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STAT News – Janet Woodcock revolutionized the way the FDA reviews cancer drugs, inspiring her supporters and raising concerns for detractors

STAT News – Janet Woodcock revolutionized the way the FDA reviews cancer drugs, inspiring her supporters and raising concerns for detractors

WASHINGTON — In 2000, the Food and Drug Administration approved just three cancer drugs. Last year, even with the agency laser-focused on the coronavirus pandemic, much of its staff teleworking, the agency still approved a record-breaking 17 different cancer therapies — more than in any other category.

That’s the legacy of FDA drug center chief Janet Woodcock.

Woodcock, a 36-year veteran of the agency, is infamous for pushing the FDA to loosen its standards for drugs for rare conditions like Duchenne muscular dystrophy. But Woodcock’s most lasting impact at the FDA is her transformation of the way the agency approaches cancer drug approvals.

Woodcock personally championed efforts to fast-track cancer therapies through FDA’s typically arduous review process, pushed the agency to embrace new types of clinical trials meant to bring these drugs to market faster, and even set up a special office at the agency, which reports directly to the commissioner, to deal with cancer — a privilege not bestowed on any other condition, no matter how deadly.

Now the nation’s top cancer doctors are emerging as Woodcock’s most vocal backers in her campaign to become President Biden’s FDA commissioner. Last month, more than 90 leading oncologists penned an open letter calling for Woodcock to get the job. In interviews with STAT, those signatories and other doctors described her as a “hero,” a “breath of fresh air” and a visionary who has helped the FDA keep up with the rapidly evolving science in fighting cancer, from bespoke CAR-T therapies engineered from patient’s own cells to tests that pinpoint the genetic mutations at the root of a patient’s cancer diagnosis.

“Based on her track record, I’m convinced that she would be outstanding,” said Carl June, the University of Pennsylvania oncologist credited with pioneering CAR-T therapy. “She’s trying to force change. The FDA was established under completely different drug development paradigms than what we have now.”

Oncologists’ embrace of Woodcock is significant because of the political connections they boast with Biden and his top staff. Seventeen of those who signed the endorsement were members of the “blue ribbon” cancer panel that Biden stood up in 2016 as vice president. Biden’s top science advisor, Eric Lander, has also been effusive about his respect for the FDA and Janet Woodcock.

Even the oncologist who treated Biden’s son, Beau, for brain cancer has a personal connection to Woodcock: She helped him design a first-of-its-kind brain cancer trial.

“She’s an innovator,” said W.K. Alfred Yung, Beau Biden’s doctor who is a professor at MD Anderson Cancer Center. “Janet is one of the people who really sees that we need to find new ways, and be more creative and more innovative to make things move faster.”

Critics say Woodcock’s cancer crusade has come at a cost. With the speed has come an erosion of the agency’s high standards and an increasing willingness to greenlight drugs that haven’t actually been proven to extend a patient’s life.

“Janet is not helping anybody by putting drugs on the market if they don’t work,” said Gregg Gonsalves, an assistant professor at Yale University who has publicly endorsed another expert for the FDA job. “To all the cancer groups who say [the FDA] brought us all these new drugs on the market, I say bring me the data that shows me they have a survival benefit for patients and then we can talk.”

It’s a view that even some former FDA officials hold; one described Woodcock as pushing “flexibility even at the expense of science.”

Woodcock wasn’t always beloved by cancer advocates.

In 2003, cancer patients and their doctors were sounding the alarm that the FDA’s unhurried regulatory process was a major problem — an echo of the arguments that AIDS activists had used a decade and a half earlier to push for accelerated approvals.

The FDA’s approach toward cancer drug reviews at the time was scattershot at best. The science around cancer drugs was rapidly improving — the FDA had approved Gleevec, which was widely regarded as one of the most effective cancer treatments ever — but the agency was still approving less than half a dozen cancer drugs per year. Responsibility for reviewing those medicines was spread throughout the agency, buoying concerns from advocates that the agency was applying wildly different standards to different kinds of cancer treatments.

