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

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Nicholas Florko, STAT News: March 1, 2021

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….. 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.

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

[.…]

“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.

 [….]

Read the full article here.

Drug Industry Pushes FDA to Solve Growing Inspection Backlog

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Suzanne Smalley, Politico: March 2, 2021

The Food and Drug Administration is under increasing pressure from the pharmaceutical industry to address the growing backlog of drug inspections — nearly a year after Covid-19 prompted the agency to halt most plant visits.

From March through September, FDA inspected just three plants outside the U.S., well below the 600-plus it visited in each of the prior two years, the Government Accountability Office said last month. FDA has also struggled to keep up with inspections within U.S. borders, conducting just 52 during the same seven-month period last year, compared with roughly 400 each in 2019 and 2018.

Inspections, which are required before a therapy wins FDA approval, are a vital tool to ensure the safety of new drugs as well as medicines already on the market. The work takes FDA inspectors all over the world. More than 70 percent of drug ingredients are manufactured outside of the U.S., largely in India and China. The two countries are also major suppliers of generic drugs.

The effects of the FDA slowdown are already becoming apparent. In recent weeks, the agency has deferred or denied at least six drug approvals because it could not inspect manufacturing sites in the U.S. and abroad. The delayed treatments include drugs for endometrial cancer and abnormally low levels of white blood cells, a condition often linked to cancer treatment; a regenerative skin therapy for adults with deep second-degree burns; and a cholesterol drug for people who cannot tolerate statins.

[….]

“There’s a huge backlog of drugs and biologics facilities that have not been inspected and it is affecting the public health. The agency doesn’t really seem to care and we are now approaching the one year point,” said Mark Schwartz, a lawyer at Hyman, Phelps & McNamara in Washington, D.C., who represents drug companies. “It is irresponsible for the gold standard of regulatory bodies to be dithering while pharma is burning.”

[….]

FDA spokesperson Jeremy Kahn said that the agency continues to perform what it calls “mission critical” inspections and is using record reviews and outside regulator reports to replace in-person visits where possible. While several drugs’ applications for approval have been deferred due to the lack of inspections, Kahn said the FDA has not experienced “a significant impact on its ability to take action on drug applications.”

“The FDA believes that maintaining oversight of manufacturing operations is critical to ensuring drugs remain safe and effective,” Kahn said in a statement. “The health, safety and well-being of all Americans — including our investigators — are of utmost importance to the FDA.”

[….]

Lawyers representing the industry have pressed the FDA to consider using virtual inspections since the pandemic began, but they say the agency has been noncommittal. Donald Ashley, the director of the Office of Compliance in the FDA’s Center for Drug Evaluation and Research, told an industry conference in December that he worried remote inspections could miss problems.

[….]

While the GAO report only documented drug inspection backlogs, agency watchdogs said the problem extends to medical devices as well. Diana Zuckerman, president of the National Center for Health Research, said she is particularly disturbed by the device backlog because devices typically do not undergo clinical trials, leaving inspections as the primary tool for assessing safety and effectiveness.

Earlier this month, a division within the FDA’s Office of Regulatory Affairs gave Zuckerman a Zoom briefing on its inspections of medical devices. She said three officials presented her with their 2019 inspection numbers and omitted 2020, which is when the pandemic hit and inspections largely stopped.

“I said, ‘Well, that’s very interesting about 2019, but what about 2020?’” Zuckerman said. “And I said I understand how difficult it is to do inspections during a pandemic, and they said basically they don’t do them.” 

 

To read entire article, click here https://www.politico.com/news/2021/03/02/fda-pandemic-drug-inspection-471979

J&J COVID-19 Vaccine Wins Unanimous Backing of FDA Panel

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Kerry Dooley Young, Medscape Medical News: February 26, 2021

An FDA advisory panel lent their support today to a rapid clearance for Janssen/Johnson & Johnson’s COVID-19 vaccine.

The Food and Drug Administration (FDA) is expected to quickly provide an emergency use authorization (EUA) for the vaccine following the recommendation by the panel.

The FDA’s Vaccines and Related Biological Products Advisory Committee voted 22-0 on this question: Based on the totality of scientific evidence available, do the benefits of the Johnson & Johnson COVID-19 Vaccine outweigh its risks for use in individuals 18 years of age and older?

The Johnson & Johnson vaccine is expected to offer more convenient dosing and be easier to distribute than the two rival products already available in the United States. Janssen’s vaccine is intended to be given in a single dose. In December, the FDA granted EUAs for the Pfizer/BioNTech and Moderna COVID-19 vaccines, which are each two-dose regimens.

[….]

Weakened Standards?

