The panel also voted 17-0 in favor of requiring new clinical trials to be conducted.
Epoetin is marketed under the brand names Epogen and Procrit, and the brand name for darbepoetin is Aranesp. The three drugs are manufactured by Amgen but Procrit is marketed by a Johnson & Johnson subsidiary.
The use of ESAs are FDA approved only to treat chronic kidney disease patients who are anemic and undergoing dialysis or cancer patients who are receiving chemotherapy or patients who are have to undergo major surgery to reduce the need for blood transfusions.
However, recent investigations have shown that the drugs are being administered off-label for profit by doctors and dialysis clinics to patients with conditions not listed on the FDA-approved labels and at much higher doses than specified which have resulted in serious adverse events for patients including death.
As of March 2007, according to the FDA, there are five randomized clinical trials that demonstrated decreased survival time in cancer patients receiving ESAs compared with those receiving transfusion support.
The agency reported a higher rate of blood clots, strokes, heart failure, heart attacks, and death were found in patients with chronic kidney failure when ESAs were given to raise hemoglobin levels higher than 12.
The FDA advisory also noted that a higher risk of blood clots was reported in patients who were scheduled for major surgery and received ESAs.
On May 10, 2007, the Wall Street Journal reported on a review of documents provided by Dean McClellan, a former sales representative for J&J involved in a whistleblower lawsuit alleging that J&J "offered excessive financial incentives for doctors" to prescribe Procrit and encouraged doctors to prescribe the drug at higher doses than were FDA approved.
One memo, described by WSJ, calculated that a doctor who purchased nearly $1 million worth of Procrit over 15 months would receive $237,885. Another program offered to discount J&J's product line to hospitals that used Procrit at least 75% of the time when prescribing anemia drugs. J&J also developed a "Right of First Refusal" contract that required doctors to allow J&J to make them a better offer if Amgen cut the price of Aranesp so that it was cheaper than Procrit.
According to the May 9, 2007, New York Times, although the safety debate has heated up over ESAs only recently, the first danger signs came over a decade ago. "That evidence emerged," the Times said, "in a trial sponsored by Amgen that was set up to show that dialysis patients would benefit from having their hemoglobin raised to 14, the level in a healthy person. "
The trial was stopped in 1996, because patients in that group had more deaths and heart attacks than a group treated with a hemoglobin goal of 10, according to the Times.
That trial should have discouraged doctors from using too much epoetin and encouraged Amgen to study the risks further, Dr Steven Fishbane, a nephrologist at Winthrop-University Hospital on Long Island told the Times.
In the same vein, J&J knew about the blood clot problems with Procrit when the drug was used at a higher dose since at least 2003, because the company halted several studies of Procrit in cancer patients in 2003, after the patients experienced a higher than expected number of blood clots, according to the January 26, 2007, New York Times.
Within 4 days of the recommendations of the FDA advisory panel, on May 14, 2006, the CMS announced that emerging safety concerns, citing thrombosis, cardiovascular events, tumor progression and reduced survival, "have prompted CMS to review its coverage of erythropoiesis stimulating agents (ESAs)."
"Liberalization of the coverage benefit for epoetin therapy over the years has created a financial incentive for its increased use," according to an October 2006 analysis in the journal Health Affairs that found ESAs represented the largest drug expense to Medicare at $1.75 billion two years ago in 2005.
The April 18, 2007, Journal of the American Medical Association, reported a study from the Medical Technology and Practice Patterns Institute that found for-profit dialysis centers were much more likely to over-prescribe the drugs than non-profit centers. On average, for-profit facilities used about 3,300 more units of the drug per week than non-profit centers, the Journal said.
The researchers reviewed records on nearly 160,000 kidney patients, with about 80% at for-profit centers. At the time, FDA guidelines recommended hematocrit levels of between 33% and 36%, but the study found that about 25% of patients at for-profit centers had levels of 39% or higher. In some cases, the study said, doses given were 3 times higher than those administered at non-profit centers.
According to the Times, "American patients receive far more of the anemia drugs than patients elsewhere, with dialysis patients in this country getting doses more than twice as high as their counterparts in Europe."