“I hated Janet Woodcock but I didn’t know why,” said Ellen Sigal, the founder of Friends of Cancer Research and now, one of Woodcock’s biggest backers. “The cancer community was really angry with her and thought the FDA was not doing everything [it] could for cancer.”

Then, in 2004, Woodcock challenged then-FDA commissioner Mark McClellan to stand up an FDA initiative to improve clinical trials writ large. Soon after, she was transferred to the commissioner’s personal office, where she jumpstarted a multi-decade effort, known as the critical path initiative, to help drug companies improve their clinical trials.

It was that initiative that led Woodcock to reach out to cancer advocates like Sigal, who used the meeting as an opportunity to argue that the FDA needed “a wholesale change” in how the FDA approached cancer treatments.

“She was fully on board,” Sigal said.

Cancer advocates saw their first major win later that year when the FDA created a new office charged with overseeing the review of nearly all the cancer drug applications submitted to the agency. The FDA insisted the office would “significantly improve efficiency and consistency of product reviews, so cancer patients will have access to new treatments quickly.”

For cancer drug makers and cancer doctors, the victories have kept coming ever since.

When cancer advocates came up with a new idea for a special pathway for drugs that showed promise in early clinical trials, Woodcock threw her support behind it. So much so that Sigal insists the pathway, now known as a Breakthrough Therapy designation, would never have existed without her support.

When a panel of cancer experts convened by then-Vice President Joe Biden pushed for the creation of a cancer office that reported directly to the FDA commissioner, Woodcock threw her support behind that, too.

Woodcock has also pushed the FDA, both publicly and privately, to accept new forms of clinical trials, much to the delight of academic researchers, pharmaceutical companies, and patient advocates.

She was an early supporter of efforts to stand up the first so-called platform trials, which test multiple drugs at once. She even sits on the oversight board of two such cancer trials: I-SPY, which studies breast cancer drugs and LungMap, which studies drugs for lung cancer — an unusual move for a regulator that some advocates have claimed is a conflict of interest.

“She saw that this was the future … even when people at FDA were fairly resistant, because it was new to everybody,” said Lisa LaVange, the former director of the FDA drug center’s office of biostatistics.

Some of the credit for cancer’s meteoric rise at the FDA also belongs to Rick Pazdur, the longtime director of FDA’s oncology office, multiple sources argued. Pazdur, who cancer advocates have also floated as a potential commissioner, has led the FDA’s cancer work since 1999.

If the ultimate measure of Woodcock’s impact on cancer drugs is the number approved by the FDA, her tenure has been a standout success.

Cancer drug approvals as a share of all U.S. drug approvals increased nearly seven-fold from 1980s to 2018, according to research from the Tufts University Center for the Study of Drug Development.

Cancer drugs were also nearly twice as likely as other drugs to get a priority rating from the FDA, a designation that entitles a drug maker to a 6-month FDA review, rather than 10-months.

The FDA is quick to note that it hasn’t formally changed its approval standards. However, multiple researchers and former agency staff who worked directly with Woodcock acknowledged that she has pushed regulators to be more flexible and more willing to approve drugs treating unmet medical needs.

“It’s a dramatic difference,” said Robert Young, president of RCYMedicine and the former president and CEO of Fox Chase Cancer Center. “They were not living in the world of physicians out there trying to figure out how to treat patients better.”

Woodcock, to be fair, can’t take credit for the rapid advances in the science of cancer drug development, although some of the cancer researchers at the heart of those advancements insist that Woodcock’s flexibility was a large factor in getting those discoveries to market.

“The cutting edge in oncology has been moving at such a clip that we would be paying a serious penalty in the field … were it not for the fact that the FDA has basically ceased to be the rate limiting step,” said Keith Flaherty, the director of clinical research at Mass General Cancer Center. “For the FDA to basically have become the enabler as opposed to a hindrance, that’s just a cultural revolution compared to how people talked about the FDA at the dawn of my career.”

