No sooner had the ink dried on my blog from last week about the problems controlling the costs and off-label uses of cancer chemotherapy drugs than the Annals of Internal Medicine published three articles and an editorial on the topic of off-label drugs in cancer treatment.
And the Annals’ conclusions weren’t any too kind to our current system of determining what drugs Medicare will or will not pay for when it comes to cancer treatment: we are—according to the journal—in a world of hurt.
The reason all of this is so important is that many of the newer cancer drugs are very expensive. In addition, probably a majority of cancer treatments today are already “off-label”, which means the drugs are being used for treating diseases or conditions which were not part of the original approval from the Food and Drug Administration.
As I mentioned in last week’s blog on this topic, Medicare relies on books called compendia to determine whether or not they are going to pay for a drug to treat a particular cancer. These compendia are published by private organizations, each with different approaches to reviews of the evidence and how the data is assessed and presented.
In the most detailed of the articles in the Annals, the authors do an in-depth analysis of these compendia to determine whether they provide “comprehensive, research-based, and timely information for off-label prescribing in oncology.”
In short—according to the research—they don’t. The bottom line finding was that these compendia lack transparency as to how they reach their conclusions and do not follow a detailed, systematic approach to review or update the evidence.
The result, according to the authors, is essentially a hodge-podge of information and recommendations that may conflict with each other and not reflect our current knowledge about which drugs work for which cancer.
A couple of comments from the article:
“These compendia have essentially functioned as gatekeepers; it is critical to examine their processes for evidence review, the reliability of the evidence they include, their decision-making pathways for adding new drugs, and their practices with regard to timely updating…
“We found little agreement between the results of systematic reviews of 14 off-label indications of cancer drugs and the evidence cited for those indications in these commonly used compendia. Cited evidence was scanty and inconsistent across compendia, which raises questions about the processes by which evidence is identified and selected to generate recommendations, the potential biases or conflicts of interest that affect decisions of whether to include an indication or how to present the evidence, and the comprehensiveness and quality of the evidence that the compendia include.”
I could go on with more quotes, but I suspect you get the idea: the researchers thought there was considerable room for improvement.
Two additional articles make recommendations on how to improve the process.
One of the articles recommends that the Centers for Medicare and Medicaid Services (which administers the Medicare and Medicaid programs) centralize the decision making process for drug payment approval. Right now, as noted in last week’s blog, that function is handled for the most part by regional companies that administer the Medicare program. They are supposed to use the compendia to standardize their decisions for drug payment, but that still leaves room for variation in different parts of the country.
In the current paper, the author suggests that we need to have better control over the use of off-label cancer treatments, particularly the newer, more expensive targeted therapies. To get this control, she suggests that after a drug is approved by the FDA that it undergo a separate review by CMS as to whether or not it is “reasonable and necessary” for the treatment of a particular cancer.
Although the author blends the issues of approval for devices as compared to drugs, there is some merit to considering a national coverage decision for chemotherapy drugs under some circumstances, as I suggested last week. (Devices can be approved by the FDA if they are safe, but the FDA does not demand the same level of proof of effectiveness for devices as they do for drugs. As a result, I agree that it is appropriate for CMS to make payment decisions for medical devices such as defibrillators. Drugs, on the other hand, have to demonstrate more rigorous evidence of safety and effectiveness for FDA approval, which suggests to me that a separate review of drugs for FDA-approved uses is not necessary.)
That said, I think it is unfair to suggest that all off-label uses of cancer chemotherapy drugs need close government scrutiny. The process could end up being too ponderous to respond efficiently, particularly when evidence of new value for a drug is substantial, such as was the case with Herceptin used in the adjuvant treatment of HER2 positive breast cancer. Another more recent example is the success of Avastin in treating a highly malignant form of brain cancer.
The third article in this series written by CMS staff details how the compendia make their recommendations, including some of the problems with their processes, such as disclosing conflicts of interest among the decision-making experts who sit on the publications’ panels.
That article concludes that “Congress has provided a broader authority to CMS to pay for anti-cancer chemotherapy drugs that may have indications that the FDA has not approved (or considered) but that compendia have listed as having some benefit. Given the high stakes involved in cancer chemotherapy, the public should know about the process by which Congress gives compendia the authority to approve specific indications for these drugs.”
The editorial in the Annals which accompanied these three articles was blunt and to the point: “In short, the compendia were inconsistent, incomplete, and out-of-date. (The) findings speak for themselves in making the case for change…In this context, clinical policies for off-label uses of drugs are a throwback to earlier, less rigorous times…
“The articles in this issue shine a bright light on a weak point in our efforts to inform clinical practice by the best possible evidence. The present system seems wanting. We have the tools to do much better.”
All of these comments are relevant and important to consider. Cancer chemotherapy drugs are expensive. They are frequently used in off-label situations, hopefully more often than not in circumstances that have been vetted through appropriate scientific research. There are situations where the use of off-label drugs such as erythropoietin (ESAs) have gathered steam and caused harm to patients, unfettered by the lack of FDA oversight.
In the interest of full disclosure, the American Cancer Society did support the use of compendia several years ago in a letter to CMS. The alternative was a non-system, where there was no reasonably current means to address the question of what drugs are effective in a rapidly changing research driven world.
That issue remains relevant today, especially in an era when new drugs and new drug uses are reported regularly—especially at the annual meeting of the American Society of Clinical Oncology. And some of these drugs are literal lifesavers which can take months to get approval from the FDA.
Just because a cancer drug is used “off-label” is not to say that it is bad medicine. To suggest otherwise is not appropriate and may even be harmful.
In the meantime, what are cancer patients and their doctors supposed to do when clinical trials show that a drug is effective in treating a particular cancer? Should we require that everyone wait for a detailed evidence analysis before the FDA or CMS can approve these drugs if they are already available? What do we do as doctors and patients if the evidence is overwhelmingly positive, as was the case with Herceptin? Do we invoke a system similar to that used in the United Kingdom where women couldn’t receive a drug that saved lives?
There is no easy answer to this dilemma and I certainly don’t purport to have all the answers. Right now, the compendia with all of their faults and warts are the best reference resources that we have.
Maybe we could and should do better. Inevitably, however, we will need to figure out some process that recognizes we cannot let the perfect be the enemy of the good.
If we don’t have that flexibility—as recent experience has shown us—we run the risk of not providing the best evidence-based care for our patients with cancer that we can offer as quickly as possible.
That, too, would be a tragic outcome.
