Twenty years after its inception, the FDA’s Fast Track designation program is going strong, with many signs that it has achieved its goal of bringing novel drugs to the market faster. Now, even with a new FDA Commissioner at the helm, the Fast Track program is unlikely to change substantially, although it may adjust to more explicitly address current areas of high-unmet medical need such as antibiotic resistance and cardiovascular disease.

Introduced in 1997 as part of the Food and Drug Administration Modernization Act (FDAMA), the Fast Track designation became the FDA’s third expedited review program after Priority Review and Accelerated Approval.

Launched in the wake of the AIDS crisis, these expedited review programs were designed to speed up drug development for life threatening illnesses. “Given that one of the primary goals of the Fast Track program was to be more inclusive and to apply to a wider swath of products, the qualifying criteria for the program were intentionally set quite low,” said Mark Mathieu, director, Publications, Parexel. “FDA guidance notes that a Fast Track designation can be obtained quite early in development, based on nonclinical evidence or even a mechanistic rationale,” Mathieu continued.

In 1998, the first year of Fast Track, the FDA received 27 requests, of which 21 were granted (78%). The number has increased steadily year over year, with 187 requests received in 2016, of which 131 were granted (70%).

If granted, Fast Track can bolster a company’s stock valuation by 18%, making it attractive to smaller biotechs. According to a 2009 review of the program, Fast Track was the most significant factor among variables affecting the chances of first-cycle approval, with 78% of Fast Track applications accomplishing this milestone.

The barriers to entry have risen over time. “Although many experts today would argue that a bit more is typically needed to gain Fast Track status (e.g., early biological response data in humans), it’s clear that the evidentiary hurdle remains reasonably low,” Mathieu said. “The success rates for Fast Track applications submitted to FDA’s Center for Drug Evaluation and Research (CDER) have ranged between 70% and 80% over the last three years.”

Once Fast Track is granted, there are significant benefits to a sponsor company, including the ability to “put in parts of your application piecemeal” and less risk of an “action by the FDA that would slow things down,” said Christopher-Paul Milne, director of Research, Tufts Center for the Study of Drug Development (CSDD).

“Basically, that’s what Fast Track is designed to do—head off problems while you’re in your normal development cycle,” Milne said. In addition, the program may trim the cost of drug development by shorting research timelines, opening up the opportunity of early approval.

Ultimately, the Fast Track program has been deemed a success, with approximately two thirds of all 770 Fast Track requests approved by the FDA from 2007 to 2015, according to the Government Accountability Office (GAO). The Fast Track program has “withstood the test of time” and is unlikely to be curtailed under the new FDA Commissioner Scott Gottlieb, said Milne.

Looking to the future, changes to the Fast Track program are likely to be modest, said Milne. “What may evolve,” Milne added, “is how the FDA develops other programs for unmet needs that would involve making such R&D programs eligible for Fast Track and other expedited review incentives.”

Milne added that Fast Track might even be more relevant today than ever before because as much as 80% of the pipeline is being developed by small and medium-sized companies. These companies are attracted to the program because of the relatively low barrier to entry, the fact that the application itself is not very labor intensive and because of the potential to generate investor attention if granted.

According to Laurie Halloran, president, Halloran Consulting Group, Fast Track designation is likely to become even more prevalent due to top-down pressure FDA’s public promises to get drugs in the hands of patients sooner, and due to a bottom-up approach from drug companies hoping to trim development costs in the face of growing pricing pressure from patients and payers alike.

Fast Track renaissance

Relative to other expedited review programs, the Fast Track designation is considered low risk, with modest rewards. In recent years, the designation has experienced something of a renaissance, Mathieu said.

“Because the Fast Track program was modestly active, with about 40 designations annually on the CDER side, in the years leading up to the introduction of the more-coveted Breakthrough Therapy program in late 2012, many may expect a decline in interest in Fast Track,” he explained.

“Instead, we’ve seen just the opposite. The Breakthrough Therapy era has ushered in a renewed and unprecedented interest in the Fast Track program, which saw a record 187 industry submissions and 131 designations (CDER) in 2016,” Mathieu said.