With that new “enabler” role has come a newfound willingness at the FDA to help researchers and drug makers understand what sorts of studies they need to do to gain FDA approval, multiple researchers confirmed to STAT.

“In the past, the FDA’s approach was: ‘We won’t tell you what we need to have … send us what you do and we will tell you if it’s okay or not,” said Young. “Now you can go to the FDA if you’ve got a new drug and say ‘this is the trial we are going to do, do you have suggestions about how that trial might be done?’”

Woodcock’s detractors see those same record-breaking drug approval numbers, however, as a major concern.

Her critics say that under her tenure, the FDA has become far too lenient toward shoddy studies that don’t actually demonstrate a drug will prolong a patients’ life.

Their complaint mostly revolves around Woodcock’s willingness to accept studies testing drugs based on so-called surrogate endpoints, measures like the shrinkage of a tumor, rather testing a drug based on how long it keeps a patient alive.

The debate over the utility of surrogate endpoints has been raging since the FDA began relying on them in response to the AIDS crisis, but it has only intensified under Woodcock’s watch.

“We know from the AIDS epidemic be careful what you ask for — I get it, when patients are desperate —  I was there, I’ve been there,” said Gonsalves, the Yale professor who also protested the FDA in the 1980s as an AIDS activist. “Janet didn’t create accelerated approval but she didn’t learn the lessons from it. The lessons from accelerated approval and AIDS were whoops we put a bunch of drugs out on the market for five years or more which we didn’t know worked.”

Woodcock’s critics point to a handful of cancer drug approvals as clear examples of the FDA’s recent missteps. Breast cancer advocates, for example, cited the FDA’s decision in 2008 to fast track the approval of the cancer drug Avastin to treat breast cancer only for the drug to be pulled off the market less than a decade later when the FDA found that it not only didn’t prolong life, but had potentially deadly side effects. Critics have also pounced on the FDA’s recent decision to grant accelerated approval for the multiple myeloma drug selinexor over the objections of an FDA expert panel.

Most critics acknowledge that there’s only a handful of clear missteps when it comes to the FDA’s cancer drug approvals of the last two decades, but they insist that more are likely hiding in plain sight. They argue that the FDA’s reliance on surrogate endpoints means that the general public just doesn’t know which cancer drugs work or don’t.

“For many cancers there is an improvement in survival, the question is which drugs are responsible for that and which ones aren’t, that’s the big unknown and that’s what’s so frustrating,” said Diana Zuckerman, the president of the National Center for Health Research.

The end result of this confusion, critics argue, is that doctors and patients are left guessing whether a drug is truly effective, or worth the money.

It’s true that under Woodcock’s watch, the FDA has become more accepting of that type of study. A review published last year in JAMA found that the FDA had approved cancer drugs based on surrogate endpoints 194 times since 1992, and that the agency’s rate of relying on surrogates was increasing.

The author, Vinay Prasad was the only cancer doctor who STAT found who would criticize Woodcock. The associate professor at the University of California San Francisco, who’s a trained hematologist oncologist, called her “generally acceptive of lax standards.”

He says he’s not surprised most of his colleagues have high praise for Woodcock, even if the FDA’s standards have been lowered.

“Everyone’s career benefits from drug approvals and whether or not those drugs actually help people live longer, live better, that’s a concern that largely doesn’t impact the careers of most oncologists,” said Prasad.

STAT could only find two cancer advocacy organizations, Breast Cancer Action and the National Breast Cancer Coalition, who were willing to criticize the FDA’s approach under Woodcock, but they, like Prasad, were emphatic in their belief that the recent advancements in cancer care touted by top oncologists were not true gains for patients.

“It’s not innovative because you can get drugs approved more quickly, that’s not innovation. Innovation is drugs that will actually have a significant impact on people’s lives,” said Fran Visco, the president of the National Breast Cancer Coalition. “If your goal is to get as many drugs out as you can, as quickly as you can … then they’re doing a great job.”…