Several researchers called on the FDA to maintain a critical attitude when assessing Johnson & Johnson’s application for the EUA, warning of a potential for a permanent erosion of agency rules due to hasty action on COVID vaccines.

They raised concerns about the FDA demanding too little in terms of follow-up studies on COVID vaccines and with persisting murkiness resulting in attempts to determine how well these treatments work beyond the initial study period.

“I worry about FDA lowering its approval standards,” said Peter Doshi, PhD, from The BMJ and a faculty member at the University of Maryland School of Medicine in Baltimore, during an open public hearing at the meeting.

“There’s a real urgency to stand back right now and look at the forest here, as well as the trees, and I urge the committee to consider the effects FDA decisions may have on the entire regulatory approval process,” Doshi said.

Doshi asked why Johnson & Johnson did not seek a standard full approval — a biologics license application (BLA) — instead of aiming for the lower bar of an EUA. The FDA already has allowed wide distribution of the Pfizer/BioNTech and Moderna vaccines through EUAs. That removes the sense of urgency that FDA faced last year in his view.

The FDA’s June 2020 guidance on the development of COVID vaccines had asked drug makers to plan on following participants in COVID vaccine trials for “ideally at least one to two years.” Yet people who got placebo in Moderna and Pfizer trials already are being vaccinated, Doshi said. And Johnson & Johnson said in its presentation to the FDA that if the Ad26.COV2.S vaccine were granted an EUA, the COV3001 study design would be amended to “facilitate cross-over of placebo participants in all participating countries to receive one dose of active study vaccine as fast as operationally feasible.”

“I’m nervous about the prospect of there never being a COVID vaccine that meets the FDA’s approval standard” for a BLA instead of the more limited EUA, Doshi said.

Diana Zuckerman, PhD, president of the nonprofit National Center for Health Research, noted that the FDA’s subsequent guidance tailored for EUAs for COVID vaccines “drastically shortened” the follow-up time to a median of 2 months. Zuckerman said that a crossover design would be “a reasonable compromise, but only if the placebo group has at least 6 months of data.” Zuckerman opened her remarks in the open public hearing by saying she had inherited Johnson & Johnson stock, so was speaking at the meeting against her own financial interest.

“As soon as a vaccine is authorized, we start losing the placebo group. If FDA lets that happen, that’s a huge loss for public health and a huge loss of information about how we can all stay safe,” Zuckerman said.

Read the entire article here. 

What you need to know about J&J’s newly authorized one-shot COVID-19 vaccine

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Tina Hesman Saey, ScienceNews: February 27, 2021

And then there were three: A single-shot vaccine is the latest weapon to join the battle against COVID-19 in the United States.

On February 27, the U.S. Food and Drug Administration gave emergency use authorization for Johnson & Johnson’s vaccine against SARS-CoV-2, the coronavirus that causes COVID-19. South Africa is the only other country to OK Johnson & Johnson’s vaccine so far, though other countries are poised to follow suit.

The FDA determined that Johnson & Johnson’s vaccine meets the criteria for safety and effectiveness and that there is clear evidence that it may prevent COVID-19, the agency said in a statement.

“With today’s authorization, we are adding another vaccine in our medical toolbox to fight this virus,” said Peter Marks,  director of the FDA’s Center for Biologics Evaluation and Research.

Its authorization for emergency use in the United States – for people age 18 and older – follows similar authorizations in December for vaccines made by Moderna and by Pfizer and its German partner BioNTech.

[….]

As of February 25, more than 52,000 people were hospitalized in the United States fighting COVID-19, according to the COVID Tracking Project. That’s down from the record-setting daily peaks of more than 130,000 in early January and the lowest since early to mid-November. More than half a million people in the United States have now died from COVID-19.

In Johnson & Johnson’s clinical trial, two of the 19,514 people in the vaccine group were hospitalized with COVID-19 starting 14 days after vaccination. That compares with 29 hospitalizations among the 19,544 people in the placebo group. None of the vaccinated people died, but there were seven deaths related to COVID-19 in the placebo group. Those numbers are small and some researchers say the data aren’t clear-cut on the benefits.

“The data indicate that the vaccine is effective, but doesn’t prove that the vaccine is especially effective against moderate to severe COVID,” said Diana Zuckerman, president of the National Center for Health Research, a Washington, D.C.–based think tank that analyzes health research.

The data were also collected after only two months of follow-up. Normally, the FDA requires a year or more of data to fully approve a vaccine. Some questions about the vaccine can’t be answered with less than six months of data, Zuckerman said during a public comment period in the Feb. 26 advisory board hearing.  “Let’s be very honest with the public about what we do know and what we won’t know” for some time to come.

