FDA Receives New Data on Risks of Anemia Drugs

[News]

The U.S. Food and Drug Administration (FDA) is reviewing new data from two studies that provide further evidence of the risks of anemia drugs known as erythropoiesis-stimulating agents, or ESAs.

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[gdpawel]

Increased death rates among cancer patients taking erythropoiesis-stimulating agents were supported in a large meta-analysis.

Among nearly 14,000 patients in 53 studies, those taking the anemia drugs were 17% (95% CI 6% to 30%) more likely to die during the study, and their overall survival chances were reduced by 6% (95% CI 0% to 12%), reported Julia Bohlius, M.D., M.Sc.P.H., of the University of Bern in Switzerland.

The findings, disclosed at the American Society of Hematology meeting, confirmed results reported earlier in individual studies.

The trials included Epogen, Procrit, NeoRecormon and Aranesp. The analysis was notable for relying on full data on each patient, contributed by the trial sponsors and individual investigators, not on outcome data as published.

And in fact, the on-study mortality results were higher than previously published. On-study mortality was defined as death from any cause occurring from randomization to four weeks after the active study's end. Overall survival was measured from randomization to the end of available follow-up.

When the patient pool was limited to about 10,000 patients treated with chemotherapy, the relationship between erythropoiesis-stimulating agents and mortality fell just short of statistical significance.

On-study mortality in the chemotherapy population was increased by 10% for those taking the anemia drugs (95% CI -2% to 24%), and the overall death rate was increased by 4% (95% CI -3% to 11%), the researchers found.

The results changed little when the researchers controlled for known risk factors.

Age, sex, hemoglobin, hematocrit at baseline, type and stage of tumor, and type of study were among the factors researchers took into account.

Patients getting no cancer treatment showed a 33% increase in on-study mortality if they were receiving erythropoiesis agents (95% CI 7% to 67%).

There were even higher increases in patients receiving other forms of cancer treatment (52% for chemoradiation, 52% for radiation alone, and 53% for "other" non-chemotherapies), but these did not reach statistical significance.

Moreover, a test for interaction among all the non-chemotherapy patient groups yielded a P value of 0.42.

Co-author Andreas Engert, M.D., of the University of Cologne in Germany, said the specific reasons for the increased deaths associated with erythropoiesis agents remained unclear, but on the basis of more recent studies, most of the excess deaths are probably from thromboembolic events.

The American Society of Hematology and the American Society of Clinical Oncology would convene a new guideline panel early in 2009 to consider revisions derived from these findings and other developments since the existing version was published.

Since the current guideline was produced, the FDA had required a boxed warning on epoetin and darbopoetin about increased mortality risks for cancer patients.

Source:

Bohlius J, et al., "Recombinant human erythropoiesis stimulating agents in cancer patients: individual patient data meta-analysis on behalf of the EPO IPD Meta-Analysis Collaborative Group" Blood 2008; abstract LBA-6.

[gdpawel]

A recent review in the Lancet suggests that using erythropoiesis-stimulating agents like Aranesp, Epogen and Procrit may reduce fatigue and combat anemia in cancer patients, while promoting tumor growth, hasten their deaths from cancer and increase their risk of early death from strokes and other cardiovascular events. The study combined data from nearly 14,000 patients in 54 clinical trials.

Although the FDA had slapped a black box warning on the drugs, the study, which was funded by firms that made them, suggested that doctors explain to their patients that treatment of anemia with EPO agents may improve their quality of life by reducing anemia and fatigue, but their survival may be shortened. According to a MedPage Today analysis of the study, the drugs, which stimulate red blood cell production, increased mortality by 17 percent.

Federal laws bar drug companies from paying doctors to prescribe medicines that are given in pill form and purchased by patients from pharmacies. But companies can rebate part of the price that doctors pay for drugs, like the anemia medicines, which they dispense in their offices as part of treatment. The anemia drugs are injected or given intravenously in physicians' offices. Doctors receive the rebates after they buy the drugs from the companies. But they also receive reimbursement from Medicare or private insurers for the drugs, often at a markup over the doctors' purchase price. I am reminded it is still a "chemotherapy concession."

