How Woodcock has changed FDA

In 35 years at FDA, Janet Woodcock has reshaped the way drugs are regulated and developed

Imagine a world in which drug sponsors must guess about FDA’s approval requirements, often learning years later that they had guessed wrong and must conduct new trials. Consider what it would mean to patients if rigid standards made it impossible to develop drugs to treat rare conditions or use accelerated approval for diseases other than AIDS or cancer. In this world, regulators dismiss patient perspectives as irrelevant distractions, and companies stick with obsolete manufacturing technologies for fear of triggering ruinous regulatory actions.  

That was the world in 1986 when Janet Woodcock joined FDA.

The situation is very different today, in large measure because of her actions and leadership.

As director of the Center for Drug Evaluation and Research (CDER), a position she held from 1994 to 2004 and returned to in 2007 after serving in the Commissioner’s Office, Woodcock transformed the way drugs are regulated, and in the process changed the pathway from the lab to the bedside.

Concerns about FDA’s failure in the 1990s and early 2000s to rein in opioids, along with a powerful senator’s personal animus, seem to have derailed President Joe Biden’s plan to turn Woodcock from acting to confirmed FDA commissioner. While Woodcock’s future at FDA is uncertain, the significance of her legacy is indisputable.

Some of the sharpest medical minds have taken to the pages of medical journals and, along with others, have employed social media platforms to express disagreement and dismay with some of Woodcock’s decisions. Few people who have closely followed FDA for the last three decades agreed with everything she did.

In addition to castigating Woodcock for approving drugs they believed did more harm than good, she has been criticized for delaying easy access to emergency contraception and for over- or under-regulating compounding, biosimilars and other drug classes. Illuminated by the clear light of retrospection, critics have detailed missed opportunities, describing actions she should or could have taken.

Even where the criticisms are legitimate, they do not tell the full story of Woodcock’s three and half decades in FDA leadership positions.

Some of Woodcock’s most important contributions have required deep dives into waters where few others would dip their toes. She has spent years identifying and trying to fix complex problems that are barely visible outside FDA.

When Woodcock discussed her tenure at FDA in an interview last week with BioCentury she declined to discuss her future or speculate on the politics of confirming a permanent commissioner, but she did discuss some of her actions that have been heavily criticized. 

Reflecting on her time as CDER director, she also highlighted activities that were not obvious to the public or even to regulated companies. “I spent a huge amount of time on improving organization, everything from making sure  FOIA requests actually were responded to, to making sure we had a budget process that was robust, and to making sure that we did planning every year,” Woodcock told BioCentury. “Despite what academia might say, compared to 20 years ago, the drug process is much more professional, much more robust, much more consistent, much more transparent.”

Woodcock led CDER from a paper-based, artisanal approach to reviewing drugs to a more systematic, professionally managed system that is held accountable for meeting tight quality measures and deadlines.

“All of those things took a really heavy lift,” Woodcock said.

She has reveled in becoming an expert in areas that most clinicians would find mind numbingly boring and then trying to apply that expertise in disparate realms, for example by improving FDA’s IT systems, applying modern quality systems to drug manufacturing, and fostering innovative trial designs.

Along the way, Woodcock changed the paradigm for drug review.

Two kinds of error

Woodcock joined the Center for Biologics Research and Evaluation (CBER) in 1986 as director of the Division of Biological Investigational New Drugs.

In 1993, as acting director of CBER’s Office of Therapeutics Research and Review, she signed off on an accelerated approval of Betaseron interferon-1B for multiple sclerosis on the basis of a single trial, disregarding objections from FDA reviewers and academics who believed two trials should be required and that MRI data on brain lesions were not sufficient to support accelerated approval. The drug is still used to treat MS today.

The next year, having been named CDER director, she took charge of a review culture that had been shaped a generation earlier by narrowly avoided tragedy. The realization that only the tenacity of a single reviewer, Frances Kelsey, prevented a catastrophic decision to approve thalidomide instilled a fear of approving drugs that could turn out to be dangerous or ineffective.  

The most fundamental change Woodcock achieved was to balance that fear with an enthusiasm for facilitating approvals of effective drugs.

