This summary of an analysis published online in the prestigious medical journal BMJ on November 23, 2015, shows that using preliminary research to approve new medical treatments has high costs for patients’ lives and healthcare dollars. These three very promising medications did not work, and one of them caused skin cancer and also made Alzheimer’s symptoms worse.
21st Century Cures Act and Similar Policy Efforts: At What Cost?
BMJ 2015; 351 doi: http://dx.doi.org/10.1136/bmj.h6122 (Published 23 November 2015) Cite as: BMJ 2015;351:h6122
By Diana M Zuckerman, Nicholas J Jury, and Christina E Silcox
A controversial proposed law in the United States, the 21st Century Cures Act, is described by supporters as an innovative attempt to jump start the process of finding new cures for the thousands of diseases that currently lack effective treatments. But would this bill promote new cures, or increase the availability of new medical products that do not necessarily work? Alzheimer’s disease is often cited as an example of a devastating disease with enormous costs and no cure in sight. We examine the potential harms and costs that would have been incurred by three Alzheimer’s drugs that were rejected under current Food and Drug Administration approval standards but could have been approved under the standards promoted by 21st Century Cures and similar legislation.
We selected for analysis all the Alzheimer’s drugs reviewed by the FDA within the past five years for which a determination was made, to determine the likely impact of the proposed changes on their approval.
All three drugs had impressive results in preliminary clinical trials. Two of the drugs showed great improvement based on the well-established biomarker of beta amyloid plaques on the brain, and the third based on tests of memory and cognition. When larger, better designed clinical trials were conducted, however, two of the Alzheimer’s drugs were found to be ineffective, and the third drug caused an increase in memory problems and an increase in skin cancer.
More than five million patients in the US have Alzheimer’s disease, about 1.3 million of whom are being treated with an Alzheimer’s drug. To conservatively estimate market share, we looked at the cholesterol lowering drug atorvastatin (Lipitor), which garnered 18% of market share during its first year on the US market based on biomarker data. If one of these drugs had gained a similar market share it would translate to 234,000 patients a year taking a drug that put them at risk of a greater loss of cognitive skills than if they had taken a drug already on the market, or perhaps no treatment at all. If semagacestat was the drug approved, almost 19,000 more patients would have developed skin cancer, based on the phase III results.
Most current Alzheimer’s drugs are available as generics, which has reduced their price. Donepezil has most of the US market share. The brand name version (Aricept) costs about $7500 a year at Walgreens, the largest pharmacy chain in the US. The brand name versions of memantine, galantamine, rivastigmine, and memantine-donepezil each cost over $5000 a year at Walgreens.
New drugs are priced based on the current market price of competing drugs, not on research and development costs. A conservative estimate is that a promising new Alzheimer’s drug would be priced similarly to Aricept ($7,500 a year). This is 87% more than generic donepezil, almost doubling the cost for any patient who switched to the new drug.
Assuming 18% of the market share before postmarket studies are completed, we estimate the cost of treating 234,000 patients at $1.76 billion a year, or $7 billion over four years until postmarket studies were completed. Given the modest benefit of current Alzheimer’s drugs, and the impact of current direct-to-consumer advertising practices in the US, a promising new drug would be expected to garner higher prices and more prescriptions, so the cost could easily double.
Since the cognitive abilities of patients with Alzheimer’s disease tend to worsen over time regardless of treatment, it would be virtually impossible for physicians to realize that semagacestat was causing cognitive decline or that the other drugs were ineffective. Physicians would also have been unlikely to notice that semagacestat increased patients’ risk of skin cancer. It would not have been until post-market phase III studies of cognitive and health outcomes were completed years later that physicians and families would have realized that the drugs were ineffective and possibly harmful.
Under pressure from Congress and industry, FDA standards have loosened in recent years, and the agency often approves products based on biomarkers that have good but inconclusive evidence of clinical benefit. For example, cancer drugs are often approved based on tumor shrinkage or progression-free survival and studies conducted after the drugs are in widespread use have shown that many do not help patients live longer. Osteoporosis drugs have been approved based on bone mineral density or microscopic bone fractures, rather than hip fractures that harm health. The proposed law and several other Congressional proposals would weaken current FDA standards further. As our examples show, this could to lead to patients taking ineffective and potentially harmful drugs and waste billions of healthcare dollars.
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