Last year, U.S. Oncology, which funds, develops and helps manage 443 cancer centers in 39 states, complained that patients were harmed by new Medicare coverage policy for anemic cancer patients. The Centers for Medicare & Medicaid Services (CMS) decision limited ESA (erythropoiesis-stimulating agents) treatment to a maximum of eight weeks after a chemotherapy session. It also required physicians to wait until hemoglobin levels dropped below 10 g/dl before starting therapy.

Because CMS did not receive any documented cases of negative outcomes from the oncology community, it stuck to its decision. The FDA backed CMS' National Coverage Decision (NCD), which limited use of the drugs because they have been shown to spur tumor growth. The FDA believed the approved labeling and CMS' NCD were generally consistent in their recommendations regarding the use of pharmaceutical EPO in patients with cancer undergoing chemotherapy.

However, major insurance companies had not embraced the CMS protocol. It was a "shot over the bow" by the oncology community of government stepping directly into patients lives and saying that they know what is a better course of treatment than doctors. During the ensuing year, we found out that drugs, given by injection, had been heavily advertised, and there was gathering evidence that they had been overused, in part because oncologists could make money by using more of the drug.

Resulting studies had suggested the drugs may make the cancer worse. Much of that evidence came from studies in which patients were treated more aggressively than the drugs' labels recommended. The FDA found mounting evidence of documented effects on survival, tumor progression and thrombotic events which required reassessment of the net benefit of this class of drugs.

Gee, could it be that increased numbers of red cells deliver more oxygen to the tumor cells and thereby their activity across the board, including with respect to invasion, proliferation and metastasis? On one hand we're developing drugs to halt and reverse angiogenesis while on the other hand we're helping the tumor to obtain more oxygen with existing vasculature.

Having said all of this, physicians, scientists and the public occasionally apply their own judgement and determine when the existing evidence is sufficient to support a personal decision to adopt - as opposed to impose upon others - certain drug treatments. No wonder the National Coalition for Cancer Survivorship emphasized the need for drastic changes in how physicians are reimbursed for care. Reward doctors for whole patient care - not just treatments.

http://www.medpagetoday.com/Hematolo...matology/14007

[gdpawel]

Nearly two years after a Food and Drug Administration advisory committee called for restrictions on the use of red blood cell-stimulating drugs in cancer patients (erythropoiesis-stimulating agents or ESAs), the agency unveiled a stringent risk management plan that should further lower use of the drugs, which are already in freefall in cancer patients. The plan, which affects Amgen's Aranesp and Epogen and Johnson & Johnson's Procrit (manufactured by Amgen and identical to Epogen), requires the companies:
Register oncologists who prescribe the drugs;

Educate them about their risks, which include tumor progression and earlier death; and

Fully inform patients about the risks with an updated medication information guide, both at the time they are initially treated and every time treatment is given; and

Obtain signatures from patients that they've been apprised of the risks.

The updated medication guide will contain information for chronic and end-stage renal disease patients, who also get ESAs for anemia. But renal physicians will not be facing the same registration and education requirements.

The company was given a year to come into full compliance. Officials at a press briefing yesterday were uncertain what would happen to oncologists or the companies if they prescribe or use the drugs without giving the proper warnings.

The program is called, appropriately enough, APPRISE. And while it's tough, it's not unprecedented. The FDA adopted a similar registration program for some opioids.

When pressed by a reporter on why it took so long to come up with the program, Richard Pazdur, head of the oncology office at the Center for Drug Evaluation and Research at FDA, said "this took many many months of discussion. It's a delicate balance. We don't want to interfere in a draconian fashion with the practice of medicine."

Pazdur distinguished between patients undergoing therapy where there is a chance of cure, and those receiving palliative care for incurable cancers. In the latter case, patients may opt for the greater energy that comes from alleviating cancer- and chemo-related anemia, even if it results in a shorter end game.

"The risks-benefit balance is a delicate one," Pazdur said. The goal of the program wasn't to restrict use of the drugs, but "to help patients make the best choice given their individual situation."

The failure to simultaneously force the companies to reeducate the renal physician community was disappointing. There's mounting evidence that high doses of ESAs in renal disease patients is associated with increased risk of heart attacks, strokes and earlier mortality. Many of these patients are poor and unaware of the quality of care they receive at dialysis centers. They, just as much as cancer patients, need to be informed about the risks posed by overuse of ESAs.