“Everyone focuses on the risk of approving a drug that doesn’t work” Lauren Silvis, SVP for external affairs at Tempus Labs Inc. and former FDA chief of staff, told BioCentury. “Janet reminded reviewers that they also had to consider the consequences of not approving a drug that does work.”

A type two error, failing to get a good drug on the market, could hurt patients as much as a type one error of allowing a bad drug to slip through the regulatory gate.

Woodcock challenged reviewers to reconsider their approach to FDA’s legal authorities, encouraging them to interpret laws and regulations in ways that meet the needs of patients.

Bringing patient perspectives into the regulatory process, broadening it from dispassionate assessments of data to include the messier realm of hopes and fears, is another underlying theme in her career.

Willingness to accept risk that a drug may not fulfill its promise, stretching laws and regulations, and giving patients a seat at the table where decisions are made have always been contentious.

In recent years these streams have coalesced into controversies that threaten to overshadow a career that includes accomplishments Woodcock’s critics may not be aware of.

Internal criticism has come from FDA staff who felt she strayed too far from objective evidence and wasn’t sufficiently deferential to precedent or respectful of opinions she didn’t share.

Outside FDA, her actions have been celebrated as examples of regulatory flexibility by those who agreed with decisions, and condemned by those who opposed them as reckless violations of FDA’s responsibility to ground its decisions in science and the law.

Chipping away at the two-trial dogma

When she became CDER director in 1994 and for several years after, “we had divisions insisting on two trials for approvals of everything, including closely related indications, or even for approvals of dosage forms,” Woodcock told BioCentury. “It was like Noah's Ark, marching two by two.”

The requirements were irrational, she said, because nothing was gained by duplicating effort when  “one more trial would really give you extremely robust evidence.”

In 1997-98, Woodcock and Robert Temple, acting deputy director of CDER’s Office of Drug Evaluation-I, co-authored guidance documents that chipped away at the two-trial dogma.

“We had many reviewers at the time who thought you should do the same study twice,” Woodcock told BioCentury. “What we said in the guidance is, no, if you study some other aspect of the disease and also show the drug’s effective, that's even more robust evidence and it's actually more informative than just repeating the same thing over and over again.”

The ideas are not controversial now, but “at the time these were new concepts,” Woodcock said. “It gets down to those weren’t the questions to ask, so why should we put patients through all these different trials just to check a box.”

By changing the standard so one highly persuasive, statistically significant study, or a single study together with confirmatory evidence, could support approval of a drug, “Janet Woodcock changed medicine,” Frank Sasinowski, a director at the law firm Hyman, Phelps & McNamara and a former senior FDA official, told BioCentury.

Ending moving target syndrome

Before the 1990s, drug companies routinely experienced “moving target syndrome,” Peter Hutt, senior counsel at Covington and Burling, told BioCentury. Hutt served as FDA chief counsel from 1971-75.

“Companies used to go into a meeting with FDA and say, ‘You told us three years ago our protocol was okay, here are our statistically significant results.’ The people on the other side of the table would say ‘We changed our mind, you have to do another three-year trial.’ That used to happen every day.”

Woodcock led the negotiation of PDUFA agreements that created commitments and timetables for meetings between drug companies and FDA reviewers.

FDA officials participate in thousands of such meetings every year, dramatically increasing the predictability and efficiency of drug development.

Industry still complains that FDA moves the goalposts, but the situation is dramatically different from the time when the agency felt no obligation to provide insights into its requirements.

Academic critics have suggested that user fees and frequent communications with industry have led FDA to become captive to the industry it regulates to the detriment of patients.

Woodcock dismisses these arguments, telling BioCentury that meetings with companies benefit patients by avoiding unnecessary trials. “If development programs go on without knowing what the FDA expects, you are wasting the lives of people who volunteer to be in trials.”

FDA has an obligation, she said, to help drug developers understand its requirements. “We can't sit back at the end of the day like the Romans and say thumbs up or thumbs down. We have to be in there setting the standards for what bar a company needs to get over, what they need to prove on behalf of the people who are going to participate in that development program and on behalf of the people who will benefit if the product actually is useful.”

