An early impetus for us to start Health Care Renewal in 2004 was our perception that the integrity of clinical research was under threat. In particular, we noted increasing number of cases in which commercial marketing concerns seemed to result in the manipulation of clinical research to enhance the apparent attractiveness of specific products, usually drugs or devices. When such manipulation failed to make products look good, research could be simply suppressed.
My personal introduction to health care dysfunction was the case of my own supervisor and friend, Dr David G Kern, who ultimately lost his academic position because he refused to go along with the suppression of research he had done on a new occupational disease, research that offended the company at whose site the disease occurred (look here).
Per the tenets of evidence-based medicine, health care professionals and patients should rely on the results of the best clinical research, sceptically appraised, to make clinical decisions. Suppressed or manipulated research could lead to bad decisions, hence patients failing to get the best tests and treatments, or getting unncessary or dangerous tests and treatments, and ultimately harming patients.
Since then, research manipulation and particularly suppression have become well known issues. For example, the international AllTrials campaign aims to prevent suppression of randomized controlled trials. Since these issues are now widely discussed, Health Care Renewal has not posted so much about them recently.
But suddenly it apprears that research suppression is again a national issue for the US. Dr Tom Price, just nominated by the Trump administration to be the US Secretary of Health and Human Services, the highest government health policy position, has been accused of involvement in an effort to suppress dissemination of clinical research at the behest of a campaign donor.
Background - Bildil
Back in 2005, we posted about the strange story of the promotion of Bildil. Briefly, Bildil is a fixed combination of two very old vasodilator anti-hypertensive drugs, hydralazine and disosorbide dinitrate. Back in the 1980s, these two drugs were shown to prolong life for patients with congestive heart failure (CHF) and systolic dysfunction. In 1991, another class of drugs, angiotensin converting enzyme (ACE) inhibitors (or ACEIs) were shown to better prolong life than hydralazine - isosorbide dinitrate.
In 2004, a company called Nitromed sponsored a trial of Bildil.(1) It recruited only patients who self-identified as "black," and 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]).
There were some issues with that trial, as we noted in 2005, 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.
Dr Tom Price, Arbor Pharmaceuticals, and the Attempted Supression of Dissemination of Clinical Research
Since then, Bildil has not sold well. As ProPublica reported
The $3 pill [now] known as BiDil was already a difficult sell when a Georgia-based pharmaceutical company bought the marketing rights a few years ago. A treatment for African Americans suffering from heart failure, BiDil had never really caught on, forcing the drug company that developed it to take a buyout offer.
The issue was a study done in 2009.
The study led by Karl Hammermeister, a cardiology professor at the University of Colorado School of Medicine, and originally published in the journal Clinical Therapeutics in 2009, found that BilDil was not actually associated with a significant reduction in death or 2009 hospitalization.(2) The study found that in all but one of its test groups the drug was associated with significantly increased risk of hospitalization for heart failure.
The drug's new manufacturers had new ideas about marketing it.
So last summer, the new owner of the drug, Arbor Pharmaceuticals LLC of Atlanta, sought to get the study taken down from a government website. For help, the company turned to the office of a congressman to whom the CEO had given the maximum $2,700 campaign donation — Rep. Tom Price, the Georgia Republican nominated by Donald Trump to become head of the Department of Health and Human Services.In particular,
Over the next few months, one of Price’s aides emailed the federal Agency for Healthcare Research and Quality at least half a dozen times, asking at one point 'what seems to be the hold up' in getting the [2009 Hammermeister] study removed from the website, which aims to help patients, health care providers and policy makers make 'better treatment choices.' In the end, the agency, which is part of the Department of Health and Human Services, kept the study online but added a note: 'This report is greater than 5 years old. Findings may be used for research purposes but should not be considered current.'
Gary Beck, a policy assistant to the congressman, first reached out to the federal research agency about the study in July, emails show. 'I have been in contact with representatives from Arbor Pharmaceuticals based in Georgia in regard to some issues they have with the study that is linked below,' he wrote, adding that the company told him 'the study might be outdated' and they wanted it removed from the website.
'I wanted to get in touch with you to get a better grasp on the situation and what seems to be the hold up,' Price’s aide wrote.
Francis Chesley, an official at the agency, responded to Beck, saying he would check into the matter. Three days later, Beck followed up again. Chesley told him the agency was examining its website archiving policy to ensure the public had access to up-to-date information, and offered to talk to the pharmaceutical company directly.