Source: Gooznews on Health

[gdpawel]

As the crimson sun slipped into the gray Pacific Ocean, a multibillion-dollar drug deal took shape. A group of board-certified doctors greeted each other in a private room at a luxury hotel in California. The oncologists were big buyers of an anti-anemia drug called Procrit, sold by Ortho Biotech, a Johnson & Johnson (J&J) division. That Friday evening, the company toasted its top clients and their wives with bottles of Beaujolais, porterhouse steaks and free weekend accommodations.

The event could have been just another "grin and grip" affair, but there was a catch: J&J wanted to pump the sales of its biotech drug to beat its rival Amgen and its anti-anemia drugs. "The idea," as J&J drug rep Dean McClellan later explained, "was to get the docs to increase their Procrit dosage to 40,000 units."

There was just one problem. Regulators had approved a weekly drug dose of 30,000 units, and J&J was prohibited by the Food, Drug, and Cosmetic Act (FDAC) from marketing its drugs in unapproved ways. But the doctors could prescribe in any "off-label" manner they wanted. So, McClellan, a star rep and medical consigliere, led a "discussion" about high-dose experiments. Taking his cue, one physician explained how he routinely injected patients with 40,000 units of Procrit. Another oncologist pumped his people with 10,000 units for ten consecutive days - triple the approved amount. "That seems a little extreme," said McClellan, frowning.

"Oh no," the doctor said. "I haven't seen any side effects so far."

A few months later, Procrit sales hit the $1 billion mark, beating Amgen by a hair. The resort trip had certainly helped. But it was just one part of an expansive, long-running off-label marketing campaign, according to sales documents. Slowly but surely, oncologists around the country began administering so many high Procrit doses that, in time, the off-label therapy became the "community standard."

There were problems since insurers don't always reimburse doctors for off-label use. In fact, when Medicare refused to pay the Arizona Cancer Center, a huge client, for its high-dose Procrit injections, an Ortho manager ghost wrote a letter on behalf of its chief oncologist Daniel Von Hoff. After a few more company calls - ipso presto! - the center began receiving more than $1 million in Medicare payments for the illegal therapy. As McClellan claimed in a whistleblowing suit, the cancer market grew so saturated with high doses, that six years later the Food and Drug Administration finally approved them.

The decision might have been defensible had the 40,000-unit regime had been proven to be safe and effective. But independent research later revealed that cancer patients died sooner than expected, and company trials found an alarming number of dialysis patients suffered strokes and heart attacks. Meta-studies showed that 17 percent of patients died from the drug, and stories told of blood counts so high, patients actually spit up blood and choked on their own tumors. Turns out there was little scientific evidence that Procrit, and its cousins Epogen and Aranesp, actually helped people at any dosage.

Last summer, regulators announced that the drugs should be avoided entirely by most patients. "It turns out many people are better off taking placebos," said Dennis Cotter, president of Medical Technology and Practice Patterns, a nonprofit research institute.

What this illustrates is that drug companies can create entire cultures of over-prescribers for untested, even fatal indications, and that doctors can be easily corrupted. In light of a flurry of recent federal settlements for off-label marketing crimes, it also underlines how you, dear taxpayer, foot the bill for reckless marketing.

In the case of Procrit, the J&J unit formed advisory committees made up of academic physicians and clinical oncologists. These key opinion leaders (KOLs) were paid honoraria of at least $1,000 for every speech they delivered touting off-label use. McClellan selected some pliant clients to be the featured speakers. "Some guys wanted to give three or four speeches a weekend so they can get three or four thousand dollars," he said. A few actually did. Many talks were delivered at company "conferences" organized for other doctors, who earned hourly credits toward their annual continuing medical education (CME) units, required by state licensing boards. As if that wasn't enough, Ortho also paid physicians for their rooms, meals and transportation.

Ortho eventually assembled boards of KOLs who specialized in every type of cancer. According to sales documents, the goal was "to build thought leader endorsement [sic] to establish Procrit as standard of care," not just for approved indications such as AIDs and chemotherapy, but for cancer-related fatigue, depression, and other off-label indications.