Critical Path report

In 2004, when she was serving as deputy commissioner and chief medical officer, then-FDA Commissioner Mark McClellan asked Woodcock to look into the causes for a slowdown in drug development and to propose ways FDA could help reverse it.

By calling attention to the applied science needed to make good regulatory decisions, the report she produced, “Challenge and Opportunity on the Critical Path to New Technologies,” changed the way FDA conceived of its mission and the way the agency was perceived.

“The critical path report really brought the importance of the science of drug regulation into sharp focus for me, and led me to position advancing regulatory science as one of my top priorities during my tenure as FDA commissioner,” former FDA Commissioner Margaret Hamburg told BioCentury.

Looking back 17 years later, McClellan pinpointed the critical path report as a turning point for FDA and more generally for biomedical innovation.

“She looked at the entire process around regulation for the most important challenges in the drug development process, the points on the critical path where things most often go wrong, and identified scientifically and regulatory-sound ways to address them,” McClellan, director of the Duke-Margolis Center for Health Policy, told BioCentury.

The critical path report broke new ground by suggesting that costs of drug development were increasing and productivity was decreasing because the “applied sciences needed for medical product development have not kept pace with the tremendous advances in the basic sciences.”

It pointed to a failure to create new tools to characterize the safety and efficacy of new products and linked the gap in applied research to the high failure rates of drugs in clinical trials. Underinvestment in regulatory science created barriers to getting new therapies to patients in part by creating uncertainties that lead to conservative standard setting.

In a call to arms, the report stated: “The medical product development process is no longer able to keep pace with basic scientific innovation. Only a concerted effort to apply the new biomedical science to medical product development will succeed in modernizing the critical path.”

Following up on the report, CDER created a critical path opportunities list and collaborated in the establishment of the Critical Path Institute, an independent non-profit organization that creates public-private partnerships that undertake applied regulatory research.

Woodcock also pushed industry to create TransCelerate BioPharma Inc. a not-for-profit that seeks to identify and solve common drug development challenges to improve the quality of clinical trials and accelerate drug development.

The critical path report spurred FDA and industry to focus more attention on the identification and qualification of new toxicology methods, as well as safety and efficacy biomarkers.

Much of the critical path agenda remains a work in progress, the vision as relevant today as it was two decades ago.

For example, the critical path report identified drug manufacturing as a sector where investments from government and industry could yield out-sized benefits to patients and the U.S. economy.

Patient-focused drug development and rare diseases

Woodcock helped open FDA to interactions with patients, personally meeting with patient advocates and pressing reviewers to consider patient perspectives.

“I was the author of patient-focused drug development, of actually asking the patients what they wanted to have relieved, what was important to them,” Woodcock told BioCentury.

Woodcock developed strong, enduring relationships with patients and their families, especially those with rare diseases.  

Pat Furlong, founding president and CEO of Parent Project Muscular Dystrophy (PPMD), and other patient advocates told BioCentury they felt Woodcock was an ally.

“She was always present,” Furlong said. “When we were meeting with her the phone wasn’t ringing, other people weren’t coming in. She paid attention.”

At their first meeting in 2009, Furlong’s goal was to explain to Woodcock and through her to FDA “what DMD is and what living with it is like,” Furlong told BioCentury.

“I asked her if we could do studies to determine how much benefit families expected from therapies, and how much risk they were willing to take,” Furlong recalled. “She said that would be helpful, and she offered her staff to help guide us. She opened the door, said we are in this together.”

In helping PPMD design preference studies, Woodcock “insisted that this could not be a one-off effort, it had to be a model” that other patient communities could follow, Furlong said.

PPMD and CDER took a similar approach to writing the first guidance document crafted by a patient group for FDA.

Empathy for DMD patients led Woodcock to undertake one of the most contentious battles of her career, pushing through the accelerated approval of Exondys 51 eteplirsen from Sarepta Therapeutics Inc. (NASDAQ:SRPT) over the nearly unanimous objections of agency reviewers who firmly believed there was no scientific justification for the approval.

Critics contend that in trying to help DMD patients Woodcock lost objectivity, allowing her personal feelings to dictate decisions that were not grounded in science or law.  

