It started as a report in a cancer professionals’ “insider” newsletter. It is becoming one of the most important cancer stories of the past several years.
It is a story that has already affected how patients with cancer are treated, and is destined to shed light on how drug companies reveal information about the side effects of their drugs, how insurers and Medicare make their decisions about paying for drugs, and perhaps how doctors are reimbursed for their treatments.
It is about to enter the national spotlight through a Congressional inquiry.
The story is about a class of drugs called erythropoiesis-stimulating agents, which increase red blood cells in our bodies.
You are most likely familiar with them through their trade names Procrit and Aranesp. The generic names of these drugs are epoetin alfa (Procrit) and darbepoetin alfa (Aranesp). They are commonly used in cancer treatment to reverse the anemia that results from chemotherapy and radiation therapy, as well as the chronic anemia that is related to the cancer itself.
If you watch TV regularly, it would have been difficult to miss the direct to consumer advertising over the past couple of years that touted the benefits of these drugs, especially for patients undergoing treatment for cancer.
This all started on February 2, 2007 when “The Cancer Letter” published a front page story headlined “Study Finds More Deaths On Aranesp Arm In Cancer Anemia Study, No Benefit Seen.”
The story reviews an FDA announcement from January 27, 2007 which indicated that in a clinical trial Aranesp, manufactured by Amgen, increased the risk of death when used to elevate red blood cell counts in patients with cancer if it was used at a time when the patients were not receiving active treatment with radiation or chemotherapy. This condition is called the “anemia of cancer.” (It is important to note that this discussion does not apply to the use of these drugs when used to boost red blood cell counts in patients who are undergoing active radiation therapy and/or chemotherapy for their cancer.)
As the article reported, doctors had difficulty putting the announcement into proper clinical context because very little information about the actual study itself was made available in the FDA announcement or elsewhere. In fact, the writer had to go to another website to find a description of the clinical trial. This description had been posted as part of a public repository of clinical trials. But this site provides no information on the results of those trials.
Here is the statement in The Cancer Letter story that got my attention:
“If the findings of the recently reported study hold up, more than one in 10 Americans getting Aranesp without chemotherapy has no chance of benefiting from the agent and could be harmed or killed by it, experts say.”
According to the article, the company was slow to release the information, saying that the study was designed to measure a reduction in the need for red blood cell transfusions and not to look at the actual causes of death of the patients in the study.
As a result, doctors weren’t able to determine whether or not these deaths were more likely or less likely related to the use of the drug as opposed to other causes, such as the underlying cancer.
This was no trivial matter. The article cites estimates that up to 12% of the use of these drugs in the United States was for this particular indication. That meant that many patients were in fact at risk, and neither they nor their doctors knew about it.
It was reasonably clear from the analysis in the Cancer Letter story that there was a considerable “off label” use of Aranesp for the cancer anemia indication, and the quotes from company officials essentially said that it would be up to doctors to decide whether or not they wanted to use this drug under these circumstances, the risk of death notwithstanding.
This high usage of erythropoietin agents for an “off label” indication that had not been supported by clinical trials did not happen in a vacuum.
Various well-established and respected professional organizations provided guidelines to use these medications in the treatment of cancer related (not treatment related) anemia at various red blood cell levels. This was a widely used and widely accepted indication in the oncology community, even though the FDA had never directly approved the use of these drugs for this particular indication.
The companies kept the names of the drugs well in the public view through direct to consumer advertising, although that advertising did conform with FDA guidelines.
The report in The Cancer Letter set off a series of events which continues to increase in intensity and concern. This issue has clearly caught the attention of the cancer community, as well as others—including Congress.
A Medicare carrier (Noridian) indicated that they would no longer cover the use of Aranesp in cancer patients with chronic anemia that is not related to their treatment.
(A little known fact is that many decisions to cover or not cover certain procedures or drugs in the Medicare program are carried out by Medicare carriers that are located in different parts of the country, and not by Medicare on a national basis. This process is called the Local Medical Review Program, or LRMP. For many situations, such as coverage with these types of drugs, there is no national coverage policy that is applied uniformly across the country by Medicare.)
The FDA, in collaboration with the manufacturers of these drugs, has moved to alert doctors and patients to the increased risks associated with this treatment for these types of cancer patients.
On the FDA website there is now a statement regarding the possible hazards of the off-label use of erythropoietin drugs in patients with anemia related to their cancer. The FDA now cautions that the use of these drugs only to treat anemia of cancer is not appropriate.
Here is a portion of the FDA statement:
For cancer patients:
- Use of an ESA in anemic cancer patients who are not on chemotherapy offered no benefit and may shorten the time to death.
- ESAs are not FDA approved to treat anemia in cancer patients not receiving chemotherapy
- There is a potential risk of shortening the time to tumor progression or disease-free survival
- ESAs are administered only to avoid red blood cell transfusions in cancer patients. ESAs do not improve the outcome of cancer treatment and do not alleviate fatigue or increase energy.
In a letter from Ortho Biotech dated March 12, 2007, the manufacturer of Procrit announced the new FDA safety information, and the addition of what is called a “black box warning” to the prescribing information for their drug. A black box warning is the highest level of warning provided by the FDA and drug manufacturers to warn physicians and patients of very serious risks regarding the use of that particular drug.
The letter continues, “The results of the following studies have not been previously communicated to physicians in an Amgen or Ortho Biotech Dear Health Care Professional Letter.”
The letter goes on to outline the poorer outcomes and increased risk of death in patients treated with head and neck and lung cancer if treated with these medications. In one study, the survival was less than half for patients treated with the drug, compared to patients who did not receive the drug.
The letter concludes with a comment that the FDA is going to have an advisory drug panel meeting on May 10, 2007 to review the safety and effectiveness of these medicines.
