There was a time when the Food and Drug Administration was so sluggish and conservative in approving new drugs that people who desperately needed access to medicines would die waiting.
But by the early 1990s, Congress had created four programs to expedite the development and approval process for new pharmaceuticals (the breakthrough drug designation, priority review, fast track and accelerated approval). These pathways were intended to push innovative new drugs — drugs to treat rare, serious, or life-threatening diseases — through the FDA more quickly.
Since these medicines were sorely needed, the idea was that rushing them through, often on the basis of more limited and preliminary clinical trials data, would help patients languishing with unmet medical needs.
Today, the FDA is now considered the fastest regulatory agency in the world. But there's some concern that these expedited pathways are being used by drug companies to speed through medicines that aren't actually helping patients with unmet medical needs — and that often aren't any improvement over what's already on the market.
In two new studies, published on Wednesday in the BMJ, a group of researchers from Brigham and Women’s Hospital and Harvard Medical School, find that while more drugs are indeed getting to patients more quickly, there's good reason to question their novelty, safety, and effectiveness.
In the first study, the researchers looked at a database of all new medicines approved by the FDA between 1987 and 2013 to find out whether the increase in the number of products coming through on expedited pathways was related to an increase in truly innovative drugs getting to market.
They found no such correlation. Over the past two decades, the number of drugs qualifying for the FDA's expedited programs has increased 2.6 percent per year, but "this trend is being driven by drugs that are not first in class and thus potentially less innovative."
In 2013, 15 (or 56 percent) of the 27 new drugs approved by the FDA reached patients via one of these expedited programs — so the programs are being used more and more. But as the researchers explain:
Though these programs were designed as exceptions to the standard drug development and FDA approval process for drugs addressing unmet needs associated with serious or life threatening diseases, by the end of our study period, a majority of newly approved drugs were associated with at least one of these special programs, meaning that the exceptions had become more common than the rule.
In a second study, the researchers looked at another related issue with drug approval: companies that seek to market their products for "supplemental indications" — beyond what the drug was originally designed to do. (For example, a birth control pill might originally be approved for pregnancy prevention, but later get approved to help control acne and PMS; the latter two would be supplemental indications.)
Here, too, the researchers found an increase. Between 2005 and 2014, the FDA approved 295 supplemental indications. But there was also a massive range in the quality of the evidence companies presented to back their approvals, with a lot of supplemental approvals being based on very limited data supporting the drugs' safety and effectiveness.
The researchers write that their findings "have important implications for patient care" and "underscore the need for a robust system of post-approval drug monitoring for efficacy and safety, timely confirmatory studies, and re-examination of existing legislative incentives to promote the optimal delivery of evidence based medicine."
When asked for comment on the studies, an FDA spokesperson said, "Generally the FDA does not comment on specific studies, but evaluates them as part the of body of evidence to further our understanding about a particular issue and assist in our mission to protect public health."
On the FDA's expedited programs, the spokesperson said, "[These are in place to speed the availability of new drugs to treat patients with serious conditions." And several of the drugs that have come to market through expedited pathways have been a remarkable help to some patients — such as Gleevec, a life-saving treatment for sufferers of chronic myelogenous leukemia.
"The programs expedite development and review, but do not change the standards for approval," he said.
This last point caught the attention of health advocates on Twitter, including the physician and author Ben Goldacre, who noted that by definition, accelerated approval permits the use of less robust data, including "surrogate endpoints." This means companies submit the results of blood tests on cholesterol levels, for example, which may or may not have an impact on the measures that matter to patients — like reducing the risk of death and disease.
"There is good evidence that drugs are permitted into the accelerated program inappropriately," Goldacre wrote. "Claiming otherwise is very serious."
Concerns are mounting about dangerous and ineffective drugs reaching patients
A number of drugs with marginal benefits and potentially dangerous side effects have also made it through the FDA recently — Belsomra for insomnia, Contrave for weight loss, Addyi (or flibanserin) to boost women's libido — drawing criticism and public concern.
This new research from the BMJ doesn't come in isolation. As a 2014 study in Health Affairs demonstrated, these drugs are part of a trend at the FDA. Since 1992, around the time expedited approval programs were up and running, there's been a 25 percent increase in the number of drugs that are put on the market with black box warnings (signaling very serious side effects) or that are eventually pulled from store shelves over safety concerns.
Again, many of these new drugs offer no clear advantage to patients. A 2010 study in the European Journal of Clinical Pharmacology looked at 122 new drugs approved between 1999 and 2005. Only 10 percent performed better than drugs that were already available. Similarly, a number of studies have found that since the mid-1990s, about 85 to 90 percent of new drugs don't offer any clinical advantages for users.
These concerns are more urgent given a couple of impending changes coming down at the agency.
The FDA will soon get a new commissioner, and President Obama just nominated Dr. Robert M. Califf for the position. According to the New York Times, he comes with "deeper ties to the pharmaceutical industry than any FDA commissioner in recent memory." If he's confirmed, critics worry he will herald an era of even looser oversight of new drugs and cozier ties to the drug industry.
There's also legislation from Congress that could further erode the standards for drug approvals.
In July, the House passed the 21st Century Cures Act by an overwhelming 344-77 vote. Critics have pointed out that hidden in the bill's 352 pages is language that could weaken the quality of evidence the FDA uses to evaluate new drugs and devices, making it easier for companies to bring substandard or dangerous medicines and medical devices to patients. And the pharma-backed bipartisan effort actually has a chance of passing through the Senate and getting signed into law.
This raises the question: Can you trust your medicine? The answer, increasingly, seems to be no.