commercial matters not pertinent to regulatory approval, but he touches on two scientific issues. The bioequivalence concerns he notes are pertinent to approval of generic drugs but do not weaken the inferences that can be drawn from differential effects in whites and blacks seen in V-HeFT I and II. Dr. Kahn also proposes a "reasonably powered" study in patients with "relevant" biological characteristics such as non-ischemic vs ischemic heart failure, or diabetes, or alcohol abuse. It is hard to know what he has in mind but any study that sought to examine effects in many subgroups of this heart failure population, where we have no idea at all as to which are relevant (and Kahn left out hypertension and cardiomyopathy as causes) would be simply vast, and would be utterly unappealing to a sponsor, absent some plausible hypothesis. Indeed what he is proposing poses the very problem Bibbins-Domingo and Fernandez are concerned about.
1. Avorn J. FDA standards - good enough for government work? N Engl J Med 2005; 353:967-972.
2. Kahn J. 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: 1-46.
3. Bibbins-Domingo K, Fernandez A. BiDil for heart failure in black patients: implications of the US Food and Drug Administration approval. Ann Int Med 2007; 52-56.
4. Yusuf S, Wittee J, Probsfield J, Tyrolar HA. Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials. JAMA 1991; 266:93-98.
5. Dahlof B, Deveraux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint Reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet 2002; 359: 995-1003.
Temple R, Stockbridge NL. BiDil for Heart Failure in Black Patients: The U.S. Food and Drug Administration Perspective. Ann Intern Med. 2007;146:57–62. doi: https://doi.org/10.7326/0003-4819-146-1-200701020-00010
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Published: Ann Intern Med. 2007;146(1):57-62.
Cardiology, Heart Failure.
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