In the current issue of the Journal of Clinical Oncology, there is a study that reports on the use of erythropoietin in patients with non-small cell lung cancer who could not receive curative treatment.
The study concludes, “An unplanned safety analysis suggested decreased overall survival in patients with advanced NSCLC (non-small cell lung cancer) treated with epoetin alfa. Although infrequent, other similar reports highlight the need for ongoing trials evaluating erythropoietin receptor agonists to ensure that overall survival is monitored closely.”
An editorial which accompanied this study acknowledged the report in The Cancer Letter.
The author of the editorial stated, “The study (as reported in The Cancer Letter) brings forth common themes; the study was evaluating erythropoietin treatment outside standard guidelines, safety concerns have been raised, and further scrutiny is needed.”
The editorial goes on, “…I would draw the reader’s attention to the importance of following practice guidelines in the management of patients with cancer related anemia, with respect to the target hemoglobin level of 12 g/dl. Meanwhile, preclinical and clinical investigation has been enhanced by this controversy, which should help us in our common goal to use this high profile/high scrutiny paradigm to achieve the highest benefit possible for our patients.”
The American Society of Clinical Oncology, which publishes the Journal of Clinical Oncology, has not updated its guidelines regarding the use of these drugs in the treatment of cancer related anemia. It does refer the reader to the FDA website for more information.
The National Comprehensive Cancer Network (another guidelines-setting group whose opinions I highly value) acknowledges the issues that arose from the trial reported by The Cancer Letter in their current guidelines for the use of these agents in the treatment of cancer patients.
They conclude, “Until new research evidence changes current benefit: risk estimates, physicians should be advised not to administer erythropoietin to patients similar to those enrolled in the Amgen trial.”
According to information from Amgen, that would be the following: Patients with active cancer not receiving or not expected to receive chemotherapy or radiation therapy. (Note: I cannot provide a direct link to their letter since it is on an area of their website restricted to health care professionals.)
As you can tell, that description encompasses a lot of people who have cancer. 60% of the patients on this trial had stage IV disease.
On March 14th, the Centers for Medicare and Medicaid Services (CMS) posted a notice on their website that they were initiating a public comment period regarding the use of these drugs for non-kidney related indications.
(That includes cancer. What I haven’t begun to get into in this blog is the other major controversy that is part of this total package, and that is the use of erythropoietin drugs in patients with chronic kidney disease, including those on dialysis. The drug that is used in these patients is called Epogen, but it is the same class of drugs as those used in cancer patients.)
What this means is that CMS has now decided it is going to make a national coverage determination on whether it will pay for these drugs in this situation, as opposed to the LMRP approach I discussed previously in this posting.
This decision is of significance beyond the safety issues.
Erythropoietin is the most expensive drug—by far—used in cancer treatment in the Medicare population. And, physicians who administer the drug receive payment for their services, which is likely not inconsequential (there are no immediately available data that I am aware of that would quantify the administration costs—exclusive of the drug costs—for administering these drugs in doctors’ offices).
One insurance company representative stated at a conference I attended recently that their charges for the administration of erythropoietin decreased by 44% in one pilot study when they asked the doctors to provide a red blood cell count along with their bill for administering the drug.
The clear implication was that physicians were giving this drug to many patients whose red blood cell counts were otherwise within acceptable (or at least reasonable) limits.
Finally, not to be outdone, letters went out yesterday from the House of Representatives Committee on Energy and Commerce to the CEOs of both companies that manufacture these drugs.
The letters state, “…We note with increasing alarm reports indicating that Erythropoiesis-Stimulating Agents (ESAs), commonly known as EPO products, when used at higher than recommended doses, appear to cause increases in blood clots, seem to grow tumors and are associated with significantly higher mortality rates than placebo.”
The letter continues, “There has been, however, no indication that (name of company) will forego its direct to consumer advertising which drives off-label uses of prescription drugs. Nor has there been any public announcement of a cessation of financial incentives to physicians to increase the prescription of (name of erythropoietin drug) to their patients.
The letters go on to say that the Committee requests the companies to cease their direct to consumer advertising and physician incentives until the FDA has had time to study the issue. The letters conclude with a series of questions relating to who knew what and when and what they did about it.
I would caution that the story is not complete at this time. There is more to learn, and more to discuss.
Knowledgeable professionals are guarding their reactions, awaiting further data and guidance.
Undoubtedly, patients are confused and probably frightened about what they should be doing if they are taking these drugs. I suspect their doctors are confused as well as to what they should be recommending to their patients with cancer related anemia.
It is clear that the FDA, Medicare, and now Congress are all going to be making some decisions about what happened here and how important this really is. The professional organizations that we look to for guidance in these matters will also be monitoring this situation very carefully, so they can adjust their treatment guidelines as appropriate.
I suspect that insurers are going to tighten their payment policies when it comes to paying for this treatment for this indication.
In the meantime, what should you do? On the one hand, if you are a cancer patient who is anemic and not receiving current treatment with chemotherapy and/or radiation therapy, you have the FDA saying that you should not be taking these drugs.
Other experts are not so certain.
Ultimately, any determination about whether or not you should be taking Procrit or Aranesp rests on a discussion with your oncologist about your specific situation, and a mutual decision about what you should do about your treatment. No one knows you better than your doctor, and you should work together to become fully informed and make the best educated decision that is right for you.
We still have much to learn about what happened here, and even more importantly what the implications are for our patients and their medical care.
What concerns me is that there remains the possibility this picture will not be a pretty one once all the investigating is finished and the dust has settled.
And, it would be a very serious matter indeed if patients were put at risk because of someone’s reluctance to make everyone aware of these serious side-effects as soon as they knew there was a problem with these treatments.
As I have said before, stay tuned.