Decoding Health Care

Part 32: The media and medicine

Unfortunately not all investigative journalism is created equal.

Erythropoietin (epo) is a hormone produced by the kidneys that regulates red blood cell production. The physiological feedback loop is elegant. The kidney possesses an oxygen sensor, and red blood cells that carry oxygen to all the tissues in the body tell that sensor whether the oxygen level is adequate. If the sensor decides oxygen levels are too low the kidney secretes epo, which goes to the bone marrow and gives the signal to make more red blood cells. If you are anemic, the kidney knows it and makes more epo. If your kidneys are failing, you cannot make as much epo and you become anemic. When I was a medical resident, patients on dialysis were often transfusion dependent. They became iron overloaded and they formed alloantibodies to the blood that was transfused. This made getting cross match compatible blood sometimes really tough.

Epo was first identified in 1977, though its existence was suspected as long ago as 1906. The gene was cloned in 1985. Along with insulin, it was one of the first peptide hormones to be made in the lab. It was first tested in patients with renal failure and the results were dramatic. Patients became transfusion independent and they felt a lot better. But an important lesson was learned. There was such a thing as too much of a good thing. Trying to normalize the hemoglobin wasn’t a good idea, and overshooting the target was particularly bad. Patients who got too much epo had hypertension, strokes, and blood clots. To this day, epo remains a cornerstone of the treatment of patients on dialysis.

This initial success led to investigations in many other conditions associated with anemia. It was tested in HIV patients, especially those on AZT (who occasionally developed a particularly severe form of anemia). It was tested in sickle cell disease. It was tested in Jehovah’s witnesses who refused blood transfusion for religious reasons. But the real opportunity seemed to be in cancer patients, especially those receiving chemotherapy.

Anemia is common in patients with cancer for many reasons. Patients with advanced cancer commonly have anemia just due to the remote effects of the tumor. In addition, classic cytotoxic chemotherapy suppresses the bone marrow, often producing anemia. Certain drugs, like cisplatin, which can injure the kidney are commonly associated with anemia. More aggressive chemotherapy causes more anemia. And the 1990’s were the decade of chemotherapy. Many of the most widely used cancer chemotherapy drugs came to market in the 1990’s. It was a perfect storm for an explosion of epo use.

Epo was studied extensively in cancer. There was no doubt that it reduced the need for transfusion in cancer patients receiving chemotherapy, and that was a good thing. Nobody wanted a transfusion. The blood supply was still suspect; remember we had just suffered through a horrible period of transfusion associated HIV. And getting a transfusion was a real pain; the patient needed to go to the hospital and spend an entire day getting blood. Epo was so much easier. And then (just as now) hospitals were a pain to deal with. They often limited the number of patients they would accept for transfusion on a given day. Epo, which was a weekly SQ injection. was so much easier.

But the real benefit of epo was felt to be in the realm of cancer related fatigue. Fatigue is an extremely common side effect of cancer chemotherapy and it can be incapacitating. Patients with severe chemotherapy induced anemia were profoundly fatigued, so it was thought that increasing the hemoglobin with epo could improve the fatigue. And there were several studies that purported to show that improvement in fatigue. Transfusion was uncommon; fatigue was universal. The cancer community was sold.

But epo has side effects. Just as in renal disease, epo increased the risk of blood clots. But blood clots are common in cancer patients and the community just shrugged and dealt with it. But a more substantial potential risk was identified. It had long been known that cancer cells had epo receptors. But a pair of clinical trials suggested that epo patients had an increased risk of death (those of Henke https://pubmed.ncbi.nlm.nih.gov/14575968/ and Leyland-Jones https://pubmed.ncbi.nlm.nih.gov/16087945/). And that led to a critical investigation of the epo safety data.

Both the FDA and CMS undertook a thorough examination of the safety and efficacy data. This is where I got involved. I was chairman of the pharmacy and therapeutics committee of US Oncology, the largest network of community oncologists. Our doctors were enthusiastic prescribers of epo. So along with leaders from the American Society of Hematology and the American Society of Community Oncology, I spent a lot of time in Washington. I remember vividly the first time I went to CMS; it was imposing, it looked like a fortress.

Ultimately, the FDA and CMS recommended restricting the use of epo to patients being treated in the non-curative setting. It also required an exhaustive informed consent process with each patient. In retrospect, this was a wise decision though I did not agree with it at the time. It minimized the risk to patients being treated for cure. But the data was really conflicting, and to this day I do not believe epo puts cancer patients at risk of tumor progression. And I thoroughly and critically reviewed the data. There are plenty of people who disagree with me. A nice summary of the conflicting data was recently published by ASCO (Management of Cancer-Associated Anemia With Erythropoiesis-Stimulating Agents: ASCO/ASH Clinical Practice Guideline Update | Journal of Clinical Oncology).