For all the vaccines, no one knows how long immunity will last. And what’s already authorized might need to be tweaked if resistant variants become widespread. Booster shots may be needed, Benjamin says.

[….]

To read the entire article, click here.

Who Will Be the Next F.D.A. Chief?

We're In the News,

Sheila Kaplan, New York Times: February 20, 2021

One month into his presidency, President Biden still has not named a candidate to head the Food and Drug Administration, a critical position at a time when new vaccines and coronavirus treatments are under the agency’s review.

The glaring vacancy lags behind the president’s selections of most other top government health posts, and has spurred a public lobbying campaign by supporters of the two apparent front-runners, Dr. Joshua Sharfstein, a former high-ranking F.D.A. official and Dr. Janet Woodcock, the acting commissioner.

It has also exposed rifts among Congressional lawmakers, within the public health and medical communities as well as the health and drug industries that depend on the F.D.A. for approval of their products. In particular, some public health officials have used the open position to debate the leadership qualifications needed to restore the agency’s morale and credibility after a year fighting both a pandemic and a president who often belittled the F.D.A.’s process for approving treatments and vaccines.

Administration officials say that Dr. Sharfstein and Dr. Woodcock have gone through at least partial vetting for the job. They attributed the delay to their focus on solving Covid vaccine shortages and distribution problems. They also noted that Xavier Becerra, the attorney general of California and who Mr. Biden has nominated for secretary of the Health and Human Services Department, faces Republican opposition that could jeopardize his confirmation.

[….]

Dr. Woodcock’s decades of service at the F.D.A. have made her more of a target for critics, and she has drawn particular fire over her agency roles during the opioid crisis.

Dr. Sharfstein, who held the No. 2 slot at the F.D.A. for nearly two years in the Obama administration, has extensive public health interests. At 51, he is a prolific writer, with more than 100 articles, editorials and journal papers published in the past few years on subjects ranging from training physicians to treating opioid addiction to reducing drug prices. He often criticized the Trump administration’s pandemic response, and called for the F.D.A. to “stand up for itself and for science, not politics.”

Early in the coronavirus outbreak, Dr. Sharfstein urged public health officials to focus on protecting racial and ethnic minorities, poor people and others who face social inequities. He has called for expanding housing to hold people with mild symptoms in quarantine; protecting tenants from eviction and offering incentives to food providers to deliver food to low-income neighborhoods for free or at a discount. He also proposed a federal coronavirus insurance program.

[….]

“I think Josh would be a good choice,” said David Nexon, a former executive at the Advanced Medical Technology Association, known as AdvaMed. “He’s a very smart guy, very committed to public health and he has a broad public health background, which would be an asset because of F.D.A.’s wide-ranging responsibilities.”

Dr. Woodcock, 72, also commands deep support, especially within the vast network of cancer-related patient advocacy groups, researchers and the drug companies that help finance them. But Dr. Woodcock, who has spent over 36 years working for the agency, has also generated much stiffer opposition in this round than Dr. Sharfstein.

“In the past, even when the F.D.A. review of the drug was scathing, quite often Janet Woodcock or another high level F.D.A. official would be at the meeting, clearly pushing the advisory committee to recommend approval,” said Diana Zuckerman, president of the National Center for Health Research, a think tank and advocacy group. “But by law, these advisory committees are supposed to make recommendations independent of any F.D.A. pressure.”

But the loudest objections to Dr. Woodcock focus on the F.D.A.’s role in the opioid epidemic during her two stints as chief of its drug division, from 1994 to 2004 and then again from 2007 until she moved to Operation Warp Speed last May. (Between those two postings, she held other roles at the agency.)

In January, a group of nonprofit advocacy groups wrote to Mr. Becerra, the health secretary nominee, and Norris Cochran, the acting health secretary, saying that Dr. Woodcock’s 25-year tenure as F.D.A.’s drug division chief should disqualify her from consideration for commissioner.

“Much of the responsibility for the opioid crisis clearly rests with industry,” the group wrote. “But the fact that opioid manufacturers for decades disseminated false claims about the risks and benefits of opioids points to a dereliction of duty” by Dr. Woodcock’s division.

The letter cited a 2017 presidential commission report on the opioid crisis, which found that it was caused in part by “inadequate oversight by the F.D.A.”

Dr. Woodcock’s role in the approval of new opioid products has also drawn strong opposition from some members of Congress, including Democratic Senators Maggie Hassan of New Hampshire and Edward J. Markey of Massachusetts. Senator Joe Manchin of West Virginia, has also been very critical of the F.D.A.’s handling of opioids under Dr. Woodcock.

