BilDil: Discrepancies and Contradictions

The BilDil saga has now gotten complex enough to merit comment on Health Care Renewal.
For some commentary on the background, see the Perspectives article in the recent New England Journal of Medicine (Bloche MG. Race-based therapeutics. N Engl J Med 2004; 351: 20). The first major study to show the benefits of what was then called vasodilator therapy was the VHeFT study, published in 1986. (Cohn JN et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. N Engl J Med 1986; 314: 1547). This study showed that the combination of the isosorbide dinitrate, a long-acting nitrate used to treat the symptoms of coronary artery disease, and hydralazine, a vasodilator used to treat hypertension, prolonged average survival in a group of patients with congestive heart failure. A later study, however, showed that an angiotensin converting enzyme (ACE) inhibitor drug, was superior in prolonging survival in a population of patients that included about 27% black patients. (Cohn JN et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of congestive heart failure. N Engl J Med 1991; 325: 303). The combination of hydralazine - isosorbide dinitrate then fell out of favor except for patients who could not tolerate ACE inhibitors.
As Bloche discussed, based on a theory that hydralazine - isosorbide dinitrate might work better in African-Amercian patients, a "biotechnology" firm called NitroMed obtained intellectual property rights to a fixed combination of these two by now quite old (and easily available generically) drugs in 1996. In 1999, the company obtained additional intellectual property rights to this fixed combination as a treatment for heart failure for African-Americans. Last year, a trial funded by the company, which recruited only patients who self-identified as "black," showed that the fixed combination of the two old drugs was superior to placebo in prolonging survival for patients already taking the current conventional therapy for heart failure (that now usually includes an ACE inhibitor or an angiotensin receptor blocker [ARB]). (Taylor AL et al. Combindation of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004; 351: 2049).
Most recently, the New York Times reported that NitroMed has set the price of BilDil, the fixed combination of 37.5 mg of hydralazine and 20 mg of isosorbide dinitrate, at $1.80 per pill. Most patients would take one or two pills three times a day, for a daily cost of $5.40 to $10.80. In contrast, similar treatment with generic hydralazine and generic isosorbide dinitrate would cost approximately $1.50 to $3.00 a day.
Finally, Newsday noted that the official label for BilDil does not carry as major a warning about the risks of developing systemic lupus erthymatosus as does the label for generic hydralazine. Development of lupus has been a well-known possible adverse effect of hydralazine since before I went to medical school. The label for generic hydralazine suggests testing patients on the drug for lupus every six months, but the label for BilDil makes no such suggestion.
So here are the discrepancies and contradictions that this all brings up:

• NitroMed patented a new "drug" BilDil, but it was simply a combination of two old drugs that were long off patent. NitroMed touts its "nitric oxide technology" on its web-site, but again, at the moment this only seems to consist of a fixed combination of two drugs from 30+ years ago.
• NitroMed got the US Food and Drug Administration (FDA) to approve a trial limited to only a single racial/ethnic group, but the US National Institutes of Health (NIH) has for years required clinical trials to include a broad selection of under-represented minorities (i.e., groups other than African-Americans), and prohibited exclusion of such groups unless there is a clear reason to do so. (See the policy here.) If NitroMed had included patients who were diverse in terms of race/ ethnicity, it might have been possible to see if hydralazine - isosorbide dinitrate actually works differently in patients with differing race/ ethnicities. But allowing only "black" patients in the trial prevented drawing any conclusions about whether the drug would work better, similarly, or not as well in, for example, Asian-Americans, Latinos, American Indians, and whites. Bloche suggestion that "market and regulatory incentives shape research agendas" seems relevant here.
• NitroMed is marketing its brand-name fixed combination drug for $1.80/pill, but a cheaper generic equivalent (requiring, admittedly, the patient to take twice as many pills, but no more often a day) costs less than $0.50. The New York Times article noted that "NitroMed has aggressively solicited the support of black physicians and politicians in promoting BilDil."
• The FDA suggests patients taking generic hydralazine should be tested periodically for lupus, but does not suggest those taking BilDil (which contains hydralazine) should be so tested.

In summary, this seems to be a story of how "market and regulatory incentives," and perhaps also some political incentives, may shape research and clinical care in confusing and contradictory ways, maybe not always in ways that primarily benefit patients of all races.