Two new studies question the value of FDA’s accelerated approval process for new cancer drugs. That is not good news. People with cancer are often enthusiastic about the latest purported advance that might offer them a better quality of life and improved longevity. Pharmaceutical manufacturers are also eager to bring their new and pricey cancer drugs to market as quickly as possible. But research just published in JAMA Internal Medicine (May 28, 2019) should give the FDA, drug companies and cancer patients pause when it comes to fast-tracking new cancer drugs.
“The Accelerated Approval regulations were first instituted by the FDA in 1992 in order to speed the availability of new drugs to treat HIV/AIDS. The designation has also been frequently applied to cancer drugs and legislation passed in 2012 included a provision to expand its use to other conditions.”
Instead of proving that the drug prolongs life, all the company has to show is that it improves some measure of the disease process. This might be tumor shrinkage, response rate or time to tumor progression. These are known as surrogate endpoints. They don’t necessarily correlate with quality of life or survival.
A commentary in JAMA Internal Medicine (May 28, 2019) points out that there is a “widespread misperception that newer generally equals better.” This is especially true in cancer treatment.
The authors go on to note that:
“Most new cancer drugs are approved through the FDA’s accelerated approval process, which allows for drugs to be approved faster based on surrogate end points that are thought to reasonably predict a drug’s clinical benefit. However, surrogate endpoints are often poorly correlated with survival, and little is known about how they correlate with other patient centered outcomes such as quality of life.”
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An example of a surrogate endpoint in the treatment of diabetes might be considered blood glucose levels. While measuring sugar in the blood (HbA1c) is a good assessment of diabetes management, it doesn’t tell us a lot about quality of life or longevity.
A drug company could develop a drug that is very good at controlling blood glucose. If it increases the likelihood of having a heart attack or stroke and does not prolong life the drug would be a great disappointment. That actually has happened.
What people with diabetes really care about are relevant clinical outcomes. Does the medicine reduce the risk of heart attacks, strokes, nerve damage, visual problems and kidney disease. Does it prolong life? If all a drug does is lower blood sugar, does it really matter?
In the case of cancer, tumor shrinkage seems like a good thing. But if it doesn’t lead to better quality of life and longer life, there are serious questions about the benefits of this surrogate endpoint.
One More Thing!
There is one additional requirement for accelerated approval. The drug maker has to do actual studies after its medicine gets marketing approval. This is supposed to determine how well the drug actually works in real life. However, not all such studies look at important outcomes like survival.
The research published this week looked at data from post-approval studies. About one-fifth of the medicines approved under the accelerated approval process were shown later to improve overall survival (JAMA Internal Medicine, May 28, 2019). Longevity is an outcome that is of great interest to cancer patients and their families.
“Accelerated Approval of Cancer Drugs—Righting the Ship of the US Food and Drug Administration”
The authors point out that drug companies, patients and their families want fast approval for life-threatening diseases. Physicians and drug watchdog groups worry about unsafe or ineffective medicines getting through a relaxed approval process.
“…the median complete response rate–when the tumor completely disappears–was just 6%.
“Response rate is not itself a meaningful clinical outcome; the size of a tumor does not matter if patients’ lives are not extended or if their quality of life is not improved. Response rate is useful only if it reliably predicts these outcomes. Somewhat counterintuitively, even high response rates and shrinking tumors are not necessarily highly correlated with improvements in survival or symptoms.”
The authors also point out that:
“Drugs with unproven effectiveness sell false hope to desperate patients, who are likely paying thousands of dollars out of pocket for them. Private insurance companies, Medicare, and Medicaid pay millions—maybe billions—of dollars for drugs for which we do not know the real benefits and risks. This raises insurance premiums and wastes tax dollars. Exorbitant drug prices are bad enough for treatments that work. Charging vulnerable patients for drugs without evidence that they actually improve patients’ survival and quality of life is unconscionable.”
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Does the FDA Care?
Even when other follow-up trials did not confirm that the drug improved length or quality of life, sometimes the FDA allowed the company to continue marketing its cancer medicine. The researchers call for more consistency in criteria for approval and also in the agency’s response to such research findings.
“For example, Genentech’s Avastin, or bevacizumab, won accelerated approval to treat the deadly brain cancer glioblastoma, but the drug did not extend the lives of patients in a follow-up study.
“Sometimes patients value drugs because they improve their quality of life.
This drug didn’t do that either, yet the FDA left it on the market as an
approved treatment for glioblastoma.
“‘So that was the most baffling thing,’ says Bishal Gyawali, an oncologist on
the research team. ‘I find it very difficult to understand.'”
“The FDA did not provide NPR with details about its decision to leave Avastin on the market for brain cancer. In a statement, an agency spokeswoman notes that the FDA weighs risk and benefits, saying, ‘It has been widely accepted that benefit can be demonstrated by a number of endpoints, not just overall survival.’
What does Accelerated Approval Mean for You?
Everyone wants the latest and greatest treatment for cancer. We completely understand that, especially if the cancer is hard to treat like glioblastoma. But cancer drugs are not benign. Side effects can be severe or even lethal.
People are willing to accept great risk if there is reasonable benefit. What the new studies show, however, is that many new and expensive cancer drugs may not provide improved quality of life or increased longevity. That’s unacceptable.
“As a consequence of the failure to ensure safety of the Boeing 737 Max 8, the Federal Aviation Authority should rethink its regulatory oversight process and emphasize safety. So too should the FDA add rigor to its accelerated approval pathway so that patients with life-threatening cancers do not take drugs that lack reliable evidence of improvements in overall survival or quality of life.”
What do you think? Please share your thoughts in the comment section.
Joe Graedon is a pharmacologist who has dedicated his career to making drug information understandable to consumers. His best-selling book, The People’s Pharmacy, was published in 1976 and led to a syndicated newspaper column, syndicated public radio show and web site. In 2006, Long Island University awarded him an honorary doctorate as “one of the country's leading drug experts for the consumer.” Read Joe's Full Bio.
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Gyawali, B., et al, "Assessment of the Clinical Benefit of Cancer Drugs Receiving Accelerated Approval," JAMA Internal Medicine (May 28, 2019), doi:10.1001/jamainternmed.2019.0462
Chen, E., et al, "An Overview of Cancer Drugs Approved by the USFood and Drug Administration Based on the Surrogate End Point ofResponseRate," JAMA Internal Medicine (May 28, 2019), doi:10.1001/jamainternmed.2019.0583
DiMagno, S., et al, "Accelerated Approval of Cancer Drugs—Righting the Ship of the US Food and Drug Administration," JAMA Internal Medicine (May 28, 2019), doi:10.1001/jamainternmed.2019.0584
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