“Multiple past F.D.A. commissioners have acknowledged that the F.D.A. made mistakes regarding the opioid crisis, yet the agency still has not fully reckoned with its past missteps,” Senator Hassan said in an email. “The F.D.A.’s decision-making processes for the approval and labeling of opioid drugs going back decades remain of serious concern, and it’s important that the next F.D.A. commissioner is someone who has demonstrated that they have learned from the F.D.A.’s past mistakes — not someone who has been involved in repeating them.”

The nonprofit advocacy groups’ letter prompted a defense of Dr. Woodcock orchestrated in large part by Ellen Sigal, co-founder of Friends of Cancer Research. Ms. Sigal is also chairwoman of the Reagan-Udall Foundation for the F.D.A., an influential organization created by Congress to help advance the agency’s mission and to speed development of new medical treatments.

Friends of Cancer Research receives much of its funding from drug companies. The 2019 top donor list for Friends of Cancer Research includes Amgen, AstraZeneca, Bristol-Myers Squibb, Eli Lilly Co., Genentech, Gilead, Merck, Pfizer and PhRMA, the pharmaceutical industry trade group. The Reagan-Udall Foundation receives funding directly from the F.D.A., but also lists drug industry donors, among them: Biogen, Johnson & Johnson, Teva and the Biotechnology Innovation Organization, known as BIO, which gave Dr. Woodcock an award in 2019 in conjunction with the Science History Institute.

[….]

Dr. Sharfstein’s supporters countered with a letter on Feb. 5, signed by 18 top academic physicians and researchers. “Dr. Sharfstein knows the F.D.A. and will ensure that its decision-making is scientifically beyond reproach, transparent and based on the principles of public health,” they wrote.

[….]

To read the entire article, click here: https://www.nytimes.com/2021/02/20/health/Covid-FDA-Biden.html

FDA blasts Merck’s Keytruda data for new breast cancer indication

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Ed Silverman, Stat News: February 5, 2021

Merck (MRK5 ) may have readily turned its Keytruda cancer drug into a medical and financial juggernaut, but its bid to win regulatory approval for at least one additional use may not come so easily, judging by documents from the Food and Drug Administration. The drug maker wants to sell the medicine to combat high-risk, early-stage triple-negative breast cancer along with chemotherapy before surgery, and then by itself after surgery.

[…]

Given the FDA review, though, the likelihood of a recommendation next week is not high, according to Ira Loss of Washington Analysis, who tracks pharmaceutical regulatory and legislative matters for investors. “The agency believes, and we think the (FDA expert) committee will agree, that further data from the trial are needed to make an informed decision,” he wrote to investors.

Another FDA watcher was even more blunt. “It’s important to have good treatment because this disproportionately occurs among Black women,” said Diana Zuckerman, who heads the National Center for Health Research, a nonprofit think tank. “But they’re saying this may not be needed, may not work and may be harmful – that’s pretty damning. And there are some real safety issues that can have terrible impact on patients… This is one of the most negative reviews I’ve ever seen.”

[….]

Read the full article here

Patients Continue to Be Inadequately Informed of Risk for Breast Implant-Associated ALCL

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Christina Bennet, MS, Cancer Therapy Advisor: February 8, 2021

Although the risk for breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) has been well-documented, patients considering breast implants continue to be inadequately informed of the propensity for disease development. Awareness of BIA-ALCL has risen since 2020, but adequate safeguards have not yet been put in place, according to experts in the field.

“There have been efforts made [to ensure patients are informed], but they have not been successful,” Diana Zuckerman, PhD, president of the National Center for Health Research (NCHR), said in an interview with Cancer Therapy Advisor.

The most recent effort to more frontally disclose the risk for BIA-ALCL is a final guidance document released by the FDA on September 28, 2020.1 The guidance, which applies to all breast implants, advised breast implant manufacturers to add a black box warning that mentions the risks associated with breast implants such as BIA-ALCL. In the guidance, the FDA also encouraged manufacturers to incorporate a patient decision checklist in the labeling to “better ensure certain information is received and understood by patients.”1,2 Manufacturers, however, are not required to follow these recommendations.

Zuckerman, who is a member of the Breast Implant Working Group, said she was surprised by the FDA’s decision to recommend rather than require these facets of the guidance. “We don’t have the answer to that question other than we have talked to FDA officials who said that at least some of this will at some point be a requirement, but we don’t know when that is,” she said.

With no mandates in place to ensure that patients receive information about the risks for BIA-ALCL—among other breast implant-associated complications—upfront, the industry is left to educate—and this does not seem to be working.

