When a new medication is approved by the U.S. Food and Drug Administration (FDA) it means that the drug has undergone years of testing, first in the laboratory, then in animals, and finally in people with the condition which the new medication is intended to treat. We expect that approved medications have two features: first, that they work for treating at least the condition for which they are approved—called efficacy—and second, that they are safe.
A recent article published last October suggests a problem with that assumption in at least one area of FDA approvals. According to the article in Fierce Pharma, “Across six cancer indications for four medicines through the FDA’s accelerated approval program which have since been pulled, Medicare had spent $224 million between 2017 and 2019, a new study published in JAMA Internal Medicine shows.” Clinical trials done on these four cancer drugs that were done after FDA approval showed a lack of efficacy and therefore the drugs were withdrawn. What is going on here and is this a recurring pattern or an isolated event?
The Accelerated Approval Pathway
The four drugs discussed in the article above were all approved under the FDA’s accelerated approval pathway, which allows a drug company to win approval using what are called biomarkers as the outcome measure during clinical trials. Ordinarily, FDA requires that a new medication—or an old medication being tested for efficacy for a new indication—must show efficacy in treating an actual disease. For example, if a pharmaceutical company has a drug that it thinks works for treating Lyme disease, it must show that the drug has a direct effect on Lyme disease itself in patients enrolled in clinical trials. But for some indications, showing a direct effect on the disease itself might take a long time and therefore using a surrogate marker for the disease can speed along drug approval. This would be a great benefit when the disease in question in very severe, like cancer. The idea is that getting potentially effective medications on the market earlier than later for potentially life-threatening illnesses could save lives.
Let’s take a theoretical example in which a type of cancer ordinarily has a median survival time of five years. That is, half of patients with this cancer live for more than five years and half live for less than five years. It will take years to see if a new anti-cancer drug improves survival time significantly better than already approved treatments. So the FDA may agree, under its accelerated approval program, that all the drug company needs to prove is that its new anti-cancer is better than existing treatments on a measure that responds to treatment more quickly, like tumor size. In our theoretical example, let’s say existing treatments reduce the size of the tumor in this type of cancer within three months of treatment for 30% of patients. Tumor size becomes the biomarker in clinical trials of the new anti-cancer drug and if it can reduce tumor size faster or in a higher percentage of patients than the existing treatments to which it is compared, then the FDA is inclined to grant it approval for broader use.
But the fact that a drug works on a biomarker does not necessarily mean it actually improves overall disease outcome, so FDA only grants accelerated approval based on a biomarker on the condition that the drug company perform confirmatory trials, also called phase four trials. In confirmatory trials, the drug company must demonstrate that its new anti-cancer drug actually makes patients live longer. And it is on this count that some new anti-cancer drugs appear to fail, prompting the FDA to request their withdrawal.
According to the Fierce Pharma article, the FDAs accelerated approval program has been criticized often:
… the program has repeatedly come under fire for its lack of accuracy and follow-on oversight. A 2019 JAMA Internal Medicine study led by Harvard researcher Aaron Kesselheim, M.D., found that only 19 of 93 cancer drug indications the FDA waved through under the pathway between late 1992 to mid-2017 had positive overall survival data from confirmatory trials.
If the accelerated approval program puts drugs on the market that turn out to lack efficacy, how often does this happen under the regular FDA approval process? Can we be secure in our belief that newly approved drugs are indeed safe and effective?
Withdrawals Are Uncommon
The FDA has the authority to ask a manufacturer to withdraw its medication from the market if it determines that the drug’s benefits no longer outweigh its risks. It turns out that withdrawals of drugs by the FDA because of safety or efficacy problems is very uncommon. In a 2017 study, Yale University investigators found that of 222 drugs approved between 2001 and 2010, three were subsequently withdrawn by FDA. It should be noted, however, that safety concerns were identified after approval for an additional 120 of these medications, some of which were deemed serious. Thus, while total withdrawal of a medication may be rare, the identification of previously undetected adverse side effects once a drug has been on the market for a few months or years is relatively more common.
There have been a few cases of medications being withdrawn that have made headlines, like the story of the anti-inflammatory medication Vioxx. Vioxx was supposed to be a safer alternative to already marketed drugs like naproxen and ibuprofen, but after its approval studies showed it caused an increased risk for heart problems and heart attacks, some of which were fatal. Five years after approval Vioxx was withdrawn from the market and the drug became the subject of thousands of lawsuits and a multi-billion-dollar settlement by its manufacturer, the pharmaceutical company Merck. Interestingly, in the original clinical trials involving more than 5,000 people that led to the FDA approval of Vioxx, these heart problems were not detected.
That’s the concern with new drugs—will serious adverse side effects turn up only years after they are approved, even though the approval process involves years of rigorous testing and hundreds to thousands of clinical trial participants? Is it safe to take a medication that has just been approved?
We can take some comfort from the fact that adverse side effects or lack of efficacy serious enough to cause the complete withdrawal of a medication are uncommon. When this does happen, as in the dramatic case of Vioxx, it makes headlines, but that situation is unusual. On the other hand, new adverse side effects do crop up that require FDA to inform prescribers and the public. And in the case of the accelerated approval process, problems with efficacy seem altogether too common.
The FDA clearly needs to review the accelerated approval process for drugs that treat the most serious and often life-limiting illnesses, like cancer. It needs to do a better job of determining how closely linked biomarkers are to actual outcomes and force drug companies to conduct and report on confirmatory trials after approval much more expeditiously than is now the case.
With drugs approved under the regular process, we can be reasonably reassured that most turn out to be safe and effective even after years of prescribing them. It is obvious to recommend that people taking any medications report adverse side effects promptly to their prescribers and that prescribers stay up to date on newly surfacing adverse events that involve drugs they prescribe. It is also important that journalists not dramatize newly emergent safety and efficacy problems with already approved drugs because in many cases they will turn out to be rare problems that can be managed or issues that apply only under special circumstances that don’t apply to most people taking the medication. Perhaps the best we can say about taking new medications is that they should be tried when patient and prescriber agree the potential risks are outweighed by the benefits; then both collaborators should remain vigilant for every piece of new information that emerges.