Beck then pressed him: 'Is it in the opinion of the Center for Evidence and Practice Improvement,' he wrote, referring to the division doing the review, 'that the BiDil study could be determined as out-of-date once the examination is completed?'
Beck sent four more emails over the next four months. In November, seemingly exasperated by the fact that the study was still online, he asked: 'Would someone else at AHRQ be able to provide me with an update to this situation?'
There was a big problem with this. While the 2009 study is no longer new, it cannot be considered outdated, because it has not been superseded by new evidence.
Since 2009, there seems to have been little original research done on hydralazine - isosorbide dinitrate for CHF. A 2013 Cochrane Collaboration systematic review (3) concluded there was no clear evidence that this combination was superior to other drugs for CHF. A study done using a clinical registry (not a randomized controlled trial) published in 2016 also showed no advantage from the combination, particularly for black patients.(4)
Furthermore, ProPublica quoted
Jonathan Kahn, a professor at the Mitchell Hamline School of Law in Minnesota who wrote a 2013 book about BiDil’s fraught history, has been a critic of marketing BiDil as a race-specific drug, arguing it was pitched as such for legal and commercial reasons, not to improve patient outcomes. He said he hasn’t independently assessed the 2009 study posted by the federal agency, but added in an email, 'there is NO WAY this study is outdated. It is much more recent than the studies underlying the approval of BiDil itself.'
Nonetheless, Arbor Pharmaceuticals persisted in its efforts to get Rep Price's office to suppress the AHRQ's dissemination of the apparently still relevant results of the 2009 study, and Dr Price appeared to gladly cooperate.
Dr Tom Price, was once a practicing orthopedic surgeon, now is a US congressman with important health care policy responsibilities, and the current nominee to be US Secretary of Health and Services, the highest health care policy position in the US government. Now there are credible allegations that Dr Price, as a congressman, aided a pharmaceutical company owned by a campaign donor in the company's attempt to suppress relevant information from clinical research on the company's product because that information questioned the product's usefulness.
We recently discussed some of Dr Price's other apparent conflicts of interest, involving his ownership of health care related stocks. It appears that Dr Price had another conflict of interest, in that he was taking campaign money from a pharmaceutical company while he had responsibilities as a legislator in the health policy arena.
ProPublica also noted,
Last month, The Wall Street Journal reported that Price had traded more than $300,000 in shares in health-related companies as he played a role in legislation that could have affected their share prices.
Last week, Kaiser Health News reported that Price was given a “sweetheart” deal to invest in an Australian biotech company — a stake that has since showed a 400 percent gain. That company could benefit from the 21st Century Cures legislation Price supported. And this week, CNN reported that Price invested in Zimmer Biomet before introducing a bill that could have helped the medical device manufacturer. The company’s political action committee then donated $1,000 to Price’s campaign.
And now appears that Dr Price also had a role in trying to suppress dissemination of potentially useful clinical research based not on considerations of patient benefit, but based on commercial concerns of a pharmaceutical company. Such research suppression could have led patients to get BiDil when better treatments are available, potentially denying them the best possible outcomes.
This suggests that Dr Price abused his entrusted power (to be part of a government of the people, by the people, and for the people) for private gain. This appears to be corruption, at least in an ethical if not a legal sense, using the Transparency International definition (corruption is abuse of entrusted power for private gain).
Dr Price's conflicts of interest are disturbing. His attempts to suppress dissemination of clinical research are more disturbing. That he is now the nominee to be the Secretary of Health and Human Services is even more disturbing.
Our new US President famously declared his intention to "drain the swamp" in Washington DC. What would be the point if he then plans to refill it, and stock it with new swamp dwellers?
1. Taylor AL et al. Combindation of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004; 351: 2049 -
2. Hammermeister KE et al. Effectiveness of hydralazine/isosorbide dinitrate in racial/ethnic subgroups with heart failure. Clin Ther. 2009 Mar;31(3):632-43. doi: 10.1016/j.clinthera.2009.03.019. Link here.
3. Wakai A et al. Nitrates for acute heart failure syndromes. Cochrane Database Syst Rev. 2013 Aug 6;(8):CD005151. doi: 10.1002/14651858.CD005151.pub2. Link here.
4. Khazani P et al. Clinical Effectiveness of Hydralazine-Isosorbide Dinitrate Therapy in Patients With Heart Failure and Reduced Ejection Fraction: Findings From the Get With The Guidelines-Heart Failure Registry. Circ Heart Fail. 2016 Feb;9(2):e002444. doi: 10.1161/CIRCHEARTFAILURE.115.002444. Link here.