According to Parexel data from 2011 to 2016, Fast Track designation may lead to a modest, seven-month advantage in clinical development timelines, Mathieu said. “[However,] because we have begun to see increasing numbers of cancer therapies skip Fast Track and gain Breakthrough Therapy designation when possible, the relative advantage that we have traditionally seen for Fast Track products has declined in recent years.”

According CDER, the agency saw an uptick in Fast Track requests in 2014, 2015 and 2016, possibly due to heightened awareness of the program after the FDA released new guidance in 2014.

“When viewed alongside something like Breakthrough Therapy designation or [Accelerated Approval], Fast Track is not typically seen as a particularly valuable designation, at least in terms of its ability to accelerate development,” said Mathieu. “On the other hand, companies continue to pursue and obtain Fast Track designations in record numbers.”

When it comes to actual approvals, approximately 35% of Breakthrough designations are probably granted every year, while Fast Track designations are granted about two thirds of the time, Milne said.

While “not all Fast Track products result in approval ... this is not a surprise, particularly given how early in development some Fast Track designations are granted, and that the qualifying hurdle remains relatively low,” Mathieu said. “On the other hand, a recent Informa Pharma Intelligence analysis shows that products with Fast Track designation have a somewhat higher likelihood of approval when compared with all products,” rivaling that of orphan drugs.

“For 2016 approvals, Fast Track and Breakthrough Therapy designations were about equal,” Milne said. “So you know it’s still tracking as an important component of development programs. It’s been around for 20 years, so regulatory affairs people kind of know it. They know the people making the decisions, they have people now who have put together numerous designations. Breakthrough Therapy designation is still new.”

Impacts to clinical research

Over the past 20 years, the existence of the Fast Track program and other expedited review programs has undoubtedly impacted the clinical research industry, changing the way protocols are run and accelerating the overall pace of research.

Importantly, Fast Track designated drugs can been approved with phase II data, making robust, early phase trials a more important part in the development process.

“It’s better to know as early as possible if the drug candidate has the potential for being Fast-Tracked,” said Halloran, meaning companies may need to design a more robust phase II study with a large number of patients because of the need to provide a more powerful statistical analysis to the FDA.

“There is no free pass,” said Halloran. “Every time you try to do an interim analysis, you have to enroll more patients to make up for the statistical impact.”

Milne agreed that companies will not want to “jeopardize momentum by under-performing in phase II trials.”

“Another effect of expedited review programs like Fast Track has been to accelerate the pace of drug development,” said Andrew Zupnick, Ph.D., vice president, Oncology Strategy at Novella Clinical. “Today, drug development in oncology has reached a near-frenzied pace thanks to these expedited programs and rapid advancements in science,” Zupnick said, noting oncology companies feel an “immense pressure to stay ahead of the development curve.”

Across the clinical research industry, this has created a “shift in the way that protocols are run,” Zupnick said. “In oncology, clinical research is still centered at larger academic institutions, which may not have as much flexibility to bend and shift. Things move quickly, and you may need to amend a protocol to move in a different direction.”

Staffing at sites has become problematic, reaching “a point where there are not enough clinical researchers for the amount of exciting science moving into the clinic,” Zupnick said. “There are thousands of open clinical research associate and coordinator positions nationwide that cannot be filled, and we have seen some clinical research sites turn down new trials because they simply don’t have enough research staff.”

“Another issue is patient enrollment,” said Halloran. “There are fewer opportunities to look for exceptions in protocol criteria” in phase II trials.

Zupnick agreed that “enrollment is always the number one challenge.”

Safety Issues

Throughout its history, the FDA has sought to balance safety and speed in its drug approval process. During the AIDS crisis, the FDA was criticized for being slow to review and approve antiretroviral treatment as tens of thousands of people died. Subsequently, the agency created pathways to dramatically speed up drug approvals, recognizing the increased risk is worthwhile because of the potential to save lives.

Today, some argue that the pendulum has swung too far, and that Fast Track and other expedited review programs unnecessarily rush drug approvals without sufficient safety data.

“The intent is to get newer therapies that address an unmet medical need into patients’ hands faster, recognizing the potential outcome that you could push something through that hasn’t been fully vetted for safety effects,” said Zupnick.