Patient advocates Terri McGregor and Jennifer Cook, both of whom have received a BIA-ALCL diagnosis, discussed a misleading patient brochure that has further contributed to the misinformation about breast implant-associated cancer risk. Sold online by the American Society of Plastic Surgeons (ASPS), the brochure featured the symbol for breast reconstruction awareness—a modified pink ribbon—and the slogan “Closing the loop on breast cancer.”3

The brochure was sponsored by several companies, including 2 prominent breast implant manufacturers, Allergan and Mentor. Though the document was promoted on Twitter by the ASPS and users were encouraged users to “stock up now” ahead of Breast Reconstruction Day,3,4  it notably made no mention of BIA-ALCL—not even on the page that describes the risks and safety issues associated with breast implants.

Conflicts of Interest Cloud Risk Disclosure

[…]

Eric Swanson, MD, a plastic surgeon at the Swanson Center for Cosmetic Surgery in Leawood, Kansas, told Cancer Therapy Advisor that plastic surgeons’ financial ties to breast implant manufacturers are part of the reason why they have been slow to respond to the issue of BIA-ALCL. “There’s a big problem with conflict of interest in plastic surgery. Once [a person has] taken funds from a company, it is very rare for the taker to be critical of that company,” Swanson said.

[….]

Zuckerman described the ASPS brochure as “terribly” out of date. “The Institute of Medicine report is more than 20 years old, and there has been a great deal of research since then,” she said.

[….]

The ASPS Brochure: Current Status

When Cancer Therapy Advisor inquired about the content of the brochure, an ASPS representative agreed that the information was “outdated” and removed the brochure from sale on its website.

Enclosed in the ASPS brochure was a list of websites that included breastimplantsafety.org, which—despites its domain name—did not include any safety information about breast implants. Instead, the domain redirected users to a different domain, smartbeautyguide.com, the patient site for The Aesthetic Society, a professional organization for plastic surgeons. A representative for The Aesthetic Society told Cancer Therapy Advisor that breastimplantsafety.org was active until 2015, when it migrated to their patient site, Smart Beauty Guide.

“We have been developing and will launch our new Aesthetic Society website that will include a dedicated section for patient education,” the representative wrote in an email. Within days of being contacted by Cancer Therapy Advisor, The Aesthetic Society updated the breastimplantsafety.org domain name to direct users to an existing page that provides resources about breast implants, including information about BIA-ALCL and breast implant illness, a systemic condition characterized by a wide range of symptoms that is currently under FDA investigation.18

Read the full article here

Statement on Keytruda for Early Stage Triple Negative Breast Cancer

Breast Cancer, Breast Cancer, Testimony & Briefings, , ,

February 9, 2021

The National Center for Health Research is a nonprofit think tank that scrutinizes the safety and effectiveness of medical products.  We don’t accept funding from companies that make those products, so we have no conflicts of interest.  We welcome the opportunity to provide our views on Merck’s application for approval of Keytruda for the indication of high-risk early stage triple negative breast cancer.

Triple negative breast cancer has a lower survival rate than other breast cancers.  However, chemotherapy clearly improves 5-year survival.  Patients need additional treatment options but the bottom line for patients is that FDA should not approve an indication that is not proven to have clinically meaningful benefits, especially when the treatment has clear risks.   

The first issue to address is whether there is evidence that immune checkpoint inhibitors (ICIs) are effective for TNBC.  We agree with FDA scientists that “there is still uncertainty regarding ICIs for TNBC” based on the results from several clinical trials.

  • KEYNOTE-119 failed to meet its primary OS endpoint. 
  • KEYNOTE-355 has not met its OS endpoint. 
  • IMpassion130: clinical benefits need to be confirmed
  • IMpassion131 interim OS results favored control group

The second major issue pertains to pCR data in the study.  The results indicate only 7.5% improvement in pCRs at IA3 (the most recent interim analysis), which the FDA scientists point out may not be clinically meaningful even if statistically significant.  We agree.  The problem is that it is impossible to determine how this slight improvement would affect overall survival, and even if it does, how much neoadjuvant and adjuvant use each contribute to any benefit. 

FDA scientists were clear to the sponsor that there were concerns with their study design and that the application for approval was premature since the study was not yet completed.  The agency made it clear that that the event free survival (EFS) study results were not statistically significant, not clinically meaningful, and did not show a “stable trend.” 

FDA reviewers are clear that data on overall survival “are too immature to provide a conclusive interpretation regarding the difference in OS between treatment arms.” 

What about safety?

At IA3 (the most recent interim analysis), there were 96 deaths, which FDA points out “accounts for only 32% of the events needed for the final analysis. Therefore, the OS estimate may be unreliable, and the treatment effect size reported is subject to uncertainty.”