The important point is that this discussion was collaborative and collegial. It did not occur in the public press. The debate was based on interpretation of the data. Ironically, the head of the coverage group at CMS with whom I met and discussed the evidence, and with whom I ultimately totally disagreed, is now one of my closest friends. We still disagree.

What really irked me recently was a piece written by an investigative reporter, Gardiner Harris. By all accounts, Mr. Harris is an accomplished investigative reporter. He has worked at the Wall Street Journal and the New York Times. He has reported on many topics, including international diplomacy as well as health care. He recently published a book, “No More Tears: The Dark Secrets of Johnson and Johnson.” A portion of this book, concerning epo, was recently published in STAT (The EPO drug scandal that explains RFK Jr.’s appeal to Americans | STAT).

I find what he has written about epo to be at best half truths and at worst slander. It is superficial and lacks any of the nuance I have described in my description of epo use in cancer patients. It is almost impossible to refute all of the absurd claims Mr. Harris makes in his diatribe. I’ll focus on a couple.

Harris argues that all oncologists prescribe drugs just to make money. The migration of chemotherapy administration from hospital based to office based is one of the great successes of the outpatient care of cancer patients in the history of oncology. And it had nothing to do with oncologists making more money. He argues that oncologists gave epo to make more money. Like all cancer treatments, oncologists get paid when they give treatment. As flawed as this “buy and bill” system may be, it has been the model since cancer treatment started. If he wants to investigate drug markups, he should look at what hospitals charge. Those drug mark-ups are what pays for the overhead oncology practices must cover to provide chemotherapy to their patients in the office.

Prior to the Medicare Modernization Act (passed in 2003 and implemented in 2006), drug pricing and reimbursement was the Wild West. Payment to physicians for physician administered drugs was based on the Average Wholesale Price, and Medicare paid doctors 95% of that number. But that number was essentially made up. Pharmaceutical firms paid rebates and offered discounts to physicians not reflected in that number. This increased profitability to the prescribing physician. It also incentivized physician prescribing of certain agents based on their favorable economic profile. Every pharmaceutical company did this, not just Johnson and Johnson. But the Medicare Modernization Act mandated the use of Average Sales Price which is calculated from drug prices reported to the government by manufacturers based on actual drug sales inclusive of rebates. There is no shady negotiating. But to be clear, this rebating behavior still exists; it’s the business model of every pharmacy benefits manager and Medicare part D plan.

What is most absurd is Harris’ claim that the number of cancer patients who died from epo rivals the victims of the opioid crisis. As I have already discussed, the data are extremely conflicting. But that doesn’t really matter for Mr. Harris’ agenda. I wonder whether he read all of the studies he cited. For example, the Henke study (https://pubmed.ncbi.nlm.nih.gov/14575968/ ) which started all of this discussion was actually a study in head and neck cancer patients receiving radiation. It was designed to answer a different question. It is well known that radiation resistance can be due to cancer cells surviving in a low oxygen environment. If you improved the oxygenation, would radiation work better? In this study, epo was given to maintain a normal hemoglobin. Epo did not yield a better outcome; to the contrary, patients receiving epo had more tumor growth.

The other study, done by Leyland-Jones (https://pubmed.ncbi.nlm.nih.gov/16087945/) is certainly more worrisome. In his study, patients being treated for metastatic breast cancer were randomized to receive epo or not. The goal was to maintain a normal hemoglobin as there had been a prior study suggesting that keeping the hemoglobin normal improved outcomes for cancer patients. This was not the reason oncologists were prescribing epo, namely to treat chemo induced anemia. The patients receiving epo had a higher death rate. But the study did not identify what caused this increased death rate. In fact, tumor progression was no different in the epo group.

Why does this matter? For one thing, I resent the fact that he suggests oncologists treat patients just to make money. For another, he suggests that there was some sort of evil cabal hiding the risks of this treatment. This is unsubstantiated hyperbole. Is epo safe? I am not totally certain. But I can guarantee you 100% that you will not learn the answer by reading Harris’ book. It’s not that he might not be able to identify “authorities” to agree with him. I am certain he would be able to. But I expect more when I read the work of a distinguished investigative journalist, just like I expect more of 60 Minutes if they choose to report on brain tumors. People listen.

So why did Mr. Harris write this nonsense? Based on the press releases surrounding his book, it’s because he thinks Johnson and Johnson is a bad company. He wants to take them down. Now I don’t really know if Johnson and Johnson is a particularly bad actor; I think of them in the same light as I think of all pharmaceutical companies. But this book has an agenda, and when the media has an agenda bad things can happen. Which brings us to a discussion of how the media has covered COVID, which I will take up in my next post.