The biotechnology giant Amgen marketed its anemia drug Aranesp for unapproved uses even after the Food and Drug Administration explicitly ruled them out, federal prosecutors said on Tuesday.The federal charges were made public as Amgen pleaded guilty to illegally marketing the drug and agreed to pay $762 million in criminal penalties and settlements of whistle-blower lawsuits.Amgen was 'pursuing profits at the risk of patient safety' Marshall L. Miller, acting United States attorney in Brooklyn, said in a telephone news briefing on Tuesday.David J. Scott, Amgen’s general counsel, entered the guilty plea at the United States District Court in Brooklyn to a single misdemeanor count of misbranding the drug, Aranesp, meaning selling it for uses not approved by the F.D.A.Amgen agreed to pay $136 million in criminal fines and forfeit $14 million, with about $612 million going to settle civil litigation.
The article noted the key charge against Amgen,
In court on Tuesday, prosecutors charged that Amgen had promoted the use of Aranesp to treat anemia in cancer patients who were not undergoing chemotherapy, even though the drug’s approval was only for patients receiving chemotherapy.A subsequent study sponsored by Amgen showed that use of Aranesp by those nonchemotherapy cancer patients had actually increased the risk of death, and the off-label use diminished.
The federal charges also say Amgen promoted using larger but less frequent injection of Aranesp than stated in the label as a way of making the drug more attractive to doctors and patients than Procrit, a rival anemia drug from Johnson & Johnson.
As is typical of such cases, the prosecutors could not figure out how to charge any individuals who might have authorized, directed, or implemented the bad behavior,
Mr. Miller said that the evidence in the Amgen case was not sufficient to charge individuals. However, he said, Amgen agreed to sign a corporate integrity agreement that requires executives and board members to personally certify compliance with regulations. That would make it easier to prosecute individuals should violations occur again, he said.
The Charges in Context
In some reports of the settlement, the issue appeared to be money. For example, Pharmalot reported that after a whistle-blower filed suit against Amgen, "a subsequent investigation by the Justice Department found that these practices induced physicians to use Amgen medications unnecessarily when lower cost alternatives were available."
However, Amgen's practices could have had much worse effects than just removing money from the US Treasury.
Consider the context. Only a few of the not very numerous articles in the media on this case noted that the key complaint was that Amgen was pushing use of Aranesp for patients with cancer, specifically those not receiving chemotherapy. (Reuters made this explicit, for example, but not so the Los Angeles Times, or Bloomberg's initial coverage.)
In fact, there has been concern about the adverse effects of Aranesp for patients with cancer for a while. In 2007, Khuri noted in a commentary in the New England Journal of Medicine(1) that "concern about a detrimental effect of ESAs [erythropoiesis stimulating agents, a class of drugs of which Aranesp is a prominent member] in patients with cancer arose" after results of a small clinical trial of epoetin beta in patients with oral, pharyngeal or laryngeal cancer receiving radiation therapy showed worse survival in patients receiving that drug. Subsequently, in 2008, a meta-analysis of multiple randomized clinical trials showed that patients with cancer receiving ESAs, including Aranesp, had an increased risk of venous thromboembolism (drug clots) and death.(2) In 2009, another meta-analysis showed that ESAs lead to decreased survival in patients with cancer.(3)
Recall, though, that Aranesp is meant to improve anemia. It was not meant to cure cancer, or even put the disease into remission. Its use therefore was mainly adjunctive. Thus, it appears its benefits for cancer patients (improved anemia, and possibly decrease in such symptoms as fatigue) could not outweigh its harms (including hastening death).
So the issue was not merely that Amgen was promoting a drug in an instance in which its use had not been improved by the US Food and Drug Administration (FDA), or that such use of the drug was unnecessarily costly. The issue was that Amgen was promoting a drug that had no proven benefits for the patients, but could hasten their death. It appears that Amgen was pursuing profits at the expense of lives.
So it is particularly disturbing that no individual apparently will be held responsible for the promotion of Aranesp for patients for whom its use might prove fatal. The assurance that the proposed corporate integrity agreement will prevent further abuse is notably hollow. I can recall no recent case in which the government authorities have used such an agreement to pursue charges against individuals. The likely deterrent effect of the monetary settlement will likely be minimal. $762 million may look just like a cost of doing business when the drug in question was bringing in over $2 billion a year (per the Los Angeles Times).
So the legal settlements march on and on. The government continues to extract fines from health care organizations whose actions endanger not only the federal budget, but patients' well being and lives, without even trying to hold individuals responsible. The impunity of health care corporate executives thus also continues.
As we have said far too many times, we will not deter unethical behavior by health care organizations until the people who authorize, direct or implement bad behavior fear some meaningfully negative consequences. Real health care reform needs to make health care leaders accountable, and especially accountable for the bad behavior that helped make them rich.
1. Khuri FR. Weighing the hazards of erythropoiesis stimulation in patients with cancer. N Engl J Med 2007; 356: 2445-2447. Link here.
2. Bennett CI, Silver SM, Djulbegovic B et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA 2008; 299: 914-924. Link here.
3. Bohlius J, Schmidlin K, Brillant C et al. Recombinant human eryhtropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet 2009; 373: 1532-1542. Link here.