It is notable that the study included patient-reported outcomes (PROs), but unfortunately, KEYNOTE-522 was not designed to compare differences in PROs (symptoms, side effects, health-related quality of life), nor were these patient-reported endpoints prospectively identified and statistically tested. 

PRO assessments should have been more frequent, both for neoadjuvant and adjuvant treatments

Since many high-risk, early-stage TNBC patients will be cured with standard therapy, the key issue is whether this drug has benefits that outweigh the risks.  The benefits are unclear.  Therefore, the evidence of the drug’s “added toxicity” is worrisome.  FDA scientists concluded that “Some of these toxicities may be irreversible or require lifelong medication in patients cured of their breast cancer.

Although the sponsor counted 2 deaths due to immune-mediated adverse events, the FDA counted 4.  Either way, these deaths must be considered worrisome given the lack of clear evidence of a meaningful benefit.  And, there are many other serious adverse events in addition to the small number of deaths.   All-grade and grade ≥3 immune-mediated AEs and infusion reactions occurred more frequently in Keytruda patients compared to placebo:    43% vs. 22% for all grade AEs, and 15% vs. 2% for high grade AEs.  In fact, 10% of Keytruda patients had immune-mediated AEs and infusion reactions leading to hospitalization compared to 1% of placebo.  These included the following relatively high number of adverse events:

  • Infusion reactions (18%), 
  • Hypothyroidism (15%), 
  • Severe skin reactions (6%)
  • Hyperthyroidism (5%), adrenal insufficiency (3%), pneumonitis (2%), and thyroiditis (2%).

It is important to note that these adverse events were not resolved at the last assessment in the study for 19% of Keytruda patients.   It is also important to note that 16% of the Keytruda patients initiated thyroid hormone replacement during the study.

In summary, we agree with FDA scientists that the deaths are “particularly concerning in this curative disease setting.”

  • “All grade and grade ≥3 immune-mediated AEs were increased in [Keytruda] patients.’
  • Some “may be severe or lifelong.” 
  • The adjuvant treatment has fewer adverse events but “has not demonstrated a significant effect on any efficacy endpoint, and may be adding risk without benefit.”

Based on our analysis, we agree with the overall conclusions made by FDA scientists: 

  1. Neoadjuvant Keytruda “confers only a small absolute improvement in pCR rate of questionable clinical meaningfulness.”
  2. Event-free survival and overall survival are “immature and unreliable.”
  3.  “The design and results of KEYNOTE-522 do not currently support a role for adjuvant [Keytruda].”
  4. “Supportive data of clinical benefit … are lacking.” 
  5. Adding Keytruda “is associated with increased toxicity … which may be severe, irreversible, and/or require life-long medication in potentially curable and otherwise healthy patients.” 

In conclusion, the FDA and the medical community do patients no favors to approve a treatment that is not proven to benefit them and at the same time is proven to cause harm for a substantial percentage of patients.  The studies should be continued to determine whether the benefit of adding Keytruda to other treatments outweigh the risks.

 

This written statement was submitted to the FDA on February 8, 2021 and an oral version with PowerPoint slides was presented at the FDA Advisory Committee meeting on February 9, 2021.

We are pleased that the FDA Advisory Committee agreed with our views and voted 10-0 on February 9 in favor of deferring an FDA regulatory decision until the study is completed.

Comparison of Acupuncture and Therapy as Treatments for Cancer Survivors with Insomnia

Quality Of LIfe, ,

Meg Seymour, PhD and Nina Zeldes, PhD, National Center for Health Research

Most cancer patients experience insomnia,[1] which is defined as having trouble falling and/or staying asleep. Most cancer patients with insomnia are prescribed sleep-aid medications as treatment,[2] which can have unpleasant side effects, such as memory problems and health risks.[3]  In fact, studies show that people who take sleep medication more often are more likely to develop many types of cancer (You can read this article for more information). Fortunately, in 2019, cancer researchers at Memorial Sloan Kettering found that there are safer and possibly more effective treatments for cancer patients’ insomnia: acupuncture, as well as a type of  therapy specifically developed for treating insomnia, called Cognitive Behavioral Therapy for Insomnia (CBT-I).

Acupuncture is a traditional Chinese treatment where a trained acupuncturist places special needles into the skin at specific points at the body, which are associated with different aspects of health. There are certain places on the body that acupuncturists place needles in order to treat sleep problems, as well as pain.

