One of the few things Americans are united on is the need to curb the high cost of prescription drugs. Novartis recently made headlines, after a $2 million drug was approved to treat a rare hereditary disease, but drugs that cost as much, or more than, an average annual salary are so common they’re barely newsworthy anymore. Patients with dangerous, serious conditions are cutting back on or forgoing medicine because of costs. I’m one of those with a serious, dangerous and expensive condition: progressive multiple sclerosis. Drug pricing isn’t a merely academic issue for me. Luckily, however, I’m that extremely rare patient who has good enough health insurance to have to pay very little of my drug costs out of pocket. This means that I can chose what drugs I take based on what my doctors and I think is best, regardless of expense. You might think that would mean that I’m on the newest, most expensive drugs. I’m not, because sometimes drug development moves sideways instead of forward. We should be doing a lot more to focus on the value and effectiveness of drugs—something which is incredibly difficult in the current information landscape. Drugs that confer only a small additional benefit, but involve enormous increases in expense, are often presented as genuine breakthroughs. By not requiring drug labels to include all known relevant scientific information, patients incur the emotional cost of false hope, along with heavy financial burdens.
I’m currently on Rituxan. Originally a cancer drug, Rituxan has been on the market since 1997, and was one of the first biologic drugs eligible to be made in a generic (biosimilar) form. Despite the fact that Rituxan showed promise in treating traditionally untreatable progressive MS in a Phase III clinical trial, its maker Genentech decided that it wasn’t worth developing on a drug near the end of its maximum profitability. Instead of pursuing FDA approval for a new use of the existing drug, they decided to take the slower (but ultimately more profitable) route of developing a slightly modified form of the drug, called Ocrevus, a medication just different enough to enjoy a new period of market exclusivity. This slower process was sped up a bit because of its regulatorily favored breakthrough therapy status. How can a drug that is nearly identical to something already on the market, which has been scientifically tested and used for the same condition, be considered a breakthrough? Words can lose their everyday meaning when used in a regulatory context.
The differences between Ocrevus and Rituxan are extremely subtle. Rituxan comes from non-genetically modified mice, Ocrevus from mice that have been genetically modified to make antibodies that look a little more human. One MS specialist I’ve talked to has seen a few patients who didn’t respond to Rituxan but have responded to Ocrevus. However, the vast majority of patients should have identical (or nearly identical) reactions to both. Rituxan may be more likely to cause a patient to make antibodies against it, but, to date, those antibodies don’t seem to have any effect on the drug’s effectiveness or patient health. Theoretically, Ocrevus should have a slightly better side effect profile—but Ocrevus may carry a small cancer risk, which Rituxan doesn’t. Otherwise the drugs are nearly identical except for a substantial difference in cost. Technology has now advanced even farther to allow genetically modified mice to make an antibody that looks yet closer to fully human. Cancer drugs using this technology are currently on the market. It’s also being tested for use in cases of MS: its selling point is that the patient can self-inject it monthly instead of going in for an infusion every six months. (The dosing regimen of the current drugs keeps the problematic cells away for at least six months.) You have to differentiate a product somehow. We’ll see how much this convenience is worth.
Drug companies are increasingly gaming their clinical trials to maximize positive results when using only slightly different new drugs. In the clinical trial of Rituxan for progressive MS, it only slowed decline in patients of fifty-one or younger. Unsurprisingly, the clinical trials of Ocrevus were designed with only relatively young patients. All the trials relied on for FDA approval excluded patients over the age of fifty-five. The same is true of the more human drug under development. There is nothing deceptive or ethically wrong with designing a trial in that way, since no drug works for every patient. If you have a clear indication that a drug isn’t going to work in a defined subpopulation, it makes no sense to expose a group of people who won’t benefit to the risks of an experimental drug. To do so would be both unethical and bad science.
What’s sketchier is the way in which the manufacturers of Ocrevus have obscured the criteria they used when selecting test subjects. The US drug labeling for Ocrevus simply states, “Clinical studies of OCREVUS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.” The actual age ranges included in the studies are nowhere to be found in the US labeling information. The FDA snapshot summary of Ocrevus is even more misleading, stating simply: “OCREVUS worked similarly in age groups studied. The number of patients above 65 years of age was limited, however, so that differences in response between patients above and below 65 years of age could not be determined.” Prescription drug labeling regulations define the geriatric population as sixty-five and over, but they also require labeling to be “informative and accurate and neither promotional in tone nor false or misleading in any particular.” Since neither statement reveals that the number of trial subjects above fifty-five years of age was zero, the current labeling is misleading in at least one particular.
