Recently, I joined the editorial board of Circulation: Cardiovascular Quality and Outcomes, the American Heart Association journal that focuses on quality of care and outcomes research. As my readers know, I became interested in cardiovascular disease because my daughter has heterozygous familial hypercholesterolemia, a genetic disease that cause high LDL-cholesterol and can lead to premature heart disease. I wrote this perspective for the November issue on how engaged patients can help bring about positive change in health care.
SPM will be hosting a tweetchat on the 2nd and 4th Saturdays of the month. The second tweetchat will be Saturday, Sept. 28 from the floor of Stanford Medicine X, where a number of SPM members will be in attendance.
The first chat on 9/14 will focus on:
- What is participatory medicine?
- How has peer-to-peer healthcare impacted you?
Anyone interested in healthcare is invited to join in.
Go to tchat.io and plug in the hashtag #s4pm at 3pm Eastern this coming Saturday.
H/T Ileana Balcu
Addendum 9/14/13: The transcript of the 9/14 tweetchat is available here.
Last week, the American College of Cardiology announced that it had named Shalom Jacobovitz as its CEO. Since 2004, Jacobovitz has served as president of Actelion Pharmaceuticals U.S., Inc., the U.S. subsidiary of Swiss pharmaceutical company Actelion Pharmaceuticals Ltd. Prior to that, Jacobovitz held positions at F. Hoffman La Roche, Abbott Canada, Nordic Labs and Marion Merrill Dow (now known as Aventis), according to the ACC press release.
A little background on Actelion. The company has several approved drugs but 90% of its revenue comes from its drug for pulmonary arterial hypertension (PAH), Tracleer (bosentan). Tracleer’s patent will expire in a few years, so the company will need a replacement drug to avoid a drastic decrease in revenues when generic versions of Tracleer become available. The company has a drug in development for PAH and other indications called macitentan. In April 2012, the company announced that the phase III trial for macitentan in PAH met its primary endpoint. In the fourth quarter of 2012, the company filed applications with the FDA and EMA requesting approval for macitentan for the PAH indication. The trial, called SERAPHIN, has not been published but the results were presented at a conference and an abstract was published in CHEST.
I did a little googling to find out more about Actelion. One of the first things I found was this 2010 FDA warning letter. The letter, addressed to Jean-Paul Clozel, M.D., CEO of Actelion Pharmaceuticals U.S., Inc. (Shalom Jacobovitz is cc’d), states that the company had failed to comply with Postmarketing Adverse Drug Experience reporting requirements relating to Tracleer and two other Actelion drugs.
The Food and Drug Administration (FDA or “Agency”) inspected Actelion Pharmaceuticals’ (Actelion’s) facility located at the above address from June 24 through July 20, 2009. The inspection focused on Actelion’s compliance with Postmarketing Adverse Drug Experience (PADE) reporting requirements relating to the following drug products: Tracleer® (bosentan), NDA 21-290; Ventavis® (iloprost), NDA 21-799; and Zavesca® (miglustat), NDA 21-348. Both Tracleer® and Ventavis® are indicated for the treatment of forms of pulmonary arterial hypertension. Zavesca is indicated for the treatment of adult patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option. FDA’s inspection found that your firm failed to comply with the postmarketing reporting requirements imposed under 21 U.S.C. § 355(k) [Section 505(k) of the Federal Food, Drug, and Cosmetic Act (the Act)] and its corresponding regulations in Title 21 of the Code of Federal Regulations (21 C.F.R.) Section 314.80. Such failure to comply with Section 505(k) of the Act and its corresponding regulations is a prohibited act under Section 301(e) of the Act [21 U.S.C. § 331(e)]. Therefore, FDA concludes that Actelion has engaged in prohibited acts in violation of Section 301(e) of the Act.
The Agency is in receipt of your responses dated August 28, 2009, and September 11, 2009. It has been determined that the corrective actions you proposed are inadequate.