CBT-I is a type of therapy that uses several different approaches to treat insomnia. It uses methods such as “cognitive restructuring,” which trains patients to reduce anxious thoughts in ways that make it easier to fall asleep. Another strategy is “sleep restriction,” in which patients primarily stay in bed for sleeping, not for watching TV, reading, or other activities. The goal is to associate being in bed with sleeping, not thinking about issues that can interfere with sleeping.

Comparing acupuncture and therapy as insomnia treatments

Acupuncture and cognitive behavioral therapy had previously been proven effective for insomnia. For example, CBT-I had previously been shown to reduce insomnia among cancer survivors,[5] and acupuncture has been found to be effective for insomnia patients without cancer.[6] The goal of the 2019 study was to compare these two treatments for insomnia among cancer survivors, to determine which was more effective. 

The study compared the two treatments in 160 cancer survivors whose insomnia was severe enough that they were diagnosed with insomnia. Participants were randomly assigned to receive either 10 sessions of acupuncture treatment over 8 weeks, or 7 sessions of CBT-I over the course of 8 weeks. The researchers measured the severity of the participants’ insomnia, as well as other symptoms such as pain and anxiety. Participants’ symptoms were measured before they began treatment, right after completing the 8 weeks of treatment, and every four weeks up to 20 weeks after they finished the treatment. Measuring symptoms at these different times compared how effective the treatments were in both the short-term and the long-term.

Which treatment was most effective? 

The researchers found that both treatments were effective at reducing insomnia, and they also helped patients reduce their use of sleep aids, even at 20 weeks after finishing treatment. About 25% of patients were using at least one prescription sleep aid at the beginning of the study, but only 17% used the medication 20 weeks after treatment. CBT-I was slightly more effective than acupuncture at reducing insomnia symptoms and improving overall sleep quality, as well as reducing the amount of time it took to fall asleep and reducing the number of times participants woke up in the night. 

Twenty weeks after completing treatment with CBT-I, participants fell asleep an average of 24 minutes faster, and those who received acupuncture fell asleep an average of 11 minutes faster than before they started treatment. That might not seem like much benefit, but it is comparable to the small benefit of sleeping pills.[7] After treatment, both groups stayed asleep for longer at night. However, those who received acupuncture stayed asleep even longer than those who received CBT-I. Right after completing treatment, participants who had acupuncture treatment slept for an average of 62 more minutes a night, 27 more minutes than those who were treated with CBT-I. After 20 weeks, those who received acupuncture still slept 51 minutes more than before treatment, which was 5 and a half minutes more than those treated with CBT-I. That is much more additional sleep than is typical of sleeping pills.[7]

However, this difference in the effectiveness of the two treatments was only true for men. The two treatments were equally effective at reducing overall insomnia severity in women. The researchers also found that CBT-I was only more effective among White participants, highly educated participants, and those with lower pain levels. Otherwise, the two treatments were equally effective. 

In addition to evaluating insomnia severity, the researchers also measured participants’ fatigue, anxiety, depression, and overall quality of life as measured by mental and physical health. The two treatments were equally effective at improving those symptoms.

The bottom line

Both acupuncture and CBT-I helped reduce insomnia symptoms in cancer survivors, but CBT-I was more effective for men, Whites, highly educated participants, and those with lower pain levels. The researchers concluded that CBT-I should be used as the first line of treatment for cancer-related insomnia, but pointed out that patients might find it difficult to find CBT-I treatment. Unfortunately, there are few trained CBT-I therapists, but acupuncture is a good alternative. In addition, acupuncture was more effective for the treatment of short-term pain than CBT-I. 

Despite the shortage of well-trained CBT-I therapists, the availability of online therapy can help those who are interested get access to this treatment. For more information on online therapy, you can read this article. 

 

All articles are reviewed and approved by Dr. Diana Zuckerman and other senior staff.

The National Center for Health Research is a nonprofit, nonpartisan research, education and advocacy organization that analyzes and explains the latest medical research and speaks out on policies and programs. We do not accept funding from pharmaceutical companies or medical device manufacturers. Find out how you can support us here.

 