BioCentury recently asked Woodcock why she had pushed so hard and whether the drug has helped any of the boys who have taken it. Her response, six years after the approval, illustrates her personal ties to the DMD community, as well as the tension between compassion and scientific rigor.

“I just heard from one of the parents this morning and I've heard from a number of parents whose children are on it,” she said. “They're convinced their children benefited.”

Woodcock added: “Of course we know we have to have scientific data.”

Woodcock plowed through criticism to get Exondys 51 approved “because I believe that for rare diseases the standard that we use for hypertension or whatever is pretty unobtainable, and we have to use biomarkers and mechanistic reasoning to advance the field.”

Ellis Unger, who as director of FDA's Office of Drug Evaluation-I led the opposition to approving Exondys 51, called the drug a “scientifically elegant placebo.” He contended while it is reasonable to believe that increasing dystrophin levels would slow the progression of DMD, Sarepta failed to present reliable evidence that Exondys had a discernable effect on dystrophin or on the course of the disease.

In an extraordinary action, Woodcock set aside her staff’s review.

“I looked at all the literature, I wrote my own review of the literature for that biomarker,” she told BioCentury. “It seemed to me it extrapolated down to very low levels because there was natural variance, such that people who had different levels of dystrophin, all the way down into 10%, 9% and so forth and still the phenotype was improved over natural Duchenne muscular dystrophy.”

Woodcock added: “I felt that over a lifetime, which for those people would be only about 20 years, that even a small amount would probably make a significant difference.”

In addition to critics at FDA, the approval infuriated some biopharma CEOs who believed it epitomized the unpredictable nature of the agency’s decision-making and was a blow to science-based regulation. Consumer advocates and payers pointed to the high cost of Exondys 51 and accused FDA of allowing Sarepta to profit from the hopes and desperation of parents facing a relentless illness.

Woodcock told BioCentury that she is aware of concerns that approving drugs based on less robust evidence can impose costs on the healthcare system.

Asked about criticisms of the accelerated approval pathway, she responded: “I understand that much of the criticism is about cost, and that's a fair point. If you have less evidence, maybe you should not be allowed to charge so much.”

Woodcock noted that pricing is outside FDA’s remit, and said that limits on the prices of drugs that receive accelerated approval could make sense. “Perhaps those who consider such things might consider different reimbursement — but not no reimbursement,” she told BioCentury. “People are considering schemes with value-based reimbursement and that's something that's worth talking about.”

McLellan, who in addition to leading FDA also served as CMS Administrator, has proposed that drug manufacturers share with payers some of the uncertainty around drugs that accelerated approval. McClellan serves on the boards of Johnson & Johnson (NYSE:JNJ) and health insurance and managed care company Cigna Corp. (NYSE:CI).

Woodcock also suggested that accelerated approval may not be the best place to look for cost-savings. “The issue is, accelerated approval is usually for people who are dying. It's for people with cancer. It's for dying children. Is that really where we want to tighten the screws, to make it harder for developers to develop treatments for dying children and really ill people with cancer? If you want to save money in healthcare, I think there are other venues you could look at.”

A backlash

The Exondys approval provoked a backlash, not only from academic critics, but also from biopharma executives who felt it set a bad precedent.

Industry argued that Exondys was an example of how FDA’s failure to systematize how it would apply flexible approval standards led to inconsistent and idiosyncratic decision-making.

While approving drugs for ultra-rare diseases like Duchenne muscular dystrophy based on what many considered a mere glimmer of hope was cheered by patients and condemned by critics, the controversy was contained within a small community.

When the pattern was repeated for Aduhelm aducanumab, a putative Alzheimer’s therapy that was targeted at millions of patients at a potential cost of billions of dollars, the issue burst onto front pages.

Woodcock’s congressional opponents seized on the issue, allowing them to add contemporary complaints about the Aduhelm approval to expressions of outrage over allegations of decades-old negligence in approving opioids.

Whatever merit history accords to these and other criticisms, a fair accounting of Woodcock’s legacy will also have to consider the depth and breadth of her contributions to FDA and the patients it serves.