Controversial Approval Puts Lack of Permanent FDA Chief in Spotlight

The controversial approval of the Alzheimer's disease medicine aducanumab has drawn new attention to the Biden administration's delay in nominating a candidate to be the top US drug regulator.

To date, President Joe Biden appears content with allowing the US Food and Drug Administration (FDA) to run under the supervision of Janet Woodcock, MD, who was named as acting commissioner in January. As of June 17, the White House had yet to nominate a candidate to lead the FDA, although leaders in other top health posts have been successfully confirmed.

A White House official, in response to a question about the expected timing of a commissioner nomination, told Medscape Medical News on June 16 that the administration is "grateful for the strong acting leadership we have at the FDA, which is critical as we navigate this pandemic."

The statement was given on background, meaning the source asked not to be named.

But there's still a sharp difference in opinion about Woodcock, who has been with the FDA since 1986. For much of her career, Woodcock led the FDA's Center for Drug Evaluation and Research (CDER). Sen. Joe Manchin III (D-WV) on June 17 publicly posted a letter he sent to Biden urging him to nominate a permanent commissioner and demanding that it not be Woodcock.

Once confirmed, an FDA commissioner could step in to address the many unresolved issues about the approval of aducanumab, wrote Manchin. The FDA rejected the November 2020 recommendation of its Peripheral and Central Nervous System (PCNS) Drugs Advisory Committee, whose members did not find enough evidence to recommend approval of the medicine.

"Having a permanent agency head in charge to answer patients and doctors questions on this approval, as well as assure the general public of the FDA's commitment to public health, is imperative, and Dr. Woodcock is not the right person to lead the FDA," Manchin wrote in the letter.

The Approval Upheaval

On June 16, the consumer watchdog group Public Citizen called for the resignation of Woodcock and two other FDA officials due to the approval of aducanumabthe, as reported by Medscape Medical News. The Washington-based group argued that the FDA under Woodcock's leadership had ignored the disappointing data from clinical trials of aducanumab and instead relied on post hoc analyses to find a path for approving the drug.

Public Citizen also objected to how the FDA went against the advice of its advisory panel to allow the use of aducanumab for all types of Alzheimer's disease on the basis of an unvalidated surrogate endpoint — reduction of amyloid-beta plaques in the brain.

"Under the leadership of Dr. Woodcock over the past three decades, the relationship between the FDA's CDER and the pharmaceutical industry has grown ever cozier — resulting in regulatory capture of the agency by the industry — and the agency's standards for approving new drugs have gradually eroded," wrote Michael A. Carome, MD, director of Public Citizen's Health Research Group, in the letter to the US Department of Health and Human Services.

One of the resignees, Aaron S. Kesselheim, MD, JD, MPH, and his Harvard Medical School colleague, Jerry Avorn, MD, detailed their concerns about the approval in a June 15 guest essay in The New York Times.

Without naming Woodcock, their article describes what they see as the long-term risk to the agency from this approval.

"If pressure from drugmakers and their lobbyists compels F.D.A. administrators to continue to loosen their standards, we need a new organization to review drug approvals and make evidence-based assessments of their clinical impact, as other countries do," they wrote.

In a 2016 viewpoint article in JAMA, Kesselheim and Avorn publicly criticized Woodcock by name about the way the FDA handled the approval of another drug, eteplirsen (Exondys 51), for the treatment of Duchenne muscular dystrophy.

In this case, Woodcock overruled the recommendations of its scientific staff and its external advisory committee. Woodcock suggested that an "extremely small increase" in the protein dystrophin might conceivably translate to clinical benefit, they wrote.

"She indicated that considering the life-threatening nature of the disease and the lack of reasonable alternative treatments, the FDA should exercise `the greatest flexibility possible' under its statutory authority in considering eteplirsen's efficacy," Kesselheim and Avorn wrote. "The internal FDA review staff took the unusual step of appealing to [then FDA] Commissioner Robert Califf, MD, who upheld Woodcock's decision."

Persisting Support

Yet, Woodcock also has drawn admiration in some circles for the accelerated approval granted to aducanumab, a drug that Biogen intends to sell in the United States at an annual cost of about $56,000. Sen. Jerry Moran (R-KS) on June 10 thanked Woodcock for the FDA's approval of aducanumab when she appeared before a Senate Appropriations subcommittee at a budget hearing.

"I want to express my gratitude for the decision that the FDA made," Moran said. "With more timely approvals, there will be more private investment in research to find these life-saving and life-improving drugs."

The approval of aducanumab "is sending a message to the market that there is a process by which there is a reward, a return on investment, is very valuable," Moran told Woodcock.

Woodcock also has support among some patient groups, including ones that have accepted donations from pharmaceutical companies. More than 80 groups, including Friends of Cancer Research, signed onto a February letter, which was published in The Los Angeles Times, urging Biden to nominate Woodcock as commissioner.