Actelion’s deviations from FDA’s reporting requirements observed during the inspection include, but are not limited to, the following: Failure to develop adequate written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse drug experiences to FDA under 21 C.F.R § 314.80, and failure to report adverse drug experience information to FDA under 21 C.F.R. § 314.80, each of which is discussed, in turn, below. These deviations resulted in Actelion’s failure to report approximately 3,500 patient deaths reported to Actelion in connection with Tracleer® and Ventavis®, without an adequate basis for not reporting them. (emphasis added)
To be clear, the FDA is not saying that it has concluded that Actelion’s drugs caused these unreported deaths, but rather that Actelion failed to report these deaths without an adequate basis for not reporting them. The letter goes on to state that Actelion’s procedures for reporting postmarketing adverse drug experiences are in violation of the relevant FDA regulations in that they do not require reporting of death reports to FDA where there is a reasonable possibility that the drug caused the death. Without getting into all the details, the letter demolishes each of Actelion’s reasons for continuing to not report the deaths. The letter also requests a meeting with senior management to discuss the development of adequate procedures. There is also a link to a “close-out letter” dated June 13, 2012, in which the agency informs Actelion that it has evaluated Actelion’s corrective actions and determined that they are adequate.
To sum up the chain of events, the FDA inspected Actelion in 2009 and found inadequate procedures and failure to report patient deaths that were required to be reported. Actelion responded with various creative interpretations and rationalizations for why it shouldn’t have to change its way of doing things. FDA responded with a warning letter demolishing Actelion’s reasons for noncompliance and told them to comply or else. FDA then apparently met with senior management to walk them through basic regulatory requirements that they should have already been aware of. Two years later, FDA was finally able to conclude that Actelion was in compliance with its responsibilities. To be honest, I’m not impressed with Actelion’s performance here.
On to my next Google find. Not hard to find, actually, as it was recently discussed in the New York Times, on the Pharmalot blog, and on the FDA Law Blog here, here and here. The facts are that certain generic companies attempted to purchase samples of Tracleer and Zavesca (miglustat) from Actelion for the purpose of conducting bioequivalence studies in preparation for filing an application for FDA approval of generic versions of the drugs. Actelion refused to sell samples of the drugs to the generic companies and in September 2012 filed suit against the generic companies seeking declaratory relief that it is not required to sell them the samples. Tracleer was approved with a Risk Evaluation and Mitigation Strategies (REMS) program that limits distribution of the drug. Actelion argues that selling the samples to the generic companies would be inconsistent with the Tracleer REMS and certain distribution restrictions it has placed on Zavesca and that, in addition, it is not required to do business with anyone it doesn’t want to do business with. The generic companies argue that Actelion’s conduct violates antitrust laws. In an Amicus Brief, summarized here, the Federal Trade Commission supports the position of the generic companies, pointing out that Congress included language in the statute clarifying that REMS provisions may not be used to impede generic competition. The applicable statutory language states that no holder of a REMS-covered drug shall use an aspect of the REMS to “block or delay approval” of a generic drug application. The FTC explains that “If successful, conduct of the type alleged in this case threatens to undermine the careful balance created by the Hatch-Waxman Act and potentially preserve a brand firm’s monopoly indefinitely.” The FTC also supports the generic companies on the antitrust issues.
My next Google find on Actelion: several years ago, Actelion purchased CoTherix CoTherix had a preexisting contract with Asahi Kasei Pharma Corporation to develop and market Asahi’s drug fasudit for PAH and stable angina. Fasudil would most likely have been sold at a lower price than Tracleer, undermining Tracleer sales. In connection with the acquisition, Actelion frustrated contractual “change of control” provisions designed to assure continued fasudil development. After the acquisition closed, Actelion informed Asahi that it was no longer interested in developing and marketing fasudil. Asahi sued, asserting that the reason Actelion purchased CoTherix was to eliminate a potential competitor drug. A key document came to light during discovery — handwritten notes by an Actelion executive saying “buying both companies will leave the market for Tracleer free for Actelion.” Asahi won a large judgment against Actelion.
