Category Archives: conflicts of interest
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.
Section 6002 of the Patient Protection and Affordable Care Act requires disclosure of payments by the drug and device industry to physicians and teaching hospitals. On December 14, 2011, the Centers for Medicare and Medicaid Services proposed regulations that would implement these “sunshine” provisions. See this Pharmalot post for background. I also recommend this commentary by Robert Steinbrook and Joseph Ross. The comment period closed on February 17, and I submitted a comment, excerpted below. You can access the proposed regulations and comments by going to www.regulations.gov and searching on “CMS-5060-P.”
Re: Transparency Reports and Reporting of Physician Ownership or Investment Interests; CMS-5060-P
Dear Ms. Tavenner:
I am writing to support the adoption of the above-referenced proposed rules implementing section 6002 of the Patient Protection and Affordable Care Act of 2010 (PPACA). As you know, this section of the PPACA requires drug, device, biological, or medical supply manufacturers to report certain payments and transfers of value to covered recipients, entities, individuals and teaching hospitals. The reported information would be available on a public website.
I believe the rules should be adopted substantially as proposed. In particular, I believe it is essential for the rules to require disclosure of both direct and indirect payments. Indirect payments include those a company makes to a third party, such as a medical society, contract research organization, or medical education and communication company, but that are ultimately intended for a physician or other covered recipient. The reporting of indirect payments is essential to meet the goals of transparency and completeness and to prevent the institution or continuation of arrangements that impede full disclosure of the financial relationships between industry and the medical profession.
In addition, I urge you to give careful consideration to the design of the proposed website. It should be designed to make possible it easy for members of the general public to find all payments to a particular provider or entity in one search regardless multiple addresses or variations in names (e.g., with or without a middle initial). I urge CMS to provide an opportunity for public discussion and comment on the proposed website design, such as through a public forum and/or focus groups.
Finally, I urge CMS to provide greater detail on specific enforcement mechanisms to ensure that manufacturers comply promptly and completely with the reporting requirements.
Thank you for the opportunity to comment on this important proposed regulation.