"Dr. Woodcock's 37 years of senior-level experience at the FDA serves as both a touchstone for how to get things done and a master class in understanding the intricacies of the agency's work," the groups said in the letter.

"This earned experience, and the respect that accompanies it, allow her to speak authoritatively on the processes that can be streamlined to ensure a rapid response to public health emergencies while ensuring that the structures that are vital to ensure the FDA's mission and standards of independence and rigor are upheld," the groups added.

Medscape Medical News checked with two of the groups that signed the letter and found they both still want the veteran FDA official to be put in charge of the agency. The American Association for Cancer Research (AACR) "holds Dr. Woodcock in high regard and stands by the letter to President Biden," Julia Gunther, a spokeswoman for the group, told Medscape in a June 16 email.

"We fully support Janet Woodcock to be nominated as permanent commissioner of the FDA and believe she is extraordinarily qualified," Ellen Sigal, PhD, chair and founder of the nonprofit group, Friends of Cancer Research, told Medscape Medical News.

Sigal, who in 2016 was named to then Vice President Biden's Cancer Moonshot Blue Ribbon Panel, has been a strong and vocal backer of Woodcock for months.

Sigal also published an op-ed in February in The Los Angeles Times, arguing for a formal nomination for Woodcock.

In the editorial, written with Phillip A. Sharp, PhD, a Nobel laureate and institute professor at the Massachusetts Institute of Technology, Sigal credits Woodcock with advancing immunotherapy as a cancer treatment.

"It has saved the lives of many cancer patients with melanoma, lung cancer and other types of cancer," they wrote.

BioCentury, a publication that describes itself as a "trusted and essential partner

to the biopharmaceutical industry," wrote a June 16 article about an interview with Woodcock.

"Acting FDA Commissioner Janet Woodcock has more experience as a drug regulator than any of her predecessors — and she has arrows in her back to prove it," Steve Usdin, BioCentury's Washington editor, wrote.

"While her decades of experience provide fodder for critics, they also inform her decisions with a perspective that crosses therapeutic disciplines and incorporates lessons from successes and failures over decades in which science and regulation have undergone immense changes," Usdin added.

Democratic Objections to Woodcock

Even before the approval of aducanumab, several Democrats earlier raised objections to Woodcock regarding the FDA's approach to regulating painkillers as the US plunged into the opioid crisis.

In a March letter to Biden, Manchin and fellow Sens. Maggie Hassan (D-NH), Angus King (I-ME), Ben Ray Lujan (D-NM), Catherine Cortez Masto (D-NV), Jeanne Shaheen (D-NH), and Ed Markey (D-MA) asked for "new" FDA leadership. The letter did not mention Woodcock by name. But it also noted cases where the FDA had rejected recommendations offered by advisers about pain medicines.

"Unfortunately, the FDA has a long track record approving dangerous opioids without considering public health," the senators wrote. "A federal judge presiding over county and state cases against opioid manufacturers and distributors recently wrote, 'It is accurate to describe the opioid epidemic as a man-made plague, 20 years in the making.' "

Cortez Mastro, a former attorney general for Nevada, in April publicly vowed to work to block Woodcock from being confirmed if she were nominated.

"We cannot have an FDA administrator who oversaw the approval of dangerous drugs without sufficient consideration of the role they play in the ongoing addiction crisis in Nevada and across the country. I am very concerned about Janet Woodcock's record," Cortez Masto said. "I am prepared to work with my colleagues to ensure that the next director is a candidate who will prioritize the health and safety of Nevadans, rather than simply rubber stamping drugs without concern for their far-reaching effects."

There have been reports that the Biden administration is considering other potential nominees for the FDA top post. Former FDA officials Joshua M. Sharfstein, MD, and Luciana Borio, MD, have been mentioned as possible candidates. Eric Topol, MD, the editor-in-chief of Medscape and a widely published cardiologist, said he was approached as a potential candidate. (He said he is not interested.)

Politico on June 11 said that the Biden administration had vetted former Obama-era FDA official Michelle McMurry-Heath for the commissioner role. But McMurry-Heath has led the pharmaceutical industry group Biotech Innovation Organization for the past year, potentially making her a harder sell for Democrats who are focused on reducing drug costs, Politico reported .

Yet the last FDA commissioner successfully nominated by a Democratic president, Robert M. Califf, MD, a Duke University cardiologist, also had significant ties to the pharmaceutical industry ― and was confirmed over the objections of Manchin and Markey as well as another Democrat, Sen. Richard Blumenthal of Connecticut.

Kerry Dooley Young is a freelance journalist based in Washington, DC. She is the core topic leader on patient safety issues for the Association of Health Care Journalists. Young earlier covered health policy and the federal budget for Congressional Quarterly/CQ Roll Call and the pharmaceutical industry and the Food and Drug Administration for Bloomberg. Follow her on Twitter at @kdooleyyoung.

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