In 2010, Actelion disclosed that its U.S. subsidiary had received a subpoena from the U.S. Attorney’s Office for the Northern District of California “requesting documents relating, among others, to marketing and sales practices of Tracleer® in the United States.” I don’t know the status of this investigation. However, Jean-Pierre Garnier, former CEO of GlaxoSmithKline, is currently chairman of the board of Actelion. Garnier was singled out by DOJ for promoting GSK’s drug Advair for unapproved uses.
All of the above lead me to believe that Actelion is a very aggressive company, one that pushes the boundaries on what is permitted under the law.
Professional medical associations such as the ACC are under intense scrutiny with respect to their relationships with industry and conflicts of interest. The ACC has extensive ties to industry, with approximately 25% of its total consolidated revenues coming from industry. What message is the ACC sending by choosing someone with this kind of background? Perhaps that the ACC wants to become even cozier with industry? In my opinion, the ACC board of trustees should have looked elsewhere for their CEO.
Cardiologist Westby Fisher weighs in here.
Addendum 1/16/2014: Actelion announced that the Department of Justice declined to intervene in the qui tam action relating to the marketing of Tracleer. The qui tam plaintiffs voluntarily requested dismissal.
In an impassioned editorial, BMJ editor Fiona Godlee calls on the pharmaceutical industry to release clinical trial data on all approved drugs, and on medical journals to publish industry-funded trials only when there is a commitment to make patient-level data available on reasonable request. She states that the BMJ will require this commitment for all clinical trials of drugs and devices, whether industry-funded or not, beginning in January 2013. In addition, BMJ is publishing online all correspondence between Roche and the Cochrane Collaboration researchers regarding the oseltamivir (Tamiflu) data. More on the battle for Tamiflu data here.
Addendum 11/2/2012: read Pharmalot’s coverage here.
Roche promised in 2009 to release full reports from clinical trials of oseltamivir in response to an investigation by the BMJ and the Cochrane Collaboration. In this open letter to John Bell, regius professor of medicine at Oxford University and a Roche board member, the BMJ’s editor in chief further urges the company to disclose the full data.
Read the full letter here.
Here is a video of Ben Goldacre speaking at the Strata Conference in London earlier this month (H/T Chris Southan).
I also recommend his book, Bad Pharma: How drug companies mislead doctors and harm patients, which goes into detail on how missing data and publication bias distort the medical literature and harm patients.
Johns Hopkins is launching a new Center for Drug Safety and Effectiveness. Via G. Caleb
On Wednesday, October 24, we will launch the Johns Hopkins Center for Drug Safety and Effectiveness, a collaborative effort of the Bloomberg School of Public Health and Johns Hopkins Medicine. The Center will fulfill its mission by supporting individuals engaged in research, training, clinical programs and public service to optimize the safe and effective use of prescription medicines in the United States and around the world.
We are delighted that Dr. Mark McClellan will deliver the inaugural lecture for the Center on October 24 at 4:00 PM, with a reception to follow.
In March of this year, Larry Husten reported on CardioBrief that a review article in the Korean Circulation Journal by Chang Gyu Park and Ju Young Lee appeared to plagiarize from a review article in the Journal of the American College of Cardiology by Franz Messerli and Gurusher Panjrath. In April, Husten reported that the article was being investigated by the publishing committee of the Korean Society of Cardiology and Korean Association of Medical Journal Editors. It has just come to my attention that the KCJ article has been retracted. Here is the notice:
On July 31, 2011, Korean Circulation Journal (KCJ) published a review article by Park et al. regarding the J-curve in hypertension and coronary artery diseases. However, a possibility of plagiarism has been raised in this article.
The Editorial Board of KCJ has examined the review article and has requested the Committee for Publication Ethics of Korean Association of Medical Journal Editors (KAMJE) to provide an adequate conclusion. After thorough investigation, the Committee for Publication Ethics of KAMJE and the Editorial Board of KCJ have concluded that the article is seriously plagiarizing from an article by Messeri (sic) et al.
In this regard, on May 8, 2012, the Executive Committee of the Korean Society of Cardiology has finally decided to retract the article completely. We apologize for any inconvenience this may have caused.
