Moving mountains: balancing safety and speed in drug development

The speedy review of urgently needed medicines is a key objective of any drug regulatory body, as is maintaining high safety standards. But what is the right balance between the two, and what can we learn from major public health crises and the practices of the US FDA, the fastest of the world’s premier drug regulators?


The investment in time and cost for a pharmaceutical company to bring a new drug to market has been the subject of much discussion in industry and regulatory circles for decades. According to the most recent data published by the US-based Tufts Center for the Study of Drug Development, the average cost – including out-of-pocket costs, time costs and expenses incurred for failed drug candidates – to develop and secure marketing approval for a new drug now tops $2.5bn, and the process can take a decade or more.

High development costs are a common explanation for high drug prices post-approval, but the stretch of time it takes to take a drug through multi-phase clinical trials and obtain marketing approval from regulators is an equal source of consternation for patients who might have to wait years for a potentially breakthrough treatment to become available.

Balancing safety and speed

There are a host of scientific and technical challenges involved in the drug discovery process, but in many ways, it’s the process starting after an experimental drug has been approved for human trials that slows the pace of new drug approvals the most. A meticulous review period is an important mechanism to ensure the efficacy and safety of a treatment before it reaches patients in earnest, but there are downsides. These include a potentially dampening effect on the innovative drug pipeline and an inability to respond quickly to emerging health crises.

As such, the regulatory authorities responsible for approving new drugs are continually working to strike the optimal balance between an efficient pace of drug development and maintaining the highest safety and efficacy standards to protect public health. A US Food and Drug Administration (FDA) white paper discussing its efforts to accelerate innovative drug approvals emphasises the importance of this balance.

“Congress’s focus on optimizing speed of access as well as safety and effectiveness is challenging but necessary – both are critical to the health of American patients,” the review notes in its introduction. “Market strength depends on American and worldwide confidence in the quality and rigor of FDA’s oversight of drug safety and effectiveness, while continued development of innovative new drugs is aided by a swift, predictable approval process.”

"Continued development of innovative new drugs is aided by a swift, predictable approval process."

The FDA certainly has some reason to claim it is doing better than its peers when it comes to navigating a course between these two objectives. While the FDA has maintained its position – alongside the likes of the European Medicines Agency (EMA) and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) – as one of the world’s most trusted regulatory agencies, it has also been leading the world in the timeliness of its approvals process, with around 60% of novel drugs introduced in the US ahead of any other country.

“Average review times by FDA have been consistently faster than regulatory agencies in other countries,” states the FDA white paper. “Indeed, 76% of the new drugs approved by Japan, [the] EU and FDA from 2009 to 2013 were approved first by FDA.”

Health crises: need breeds speed

Major public health crises often prompt the pharmaceutical industry and associated institutions to come together to accelerate the development of a given treatment or preventative measure. One of the most prominent recent examples is the widespread Ebola epidemic in West Africa, which claimed more than 11,000 lives between 2014 and 2016, primarily in Guinea, Sierra Leone and Liberia.

Although numerous Ebola vaccines had been under development prior to the outbreak, it took the urgency of an emerging epidemic and the threat of pandemic to push a vaccine candidate through trials at an accelerated pace. The scale of the crisis, not to mention the political pressure from the many groups demanding a more robust international response, effectively condensed a decade of R&D into a 10-month period.

The breakthrough – the rVSV ZEBOV vaccine discovered by the Public Health Agency of Canada and now being developed by Merck – didn’t come quickly enough to be a factor in the outbreak itself. The epidemic was in decline by the time clinical trials took place in 2015, so a ‘ring vaccination’ approach was adopted, whereby the immediate contacts of infected individuals were vaccinated to prevent further spread.

Nevertheless, the trial’s final results, published in The Lancet in December, demonstrated 100% efficacy against Ebola virus infection. Merck is now conducting additional safety studies for children and other patient groups, and is looking to obtain FDA approval by the end of this year. The company’s commitment to making 300,000 vaccines available in the case of another epidemic should help to ensure that any future outbreaks are much more effectively contained.

“The Ebola vaccine studies during the Ebola outbreak were one of the few successes of the collective international response,” said John-Arne Røttingen, director of infectious disease control at the Norwegian Institute of Public Health, which contributed to the rVSV ZEBOV study. “The world managed to plan and conduct more than 15 clinical trials in less than a year. And this ring vaccination trial, with its innovative research design, managed to demonstrate efficacy for one of the vaccines.”

