FDA Expedited Approval Process Raises Concerns About Risks

Roxanne Nelson, BSN, RN

July 18, 2018

The Breakthrough Therapy designation created by the US Food and Drug Administration (FDA) expedites the approval of drugs intended to treat serious or life-threatening conditions, thus allowing patients quicker access to therapies. But the shorter approval process leads to great uncertainty about safety and efficacy. Are the risks greater than the benefits?

These concerns have been raised again in a new study published online July 17 in JAMA and in an accompanying commentary in the JAMA Forum.

The findings from this study "suggest that the FDA's expedited review programs may invite greater risks than benefits," writes Austin B. Frakt, PhD, director of the Partnered Evidence-based Policy Resource Center, Veterans Health Administration, Boston, Massachusetts, in the commentary.

"The idea that doing something more quickly means it is not done as well has considerable face validity," he comments.

Shorter Trials Lacking Controls  

The new study reviewed all FDA approvals given Breakthrough Therapy designation from 2012 through 2017 and found that the pivotal trials used as a basis for these approvals more often than not lacked randomization, double-blinding, and control groups. They also tended to use surrogate markers as primary endpoints and had small patient cohorts.

In addition, over half of the approvals were based on the results of a single trial.

This leads to greater uncertainty, say the authors, led by Joseph S. Ross, MD, MHS, an associate professor of medicine at Yale University School of Medicine, New Haven, Connecticut.

It is not known whether the effect observed in the single small trial will be observed in a larger population or replicated in another trial, or whether the effect observed over the short term will persist over the longer term.

"There is also uncertainty over whether the effect observed on the outcomes used in these shorter trials, such as surrogate markers of disease, will be confirmed by eventual demonstration of benefit and safety based on clinical outcomes like improved mortality or improved symptoms," Ross told Medscape Medical News.

Ross said that the FDA "is doing everything it can to expedite the development and review of drugs that treat serious and life-threatening conditions."

"My expectation is that this is what the public and clinicians — and Congress — want," he told Medscape Medical News. "More novel therapies coming to market as quickly as is reasonably possible, while still assuring drug safety and efficacy."

But their research suggests that FDA approval of these breakthrough therapies is generally based on shorter and smaller clinical trials than those that support FDA approval of non–breakthrough therapy drugs.

If this "trade off" is going to be made, with novel drugs entering the market on the basis of evidence that is generally accompanied by greater uncertainty, "we must be committed as a clinical and scientific community to ensuring that high-quality, rigorous postmarket trials are conducted within a reasonable period of time," he added. "This will resolve some of this uncertainty and ensure that the drugs are associated with the benefit/safety profile that we expect based on the initial clinical studies, allowing clinicians and patients to make fully informed decisions about whether to use these novel treatments."

Minimal Evidence

In this study, Ross and colleagues reviewed all new FDA approvals that had been granted Breakthrough Therapy designation, looking at the pivotal clinical trials that serve as the basis for approval as well as pre-market development and review times.

They identified 46 agents that had received Breakthrough Therapy designation between 2012 and 2017, based on 89 pivotal trials. Of these, more than half were for oncologic indications (n = 25 [54.3%]), followed by infectious disease (n = 8 [17.4%]); just over half the drugs (n = 25 [54.3%]) were considered to be first in class.

In addition, nearly two thirds of these agents were designated as orphan products (n = 30 [65.2%]) and qualified for Fast Track review (n = 24 [52.2%]) and Accelerated Approval (n = 18 [39.1%]).

Many of these drugs had only one clinical trial (median, 1; interquartile range [IQR], 1 - 2), while the median number of patients enrolled in these trials was 222 (IQR, 124 - 796). Roughly half of all approvals were made on the basis of a randomized trial (n = 27 [58.7%]), while 21 studies used double-blind allocation (45.7%), 25 had an active comparator or placebo control group (54.3%), and 10 had a clinical primary endpoint (21.7%).

Clinical trials that supported breakthrough approvals with Accelerated Approval status were less likely to be randomized than those without Accelerated Approval (3 trials with Accelerated Approval [16.7%] vs 24 trials without Accelerated Approval [85.7%]; P <  .001).