References 

  1.     Savard J, Ivers H, Villa J, et al. Natural course of insomnia comorbid with cancer: an 18 month longitudinal study. Journal of Clinical Oncology. 2011; 29(26):3580–3586.
  2.     Berger AM, Matthews EE, Kenkel AM. Management of sleep-wake disturbances comorbid with cancer. Oncology. 2017 Aug 16;31(8).
  3.     Kripke DF. Hypnotic drug risks of mortality, infection, depression, and cancer: But lack of benefit. F1000Res. 2016;5:918.
  4.     Garland SN, Xie SX, DuHamel K, Bao T, Li Q, Barg FK, Song S, Kantoff P, Gehrman P, Mao JJ. Acupuncture versus cognitive behavioral therapy for insomnia in cancer survivors: a randomized clinical trial. JNCI: Journal of the National Cancer Institute. 2019; 111(12):1323-31.
  5.     Johnson JA, Rash JA, Campbell TS, et al. A systematic review and metaanalysis of randomized controlled trials of cognitive behavior therapy for insomnia (CBT-I) in cancer survivors. Sleep Medicine Review. 2016;27:20–28.
  6.     Yin X, Gou M, Xu J, et al. Efficacy and safety of acupuncture treatment on primary insomnia: a randomized controlled trial. Sleep Medicine. 2017;37:193–200.
  7. Carr, T. The Problem With Sleeping Pills. Consumer Reports.com. https://www.consumerreports.org/drugs/the-problem-with-sleeping-pills/. Updated December 2018.

A C.D.C. analysis describes anaphylaxis after people have received the Pfizer-BioNTech vaccine as ‘rare’

We're In the News, , , , ,

Roni Caryn Rabin, New York Times: January 11, 2021

Any site that administers the currently authorized vaccines must be prepared to recognize and treat a severe allergic reaction that may occur, though it is “a rare outcome,” federal health officials said.

Of the nearly 2 million Americans who received coronavirus vaccinations developed by Pfizer and BioNTech during a 10-day stretch last month, 21 experienced a serious and potentially life-threatening allergic reaction called anaphylaxis, federal health officials said Wednesday.

Although the risk is ten times higher than the risk for anaphylaxis after a seasonal flu vaccine, officials described the reaction as “a rare outcome.”

The rate of anaphylaxis following vaccination was estimated to be 11.1 per million doses administered, compared with 1.3 cases of anaphylaxis per million doses of influenza vaccine administered, officials said.

“We know that safety is one of the public’s biggest concerns about the Covid vaccine,” said Dr. Nancy Messonnier, director of the National Center for Immunization and Respiratory Diseases at the Centers for Disease Control and Prevention.

“The anaphylaxis rate may seem high compared to the flu vaccine, but I want to reassure you: This is still a rare outcome.”

Any site that administers the vaccine must be prepared to recognize and treat a severe allergic reaction that may occur, federal health officials said. And though there is less information about reactions to the Moderna vaccine than to the Pfizer-BioNTech vaccine, Dr. Messonnier said, “At this point we really don’t have enough data to say there’s any difference in the risks, so the recommendations apply to both.” Recipients who experience anaphylaxis after receiving the first dose of the vaccine should not receive the second dose, officials said.

Other than the anaphylaxis reactions, which occurred shortly after vaccination, “Our vaccine safety systems haven’t picked up any worrisome signals,” Dr. Messonnier added. “The known and potential benefits of the Covid vaccine outweigh the risk of getting Covid-19.”

The C.D.C.’s analysis of adverse reactions, published on Wednesday, included only those to the Pfizer-BioNTech vaccine administered between Dec. 14 and Dec. 23.

[…]

The vast majority of anaphylaxis reactions — 90 percent — occurred in women, who made up slightly more than half of vaccine recipients. A surprising number of those who went into anaphylaxis — 14 of the 21 — had never experienced an anaphylactic reaction prior to receiving the vaccine, and four had no known allergies at all.

Of the 21 who had reactions, 20 had recovered or been discharged home, and information was lacking on one individual. Nineteen were treated with epinephrine, and four were hospitalized, including three in intensive care. Seventeen were treated in an emergency department.

The C.D.C. said it was still investigating another seven reports of anaphylaxis following the vaccine, which have not been confirmed. The Vaccine Adverse Event Reporting System also identified 83 cases of nonanaphylaxis allergic reactions after the Pfizer-BioNtech vaccination; these people developed symptoms like rash and mild respiratory symptoms within a day of receiving the vaccine.

Among the 21 vaccine recipients who experienced anaphylaxis, 17 were known to have allergies to a variety of triggers, including foods, insects, pets and medications. The median time for anaphylactic reaction was 13 minutes after immunization, but one patient developed the reaction two and a half hours afterward.

Patients with known allergies have been warned to bring an epinephrine injector when they get vaccinated, and providers have been advised to keep patients with allergies for observation for 30 minutes following inoculation.

The new information is disconcerting, said Diana Zuckerman, president of the National Center for Health Research.

“The flaw in the system is that there was a small number of people who had a reaction 30 minutes or later,” she said. “It’s one thing to say everybody should hang around for 15 minutes. But the range was up to 150 minutes, and people aren’t going to hang around that long.”

To read entire article, see https://www.nytimes.com/live/2021/01/06/world/covid-19-coronavirus