We all know the saying that ‘speed kills,’ but how fast is too fast when it comes to approving new drugs? The answer may not always be obvious, but a recent essay in The Journal of the American Medical Association chastised the FDA for moving too quickly when making use of its various expedited approval programs — Fast Track, Priority Review and Accelerated Approval.
In the FDA’s quest to speed approval times and meet unmet medical needs, the essay argues that the agency may be jeopardizing public health by relying too often on limited clinical trial data that, in some instances, has raised troubling questions about safety. The researchers cite three drugs as examples, including two that generated some sensational headlines about serious side effects.

Which drugs? There was the Gilenya treatment for multiple sclerosis, the Caprelsa medication for thyroid cancer and the Pradaxa blood thinner. In each instance, the JAMA authors cited evidence that safety was problematic, yet the FDA expedited approvals and, ultimately, created risks that continue to outweigh the benefits.

“Although enabling new drugs with a favorable benefit-to-harm balance to become available to patients more rapidly is a laudable goal, the underlying question is what public health risks are taken when drugs are approved for widespread use while important safety questions remain unanswered,” wrote Thomas Moore, a senior scientist at the Institute for Safe Medicine Practice, and Curt Furburg, a health sciences professor at the Wake Forest School of Medicine.

Before digging into the trio of examples, they offered some data. For instance, the FDA used expedited approvals for 16 of 35 new drugs, or 46 percent, endorsed in fiscal year 2011. All of them received Priority Reviews; 13 drugs were also designated for the Fast Track program that allows reviews to begin before clinical studies are complete for drugs that may fill serious unmet medical needs; and three drugs received Accelerated Approval, which does not require definitive evidence of any benefit.

As to those three drugs, the authors pointed to ‘haste makes waste’ scenarios. Consider Pradaxa: the blood thinner was approved for lowering the risk of stroke in patients with atrial fibrillation, and received both Fast Track and Priority Reviews. But Pradaxa was studied only in a single large Phase III trial, rather than at least two pivotal trials, as normally required, the authors noted. The trial compared Pradaxa with warfarin and showed a serious bleeding risk was similar for both.

The FDA approved just a single primary dose of 150mg, but unlike regulators in Canada, Japan, and Europe, the agency did not approve a lower 110mg dose. “Within less than a year of approval, a survey showed Pradaxa accounted for more serious adverse drug events reported to the FDA during the second quarter of 2011 than any other regularly monitored drug,” they wrote. In particular, the risk of hemorrhage was prominent in older patients — with a median age of 80 years — “a subgroup for whom declining kidney function or other factors may have increased bleeding risk.”

Gilenya was equally problematic. A two-year clinical trial showed an advantage over interferon beta-1a in preventing relapse, but also disclosed numerous safety issues, including adverse effects on heart rate, opportunistic infections, reduced pulmonary function, liver toxicity, teratogenicity, macular edema and possible cancer risks.

Dosing, the authors noted, was also an issue. Testing in a kidney transplant population was halted because of safety concerns at 5mg and 2.5mg daily doses. Then a 1.25mg daily dose in all ongoing trials was terminated over safety. In the end, only the 0.5mg daily dose was tested and pursued for FDA approval. An FDA panel voted that a 0.25mg dose should be tested, but also voted not to delay approval. And so, the agency approved Gilenya for first-line use but required 10 post-marketing studies, including one at a lower dose. Meanwhile, the European Medicines Agency restricted the pill to second-line use.

Finally, the essay cited Caprelsa, which was approved after one trial of 331 patients with late-stage medullary thyroid cancer. The trial showed the drug had an advantage in improving an endpoint of progression-free survival, but was also toxic and overall survival was no different from results with a placebo. Consequently, the JAMA authors questioned whether overall survival should be an acceptable trial end point for expedited approval. “The lack of sufficient clinical data left FDA reviewers uncertain whether a lower dose would reduce toxicity while maintaining efficacy,” they wrote, adding that the drug was approved under a restricted distribution program that requires special training.

For its part, the FDA was not silent. Although the essay was just two pages long and focused on only three drugs, its publication in the high profile JAMA yielded widespread media coverage. Moreover, the two authors are known for publicizing findings that question drug safety. In addition to publishing the ISMP QuarterWatch newsletter that tracks adverse events, Moore also served as a consulting expert in the civil litigation regarding Chantix. And Furburg recently agreed to become a consultant for plaintiffs in litigation concerning side effects related to Pradaxa. They both have high profiles themselves.

So the FDA was not hesitant to respond. Of course, the agency offered boilerplate language — there is always an evaluation of risks and benefits, and monitoring is always under way. But the agency then went on to make an important point, which is that expedited approval for medicines to treat serious or life-threatening ailments can make a difference in people’s lives. Priority review and accelerated approval have been around for nearly two decades, and fast track approval for almost 15 years. The programs are a legacy of the societal turmoil that ensued in the wake of the AIDS epidemic.

The agency then argued that these programs do not change the statutory standard for approval but rather allow some flexibility in meeting that standard. “FDA works directly with the affected patient populations and treating physicians when considering just how much uncertainty and risk are reasonable to accept,” the FDA stated. “We know, for example, that patients and physicians are willing to accept more risk with a treatment that is effective for serious diseases, particularly if existing treatment options are limited, and we factor this risk tolerance into our decision making.”

In other words, the agency is trying to get everyone to take the longer view. The JAMA authors raised important questions and cited disturbing examples when there is a perceived need to move a drug through the process quickly. But should there be the proverbial all-or-nothing approach to sorting out whether expedited approval programs are worth having? Clearly, the FDA believes the answer is not and, most likely, many patients and their advocates would agree. We already know what drug makers think, but that is beside the point.

The hard reality is that mistakes in judgment will be made. Given the increasing number of drugs approved under these programs — which reflects ongoing clamor by the public — it is not at all surprising that Moore and Furburg were able to find a few eye-popping examples of approval gone awry, egregious or not. But this was part of the grand bargain that came with creating these programs. And the results, therefore, may sometimes contrast with the usual approval process, for better and worse.

This is not to say that such examples are acceptable. Moore and Furburg make clear that the agency could have done certain things quite differently to avoid such unwanted outcomes. But should these instances then be used to question the validity of expedited approvals altogether? Or should these blunders, instead, be used as a learning experience for improving the approach toward decision making? And if so, how can that be accomplished?

This, of course, is the hard part. The age-old need to balance safety and risk is growing tougher for the FDA each year as patients become aware of improved technologies and updated scientific understandings — and then grow restive over regulatory requirements that appear unfathomable or unnecessary. As the cliché goes, throwing out the baby with the bath water accomplishes nothing. There is a legitimate need for expedited approvals. But the JAMA authors do make an important and that is more due diligence is going to be required if such debates are going to be quelled.