The median time to FDA approval was 4.9 years (IQR, 2.7 - 7.6 years), and all eight agents (100%) that received accelerated approval had at least one clinical safety or efficacy-focused postmarketing requirement, as did 18 (64.3%) without Accelerated Approval designation.

Information Lost

Approached for comment, Diana Zuckerman, PhD, president of the National Center for Health Research, noted that historically, the FDA required two clinical trials with clinically meaningful endpoints, and for cancer, that was survival.

"That was the standard, and it did result in complaints," she told Medscape Medical News. "There were complaints that trials take too long and are too expensive, and complaints from patients and physicians that the drugs weren't available."

"This research letter in JAMA is important, as it is a very well done reminder what you lose when you speed things up," Zuckerman added.

The FDA required two studies because the second study shows replication of the results, and that is the keystone to research. "You need to replicate the results," Zuckerman commented.

"This paper also shows that we have lost double-blinding and active comparators and placebo groups half of the time," she said. In addition, "very few trials had a clinical endpoint."

"We lost a lot of information, and this means that patients are using drugs that may not be as effective as older treatments, but yet are much more expensive," she said.

Zuckerman pointed to a study that she coauthored in 2016, which found that many new cancer drugs approved on the basis of surrogate endpoints retain their approval status and remain available to prescribing physicians even though postmarketing studies show no survival or quality-of-life (QoL) benefit compared with placebo or observation groups.

Of 36 drugs that were approved between 2008 and 2012, 18 did not significantly prolong overall survival in postmarket studies. QoL information was available for 7 drugs, and compared with placebo or observation groups, 2 drugs demonstrated worse effects on QoL, 4 drugs showed no statistical difference, and 1 drug had mixed results. In addition, 1 drug reduced overall survival and 6 offered no survival benefit compared with placebo or observation groups.

"These drugs are very expensive," Zuckerman explained, noting that they ranged in price from $20,237 to $169,836 per year. "There is no relationship between cost and evidence."

The FDA does allow access to experimental drugs, and with the Right to Try law, it is now easier for patients to gain access, she said. "At least patients know that they are getting an experimental treatment, and that long-term safety and efficacy are unknown. But with expedited approval, they believe they are getting something backed by evidence."

Right now, the model is "unsustainable," she said.

Zuckerman also added that the FDA is not responding to these concerns by enforcing requirements for postmarketing studies, and those that are completed are not giving useful results.

Greater Risks Than Benefits?

In the related commentary, Frakt says the findings suggest that the FDA's expedited review programs may invite greater risks than benefits.

He notes that most of the new drugs are approved even though information concerning long-term outcomes is limited, and more than two thirds are approved on the basis of clinical trials lasting under 6 months.

In addition, the median approval for cancer drugs in the expedited process is 6 months, which is much quicker than in Europe and Canada.

However, it remains an "empirical question" as to whether the drugs that receive an expedited approval have a worse or better benefit/risk balance compared with drugs that receive standard approval.

Frakt points out that over time, safety concerns may arise for drugs with expedited approval. "Drugs subject to less FDA scrutiny are more likely to exhibit safety problems, be withdrawn from the market, or carry black box warnings," he says. "We should therefore continue to monitor these drugs and update the performance of expedited approval programs as more information is available."

But another concern, he adds, is that from 2009 through 2013, only a minority of drugs with expedited approval had their efficacy tested in a postmarket trial within 3 years, as previously reported by Medscape Medical News.

Accepting greater risks may be "reasonable and consistent" with patient preferences, as the expedited review programs are for new agents designed to treat serious conditions and address unmet medical needs. But because many of these new drugs are quite costly and are paid for with public funding through Medicare, Medicaid, and other programs, Frakt notes that "the patients' point of view is not the only one of relevance. A consideration of cost is also reasonable from the point of view of taxpayers."

Ross reported receiving grant funding from the Laura and John Arnold Foundation, Johnson & Johnson, Medtronic, the FDA, Blue Cross–Blue Shield Association, Centers for Medicare & Medicaid Services, Agency for Healthcare Research and Quality, and the National Heart, Lung, and Blood Institute of the National Institutes of Health. Coauthor Joshua Wallach reported receiving grant funding from the Laura and John Arnold Foundation. Zuckerman reports owning stock in Johnson & Johnson.

JAMA. 2018;320:225-226, 301-303. Abstract, Commentary

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