FDA approvals: life on the fast track

It was a similarly dire public health crisis that laid the foundation for the FDA’s sustained efforts to expedite its drug approval process. As the HIV/AIDS epidemic – the epicentres of which were US cities including New York, Los Angeles and San Francisco – continued to claim tens of thousands of lives and ravage inner-city communities through the 1980s and 1990s, political pressure quickly built up to demand a faster pharmaceutical response to the virus. This galvanising energy was harnessed potently by advocacy groups like ACT UP, which organised large-scale demonstrations and protested outside the FDA’s then-headquarters in Rockville, Maryland, chanting “42,000 dead from AIDS, where was the FDA?”

It was this pressure that helped prompt a new accelerated approval system, along with the orphan drug designation launched in 1983, which brought AZT (zidovudine), the first antiretroviral therapy to prevent and treat HIV/AIDS, to the market in record time. The drug was brought through clinical trials and approved by the FDA between July 1985 and March 1987 in a 20-month period that still ranks as one of the shortest drug development periods in history.

From there, the FDA has continually expanded its expedited review initiatives, funded by the 1992 Prescription Drug User Fee Act, which authorised the agency to collect fees from pharma companies to invest in new drug approval processes.

"The FDA has continually expanded its expedited review initiatives, funded by the 1992 Prescription Drug User Fee Act."

These have included the accelerated approval designation, launched in 1992, which allows important drugs to use a surrogate endpoint without the need for extensive Phase 3 trial results before approval. Priority review, launched in same year, provides a shortened six-month review period for new drug applications with the potential to meaningfully improve the treatment of serious conditions.

The fast track designation was introduced in 1997, giving drug developers more opportunities to interact with the FDA and allowing a rolling review of data, which allows companies to submit sections of their new drug applications for review before the whole application is complete. And more recently, the breakthrough therapy designation was launched in 2012 under the Food and Drug Administration Safety and Innovation Act (FDASIA), allowing rolling review and essentially making the FDA a partner to breakthrough developers, with the agency providing extensive guidance on efficient drug development and making every effort to expedite the review process.

Expedited approval: a victim of its own success?

The FDA’s growing list of expedited approval programmes has been a major success by many metrics, embraced by the industry and dramatically speeding up drug development and review times in the US. These programmes have rapidly ushered in many innovative new treatments, such as Bristol-Myers Squibb’s anti-cancer immunotherapy Opdivo (nivolumab), which benefited from breakthrough therapy and fast track designations, as well as priority review status. Other speedy approvals include Novartis’s cancer treatment Gleevec, which was approved in 2001 after less than three months of review, having gained fast track and priority review.

There have been concerns, however, that the popularity of these schemes might be undermining their original purpose. Some critics have pointed out that these designations are intended for the cream of the crop of innovative drugs, and the broad language used to define the designations’ entry criteria (usually a variation of providing a “significant improvement” in the treatment of “serious conditions”) has left the door open to too many therapies, with expedited approvals becoming the norm rather than the exception. This could be accelerating the introduction of a whole slew of incremental therapeutic improvements at the expense of the most innovative and urgently needed treatments.

A 2015 study published in the British Medical Journal (BMJ) found that the proportion of new drug candidates using one or more accelerated-review designations has increased by an average of 2.4% a year since 1987, and in the 21st century, the proportion of drugs developed under expedited review or orphan drug designations has regularly reached or exceeded 60% in a given year.

“One possibility is the idea of designation creep,” Harvard Medical School research associate Dr Aaron Kesselheim, who contributed to the BMJ study, told The Scientist in a January 2016 interview. “Over time…the application of these pathways broadens to encompass drugs that the pathways were maybe not intended to encompass.”

Others simply focus on the public safety risk of having so many drugs approved on an expedited schedule. The breakthrough therapy status, for example, was originally envisioned in 2012 as a designation that might be applied to only a few drugs a year, but just over three years after the launch of the programme, 104 of these designations had been issued from 337 applications. Could these schemes be threatening public safety by becoming victims of their own popularity?

“There’s clear evidence that when reviews are done in half the time, it significantly increases the risks of hospitalisation and death,” Rowan University professor of comparative health policy Dr Donald Light – a long-time critic of the FDA’s practices – told The Scientist last year.

In the delicate tightrope walk between speed and safety in drug development, has the FDA lost balance in the quest for accelerated access to new drugs? Certainly the agency has maintained its reputation as a world leader in rigorous oversight while revolutionising the efficiency of its review processes, but whether its expedited programmes have become too bloated and compromised remains to be seen. In the meantime, the discussion continues.