In fact, explained Halloran, due to the reduced time before drug approvals over the last five years, 57% of drugs approved through the Fast Track pathway received a black box warning after approval.

“Black box warnings open up complicated and potentially negative pathways forward, and could be a topic for a more expanded discussion all on their own. If they can be avoided, it’s ideal,” said Halloran.

Zupnick added that the FDA has signaled to the pharmaceutical industry that it prefers to get life-saving drugs onto the market faster, with the risk that some may eventually be pulled or labels modified as longer term or unexpected safety data emerge.

Ultimately, however, the concerns hovering around the Fast Track program cannot be divorced from other expedited review programs, which have also faced criticism for neglecting safety signals. In fact, a recent analysis of all drugs approved by the FDA from 2001 to 2010 found that nearly a third had major safety issues after approval, according to researchers at Yale School of Medicine.

According to a 2015 report by GAO that evaluated Fast Track and Breakthrough designations, the most important way to improve public safety is to better track and enforce post-market safety studies rather than dramatically altering the review programs themselves.

“The thing is,” said Tufts CSDD’s Milne, “these drugs are more risky because they are more novel. I think if there were really compelling evidence over 20 years that these programs are leading to more risky drugs coming out onto the market, then the FDA would do a review.”

Looking to the Future

While the Breakthrough Therapy designation is likely to remain a popular choice for companies pursuing oncology agents, the Fast Track program has a bright future as a harbinger of high-unmet-need drug candidates.

“The current trend appears to be that there is less interest in Fast Track among companies developing cancer products, in large part because the state of the science has created an environment in which companies can show striking efficacy signals very early in development in select patient populations,” said Parexel’s Mathieu. “This is leading to greater numbers of companies skipping Fast Track and going to Breakthrough.”

However, Mathieu noted, the Fast Track program is now being driven by neurology products, and a “sudden rise in Center for Biologics Evaluation and Research (CBER)-regulated product designations for gene and cell therapies.

“We have so many small and medium sized startup companies doing research into areas with unmet medical need, [the FDA] may start to put together targeted programs using Fast Track as the basic incentive program to encourage development in those high unmet need areas,” Milne said.

Indeed, there is already one such program designed to address the threat of antibiotic resistance—the 2012 Generating Antibiotic Incentives Now (GAIN) Act, passed as part of the Food and Drug Administration Safety and Innovation Act.

“Under GAIN, a drug or biologic may be designated as a qualified infectious disease product (QIDP) if it meets the criteria outlined in the statute,” said a CDER spokesperson. “A drug or biologic that receives QIDP designation is eligible under the statute for Fast Track designation (upon request) and/or Priority Review.”

In the future, the FDA might do something similar to encourage drug development in other conditions such as cardiovascular disease, which is still a top killer in the U.S., Milne noted.

It’s unlikely that Fast Track will change much under new FDA Commissioner Scott Gottlieb, agreed Halloran and Milne. Broadly, the new administration appears to be focused on decreasing the cost of drugs, Halloran noted.

“There are two ways to do that—encourage market competition or introduce generics earlier,” she said. “Fast Track is at the opposite end of that spectrum because it is designed to usher in drugs for which there are no alternative treatments.”

“In my opinion, Fast Track designation products will be at the lower end of the list in terms of scrutiny over pricing,” she said, adding it would still be poor positioning for sponsors to aim for the high-end price of what the market can bear with Fast Track approved drugs.

In addition, “with the President’s budget being tight,” most of the discussions at the FDA appear to be focused on improving generics and competition rather than changing the Fast Track program, said Milne.

As a low-risk program with modest rewards, Fast Track has emerged as something of an enigma among its peers and demonstrated staying power over several decades.  

 

Sony Salzman is a freelance journalist reporting on healthcare and medicine. She earned her Master’s degree from Boston University’s Science Journalism program, and has won multiple awards for narrative writing and radio journalism. She can be reached at sonysalz@gmail.com, or on Twitter @sonysalz.

This article was reprinted from Volume 24, Issue 10, of The CenterWatch Monthly, an industry leading publication providing hard-hitting, authoritative business and financial coverage of the clinical research space. Subscribe >>