These friendly prescribers were not Dr. Feelgood types working the tenderloin. They were distinguished professors from respected institutions such as John Hopkins University, Harvard Medical School, University of Chicago, Memorial Sloan-Kettering Cancer Center, Emory University Hospital, Cornell University, Long Island Jewish Medical Center, University of Texas MD Anderson Cancer Center, and others. Dr. Nicholas J. Vogelzang of the University of Chicago was a paid spokesman for the Fatigue Coalition, a group bankrolled by Ortho. Dr. John Glaspy of UCLA penned a seminal article in the Journal of Clinical Oncology that drew rosy conclusions about high-dose Ortho-sponsored studies.

Dozens of other doctors agreed to "influence their colleagues to use Procrit" for unapproved indications such as cancer-related fatigue. One was Dr. von Hoff, the director at the Arizona Cancer Center. He collected advisory fees and perks from not just Ortho, but from about 30 other pharmaceutical firms, earning directors' fees for sitting on several companies' boards. "When I saw how many shares he owned in biotech and drug firms, my jaw dropped," McClellan later said. Many others, like Dr. Jerome Groopman of Harvard Medical School, performed J&J-funded clinical trials. He was paid to sit on Procrit's "fatigue" advisory board and was quoted often in The New York Times extolling the drug, according to public records.

Groopman also penned a bestseller called "How Doctors Think." In it, he talks about the importance of talking with patients about their diagnosis and treatments. But Groopman doesn't explain what role Big Pharma checks and trips play in his own decision making. This is noteworthy since he goes on about the influence of high-pressure drug reps and the need for physicians to weigh scientific assessments against "going with your gut."

Clearly, even esteemed doctors were swayed by Procrit's marketers. In reviewing the basic science research behind these costly anti-anemia drugs, Dr. Charles Bennett of Northwestern University found that physicians and investigators who collected money from the two drug makers were "less likely to criticize the safety, effectiveness, or cost-effectiveness of drugs" and "more likely to endorse novel and less proven treatments" like off-label. No matter what prescribers say, they seem to have indeed been bought by golf trips, grants and banquets.

The overprescribing of anti-anemia drugs roared alongside an astonishing rise in American health care expenses. For several years, Procrit and the others topped Medicare's reimbursement list. By 2007, the drugs' domestic sales approached $11 billion a year. So far, US taxpayers have shelled out more than $60 billion over the past 20 years, reimbursing doctors, KOLs and hospitals for a drug that never worked as advertised.

McClellan's whistleblowing case may be in limbo. But many prestigious doctors will soon wind up in the confessional. Thanks to the Physician Payments Sunshine Act, doctors who accept speaking fees, meals, travel, stock options, or any other compensation from drug or medical device companies will soon see their names - and their gifts - revealed publicly on the web. The rule is part of the Patient Protection and Affordable Care Act, aka "Obamacare." Data collection was supposed to begin this January, but the first report won't appear until March 31, 2013. When that day dawns, patients will gain some insight into their treatments. Was that off-label prescription supported by scientific evidence; or did my doctor "go with his gut?" If so, how often was that gut filled by the maker of my medication?

From Kathleen Sharp's book, "Blood Feud: The Man Who Blew the Whistle on One of the Deadliest Prescription Drugs Ever."

"Dozens of other doctors agreed to 'influence their colleagues to use Procrit' for unapproved indications such as cancer-related fatigue. One was Dr. Von Hoff, the director at the Arizona Cancer Center. He collected advisory fees and perks from not just Ortho, but from about 30 other pharmaceutical firms, earning directors' fees for sitting on several companies' boards. 'When I saw how many shares he owned in biotech and drug firms, my jaw dropped,' McClellan later said. Many others, like Dr. Jerome Groopman of Harvard Medical School, performed J&J-funded clinical trials. He was paid to sit on Procrit's 'fatigue' advisory board and was quoted often in The New York Times extolling the drug, according to public records."

In 2010, Dan Von Hoff got the Karnofsky award from the American Society of Clinical Oncology (ASCO), which is sort of a lifetime achievement award for clinical research. This is a nuclear explosion for clinical oncology. I'm wondering who was involved in the Harvard side of it? Interestingly, it is the highest levels of academia who are most tainted. One in particular, Dan Von Hoff. These ivory tower docs were the culprits. Unfortunately, this will probably play out as one more cudgel to beat the more reasonable and gentle practitioners, who either largely avoided such abuse or were led down the path by the scholars, who will themselves skip out unfazed.