For the past several years I have been following the ezetimibe controversy (see these posts on Gooznews and this blog here, here, here, here, here, here, here, here, here, here, here, here, here, here, and here). In my view, we continue to lack evidence of ezetimibe’s clinical benefit, or even safety, 10 years after FDA approval.
I have a Google Scholar Alert for ezetimibe, so often links to articles on ezetimibe arrive in my email inbox. Recently, two review articles on ezetimibe were published that were a study in contrasts. The first, by Sheila Doggrell, takes a skeptical view toward ezetimibe and reaches the following conclusion:
The comparison of clinical trials with simvastatin and ezetimibe alone and together has clearly shown that simvastatin decreases LDL-cholesterol and this is associated with improved clinical outcomes. Also, ezetimibe alone or in the presence of simvastatin lowers LDL-cholesterol. However, ezetimibe alone or in the presence of simvastatin has not been shown to have any irrefutable beneficial effects on clinical outcomes. Thus, until/unless the use of ezetimibe is clearly shown to improve clinical outcomes, its use should be largely restricted to clinical trials investigating clinical outcomes, and ezetimibe should not be used routinely in everyday practice.
The second, by Binh An Phan, Thomas Dayspring and Peter Toth, takes a much more optimistic view:
In the current treatment of cardiovascular disease, many subjects fail to reach LDL-C targets or remain at high risk for CHD events despite optimal statin and medical therapy. Ezetimibe inhibits intestinal cholesterol absorption and is effective in lowering cholesterol as monotherapy or in combination with statins in several populations, including those with FH, sitosterolemia, and insulin resistance. Significant controversy has been generated regarding the clinical effectiveness of ezetimibe, particularly after the publication of ENHANCE and ARBITER-6 despite both trials having significant methodological flaws that limited their ability to evaluate the benefit of ezetimibe. Growing data suggest that ezetimibe in combination with statin has a positive effect on the progression of atherosclerosis and reduces cardiovascular events in subjects at risk for CHD, including those with chronic kidney disease. Results from IMPROVE-IT are forthcoming and may help to guide better the use of ezetimibe in very high-risk CHD populations. Until that time and based upon the current available data, ezetimibe should remain a viable adjunct to statin therapy in the treatment of hypercholesterolemia.
Dr. Phan and colleagues find reasons to dismiss the negative results of ENHANCE and ARBITER 6-HALTS as due to “methodological flaws” and use copious amounts of hand-waving to find support for ezetimibe in the SEAS and SHARP trials, even though those trials compared the combination of simvastatin and ezetimibe with placebo and thus can tell us nothing about what, if anything, ezetimibe added to those results. Could the differing views of Doggrell and Phan et al. have anything to do with the fact that Dr. Doggrell declares no conflicts of interest relating to ezetimibe, while Phan, Dayspring and Toth declare the following conflicts:
Binh An Phan is a speaker for Abbott. Thomas Dayspring consults for Abbott, GSK, Health Diagnostic Labs, Kowa Company, Eli Lilly, Merck, Genentech, The Roche Group, Genzyme, and Omthera. He is on the Lecture Bureau for Abbott, GSK, Health Diagnostic Labs, Kowa, Eli Lilly, LipoScience, Merck. Peter P Toth is a speaker for Abbott, AstraZeneca, Amylin, Boehringer-Ingelheim, GSK, Kowa, Merck and consults for Abbott, Aegerion, AstraZeneca, Atherotech, Genzyme, Genentech, Kowa, and Merck.
It is not too surprising that authors who are consultants and on the speaker’s bureau for Merck would take a favorable view of ezetimibe. What is surprising is that anyone would take their word for it.
Doggrell SA. The ezetimibe controversy — can this be resolved by comparing the clinical trials with simvastatin and ezetimibe alone and together? Expert Opin. Pharmacother. (2012) 13(10):1469-1480.
Phan BAP, et al. Ezetimibe therapy: mechanism of action and clinical update. Vascular Health and Risk Management 2012:8:415-427.