Need for Speed: The Effects of an Expedited FDA Approval Process

The US Food and Drug Administration (FDA) is pushing new drugs to the market faster than ever, using 4 expedited pathways to cut down the time it takes to conduct a clinical review.

In some ways, the FDA’s accelerated regulatory process is on par with mounting expectations for improved therapies that enter the market swiftly. At the same time, the move to expedited approvals is causing trepidation in cautious physicians.

How Fast is a Fast-track Designation?

New Drug Applications (NDA) can undergo 1 of 4 expedited reviews:

• Priority review: drugs slotted to receive an FDA decision within 6 months of application
• Breakthrough therapy: drugs that demonstrate substantial improvement over available therapy for serious conditions in preliminary clinical endpoints
• Accelerated approval: drugs for serious conditions that fill an unmet medical need, whether it has effect on a surrogate or intermediate clinical endpoint
• Fast-track designation: drugs designed to treat serious conditions and fill an unmet medical need

According to a recent review, non-expedited drugs have a median clinical review time of 8 years, defined as the time from the Investigational New Drug (IND) application to FDA approval. IND approvals indicate when clinical trials can be initiated by the drug’s manufacturer.

Evidence shows that drugs in at least 1 expedited review program spent an average of 1 fewer year in clinical development. Specifically, drugs granted breakthrough therapy designation spent an average of 3 fewer years in development.

The study, from researchers with the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital in Boston, MA, found that breakthrough drugs reported the shortest development time at 4.8 years — a rate 32% shorter than fast-track drugs.

The Policies for a Faster Market

In an accompanying essay published in New England Journal of Medicine, researchers reported that standard drug applications are speeding up, as well.

In 1979, the mean length of time a drug spent between an NDA application and FDA ruling was nearly 3 years, as the process was impeded by Congressional oversight and limited FDA funding. In response, the first Prescription Drug User Fee Act (PDUFA) was passed in 1992. PDUFA proved successful, as the mean non-expedited NDA and BLA review time gradually dropped from less than 2 years in 1993, to just 10 months in 2016.

With a growing rate of user fees over time, more funds have been allocated to rapid evaluations, NDAs, and post-market analysis, researchers noted.

The post-market analysis funding was bolstered in 2007 by PDUFA IV, a more structured and proactive system for “adverse-event surveillance” on drugs entering the market. The administration was pressured into implementing the system following the 2004 market removal of nonsteroidal anti-inflammatory drug rofecoxib (Vioxx), due to unforeseen and substantial cardiovascular event risks in tens of millions of US patients, researchers wrote.

Trusting the Doctors

Mark E. Dunlap, MD, told MD Magazine he remembers rofecoxib’s recall. At the time, the drug had been on the market for about 5 years, and its removal left a gap in efficacious cardiovascular medications.

“We ran into a situation quite a while after that, in finding medications as effective as that,” Dunlap, director of the Heart Failure Section at the Heart and Vascular Center of the MetroHealth System in Cleveland, OH, said.

From Dunlap’s perspective in the cardiovascular field, the FDA tends to be “over-deliberate” on drug regulation. Though he credited the agency with striking a balance between safety and efficacy evaluation, Dunlap wished physicians were better trusted with prescribing drugs that may carry safety concerns.

Handling Breakthrough Therapies

In other fields, such as in migraine therapy, new drugs are flooding the review pipeline. Calcintonin gene-related peptide (CGRP) antibodies are poised to hit the market in droves — the FDA accepted the BLA for the review of galcanezumab last week, and erenumab’s application this past summer. The BLA for fremanezumab was submitted in October, and eptinezumab’s clinical profile was bolstered by second phase 3 study results last month.

Brian Grosberg, MD, director of the Hartford Healthcare Headache Program in Hartford, CT, told MD Magazine he hopes the antibody drug class keeps its clinical promise and reaches the market, but he’s not looking to “hasten the process any more than it needs to be.”

“I think it’s going at an appropriate pace, and I think the testing is sufficient,” Grosberg said about current FDA regulation standards.

Grosberg noted patients on the initial class of CGRP antibodies had reported elevated liver function issues. He said it’s just as important for manufacturers to stay judicious on the safety and efficacy of the new antibody class — which they have.

“Though the new ones haven’t shown [adverse effects], I’m for having a degree of caution,” Grosberg said. “I wouldn’t necessarily want them to rush these processes of medication until safety is proven.”

Giving the FDA Something to Work With

While Grosberg is practicing patience, other specialists have already lost theirs while waiting for new therapies in their field. With Alzheimer’s disease (AD) prevalence expected to more than double in the US by 2060, Howard Fillit, MD, has had little experience with breakthrough therapies designated for the mental condition.

Fillit, founding executive director and chief science officer of The Alzheimer’s Drug Discovery Foundation, told MD Magazine the FDA has been very responsive to the AD community, by contributing guidance on biomarkers and mild cognitive impairment associated with therapies. Still, new therapies are lacking.

“I can’t really talk to whether the FDA should be more or less regulatory in their process. I think the best quote I can attribute to the FDA regarding Alzheimer’s is, ‘Show us a drug that works, and is safe, and we will approve it!’,” Fillit said. “Achieving cognitive and functional outcomes with enough of an effect size that is clearly apparent to patients and caregivers and physicians is the challenge.”

Once that challenge is met, recent history shows the FDA will get it on the market as soon as it can.