Drug companies can’t get away with this in other markets. Contrast the US drug label with the Canadian one: “The safety and efficacy of OCREVUS in patients > 55 years of age has not been established.” Or the Australian one: “The safety and efficacy of Ocrevus in patients > 55 years of age have not been established.” The EU labeling clearly shows the ages of the patients tested in the Ocrevus clinical trials. (Tables 4 and 5.) New Zealand’s label contains some language almost as deceptive as that of the US one: “The safety and efficacy of Ocrevus in patients ≥ 65 years of age have not been studied,” but at least it clearly shows that only patients aged 18–55 were included in one study. (Table 5.) Ocrevus is hardly an isolated case. Misleading drug labeling is a pervasive enough problem in the US that at least one pharmacy school has started creating drug monographs that more realistically reflect the results of clinical trials.
I’m fully confident that my main treating physicians have accurate information about these drugs, because the physician who heads the MS group within the large neurology department where I am treated is a former high-level employee of Genentech, who worked directly on Rituxan and Ocrevus and quit in disgust at the way this was handled. This is also why I was fortunate enough to start Rituxan a couple of years before Ocrevus came on the market. My other treating physician is part of a renowned MS specialty center, which is equally conversant with the realities of the drugs. But there are around one million people with MS in the US, and not all of us are being treated by expert sub-specialists. Their doctors may be excellent physicians. But no one who is responsible for treating dozens—perhaps hundreds—of conditions can realistically be expected to have the time and resources to dig deep into expensive medical literature in order to uncover obscure information about every drug used for each one. The prevalence of MS is highest in the 55–64-year-old age group: hence, the group most vulnerable to false hope and unnecessary financial risk is also the most likely to be prescribed the drug.
And, although there’s been some debate about the similarities of the drugs, the age issue has been obscured. I found this information out while doing my own research on whether to take Rituxan, and then whether to push for a change to Ocrevus when it came on the market. I’m unusually well-positioned to do this: I work at a large research university, and I teach students how to search biomedical databases like Pubmed and Embase. Even UpToDate, a common reference source compiled by physicians, generally considered the “best source for evidence-based information,” doesn’t mention the age issue: it merely directs the reader to the FDA-approved drug label for more information. Without easy access to accurate information, older patients are being exposed to the medical and financial risks of the drug without a realistic sense of how unlikely they are to benefit from it. And those financial risks are substantial. MS patients on Medicare spend an average of nearly $7,000 a year on drug co-payments. Patients with private insurance who pay a percentage of the cost of a drug (co-insurance), rather than a fixed drug co-payment, are even more financially vulnerable to the costs of drugs, potentially spending upwards of $1000 a month for MS drugs.
Rituxan’s list price is a little more than $11,000 a year, Ocrevus’ is $78,000, slightly under the roughly $86,000 average cost of disease-modifying drugs for MS. It shouldn’t be hard to find the information that would let physicians know what they’re selling, and patients know what they’re buying, at those staggering costs. Physicians and patients should be able to rely on a drug label. The most accurate information should be transparent, not hidden behind a statement that may meet the letter of the regulations, but not the spirit of them.
The only people who benefit from the currently allowed opacity of information are the corporate executives and shareholders who profit at the expense of patients and society. If I were a fifty-eight-year-old patient with progressive MS, who had just heard about a breakthrough drug and wanted to talk to my doctor about it, I would want all the relevant facts. I would want to know that there’s no scientific proof that the drug would help me, and some evidence that it might not work. I’d want to know that there are two similar drugs, one of which might cause cancer. Manufacturers might lose out on a few sales if they practiced greater transparency. But if I were fifty-eight and still in the condition I am currently, at age forty-one, I’d probably be desperate enough to try the drug with a small cancer risk, despite a lack of evidence of its effectiveness, and regardless of the almost certainly wasteful expense. On the other hand, I would feel betrayed and furious if my physicians and I had been denied information about the risk, I developed cancer, and I discovered I had been put at risk despite the fact that there was no reasonable expectation that the drug would improve my MS. Encouraging false hope in order to peddle useless and sometimes harmful, scientifically untested cures to desperate, vulnerable patients is deeply unethical. The advantage regulated pharmaceuticals have over snake oil is scientific proof: any movement away from that is dangerous.