"Cancer care shows a similar pattern", the Times reports. "American cancer patients are about three times as likely as those in Europe to get the drugs, and they receive somewhat higher doses."
Medicare coverage policies that allow payment for the over-use of ESAs are killing patients, according to then House Ways and Means Committee chairman Bill Thomas (R-CA) at a December 6, 2006 hearing. "We have a payment policy that perhaps is killing people; and we are using $2 billion, the highest price paid in a relatively narrow area for the use of the drug through the payment policy, that may in fact be doing that."
In announcing the new coverage proposal, CMS said the agency was concerned that a number of clinical trials were terminated, suspended or otherwise not completed, "possibly due to signals of harm, and that the existing fund of published evidence may reflect a bias toward ESA use."
CMS noted that the drugs are "not reasonable and necessary for beneficiaries with certain clinical conditions, either because of a deleterious effect of the ESAs on their underlying disease, or because the underlying disease increases their risk of adverse effects related to ESA use."
The new CMS proposal states that ESAs will not be covered to prevent anemia or if after four weeks of treatment there is evidence of "poor drug response." In addition, 12 weeks is the maximum time that Medicare will pay for the drugs per year.
An editorial by Dr Daniel Coyne, a professor at Washington University School of Medicine, in the April 18, 2007, Journal of the American Medical Association, estimated that the cost to Medicare be $1,700 more a year for patients on higher dose. "Physicians need to challenge industries that appear to be using patients as profit centers based on bad science," he said in the editorial.
Apparently Amgen has caught the eagle eye of the SEC. According to Amgen's 2007 Annual Report, the SEC is investigating the firm's failure to inform investors until February 2007 that a Danish study that was terminated early in October 2006, due to safety concerns.
It should be noted that the Danish study was conducted to fulfill a commitment to the FDA for a study on tumor progression and survival.
After watching profits drop for just about every major company within the last year as a result of being busted for illegal marketing practices of dangerous products for profit which ended up causing many injuries and deaths, it appears that Amgen shareholders plan to get in the game early to try and recoup their losses from this drugging-for-profit scheme.
No doubt they have been wisely advised that it's only a matter of time before thousands of victims start filing lawsuits, and even that will probably turn into a race to court houses across the country between the injured and the state attorneys general, hand-in-hand with the feds, filing legal claims for Medicaid and Medicare fraud.
On May 11, 2007, the Kaplan Fox & Kilsheimer law firm announced the filing of a class-action suit in the US District Court for the Central District of California on behalf of all persons who purchased the publicly-traded securities of Amgen during the class period from May 4, 2005 through May 10, 2007 against the company and "certain of its officers and directors for violations of the Securities Exchange Act of 1934."
The Complaint alleges the defendants improperly marketed Aranesp and Epogen to doctors for off-label uses, and as a result, "Amgen sold several hundred million dollars worth of drugs each year for off-label uses."
The Complaint further alleges that in October 2006, a group of researchers conducting a clinical study of head and neck cancer patients immediately discontinued the study, prior to its completion, because more deaths occurred in patients taking Aranesp than in those taking a placebo, which was not disclosed to investors, and that on February 16, 2007, a publication called The Cancer Letter published an article about the results of the study.
The Complaint further notes that on March 9, 2007, the FDA mandated a "black box" warning regarding the off-label use of both Aranesp and Epogen, and then on May 8, 2007, in anticipation of an advisory panel meeting, the FDA issued a report suggesting that there is not enough data to ensure that Aranesp is safe even when used as directed.
It further says that on May 10, 2007, it was reported that an FDA outside panel voted to expand warnings and require Amgen and J&J to conduct new studies to test the safety of ESAs and that these revelations caused Amgen's stock price to significantly decline on high trading volume. ?
The shareholders may have decided that it was definitely time to file a lawsuit after watching Amgen shares fall $3.83, or 6.1%, to $59.25 on May 10, 2007, according to CBS News on May 10, 2007.
Also see: Anemia Drug Profit Scheme Screeches to a Halt - Part I