POST 210. October 31, 2021. CORONAVIRUS. “Some people want the FDA to speed up. Others want it to be more cautious…There’s a fundamental tension between the right to get access to a drug people are desperate for and the right to protection from dangerous failures of quality. The first demands speed; the second requires time…”

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“A panel of independent advisers to the Food and Drug Administration is recommending that the agency issue an emergency use authorization for the Pfizer-BioNTech vaccine in children ages 5 to 11 years old. The vote was 17 in favor and one abstention.

The FDA panel accepted Pfizer’s data indicating the vaccine is safe and 90.7% effective in preventing COVID-19 infections in this age group.

The agency typically goes along with the advice of its expert panels, though it isn’t bound to do so. It will issue a decision within the next several days. If the FDA authorizes the vaccine for these younger children, as seems likely, another panel of experts advising the Centers for Disease Control and Prevention would make its own recommendations and offer guidelines next week on its use among this age group…

Children 5-11 years of age have accounted for approximately 9% of reported COVID-19 cases in the U.S. overall, and currently account for approximately 40% of all pediatric COVID-19 cases, says Dr. Doran Fink, clinical deputy director of the division of vaccines and related products for the FDA. Currently, the case rate among children ages 5 to 11 is “near the highest” of any age group, he says.

Fink and others testifying at the meeting acknowledged that serious effects of infection, including long COVID-19, hospitalizations and deaths are less frequent among children than among adults. But they also argued that the significant numbers of serious illness in young children warrant concern.

Unvaccinated children with COVID-19 can develop a serious complication called multisystem inflammatory syndrome or MIS-C, as well as an inflammation of the heart muscle called myocarditis.

Myocarditis occurs naturally after infections with other viruses and it has also been seen as a rare side effect after vaccination with the two mRNA vaccines, Pfizer and Moderna, especially in young men.

Myocarditis was a focus of the scientific presentations and discussion on the possible risks of the vaccine if authorized for young children…

Researchers observed no cases of myocarditis in studies of young children submitted by Pfizer to the FDA. But Dr. Leslie Ball, a medical officer at the FDA, said the studies seeking emergency use authorization were not large enough to necessarily pick up an uncommon side effect like myocarditis.

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The committee’s recommendation comes as more than 1.9 million cases have been reported among children ages 5-11, with approximately 8,300 children hospitalized to date, according to the CDC. About one-third of these hospitalized children required treatment in the ICU. The rate of hospitalization is three times higher among children of color than among white children.

Many in the public health community see an urgent need to get vaccinations started in young school-age children, in part to address the unequal effect of the pandemic on people of color.

Dr. Fiona Havers of the CDC presented data to the FDA committee showing that between August and early October, COVID-19 outbreaks have closed 272 school districts, affecting 2,074 schools. Some 1,069,116 students and 68,718 teachers were affected. She said there was a disproportionate impact on children of color.

Havers further said 5,217 children had gotten MIS-C, a serious complication of COVID-19. Nearly 40% of cases occurred among kids 6 to 11; more than 60% of those cases were in children of color. The complication causes serious inflammation of several organ systems in the body…

The pediatric dose to be used is not only smaller than the one given to adults, but the formulation is slightly different, too; the company is using a different substance to maintain biological stability of the vaccine so that it can be stored for up to 10 weeks in a refrigerator. The doses for those ages 12 and up must be kept frozen, and have a more limited shelf life.” (A)

“Vaccine development is a long, complex process, often lasting 10-15 years and involving a combination of public and private involvement.

The current system for developing, testing, and regulating vaccines developed during the 20th century as the groups involved standardized their procedures and regulations.

At the end of the 19th century, several vaccines for humans had been developed. They were smallpox, rabies, plague, cholera, and typhoid vaccines. However, no regulation of vaccine production existed.

On July 1, 1902, the U.S. Congress passed “An act to regulate the sale of viruses, serums, toxins, and analogous products,” later referred to as the Biologics Control Act (even though “biologics” appears nowhere in the law). This was the first modern federal legislation to control the quality of drugs. This act emerged in part as a response to 1901 contamination events in St. Louis and Camden involving smallpox vaccine and diphtheria antitoxin.

The Act created the Hygienic Laboratory of the U.S. Public Health Service to oversee manufacture of biological drugs. The Hygienic Laboratory eventually became the National Institutes of Health. The Act established the government’s right to control the establishments where vaccines were made.

The United States Public Service Act of 1944 mandated that the federal government issue licenses for biological products, including vaccines. After a poliovirus vaccine accident in 1954 (known as the Cutter incident), the Division of Biologics Standards was formed to oversee vaccine safety and regulation. Later, the DBS was renamed the Bureau of Biologics, and it became part of the Food and Drug Administration. It is now know as the Center for Biologics Evaluation and Research.” (B)

“Vaccine development is typically measured in years, not months. But as the COVID-19 pandemic rages on, scientists are racing the clock—and breaking records—to develop an immunization that provides protection against the virus.

The nation’s scientific community also faces another obstacle: convincing the public that the COVID-19 vaccine is safe, and how important it is to get a COVID-19 vaccination in the first place.

“Even the most effective vaccine can’t protect us or our loved ones if people are afraid to take it or will not take it,” said Kathleen Mullane, director of infectious disease clinical trials at University of Chicago Medicine. “We know things are moving faster than ever, but the nation’s scientific community has cooperated and collaborated in ways as never before and we are absolutely committed to making sure whatever is ultimately approved works and is safe. I am going to get vaccinated and am recommending vaccination for my family and friends because I believe in the safety and efficacy of these agents.”

The rapid progress on a COVID-19 vaccine means that data regarding the long-term safety and durability of these vaccines will still be flowing in long after a vaccine has been approved for emergency use. Nevertheless, those wondering about vaccine safety may be encouraged that despite the speed in which these vaccines have been developed, the important regulatory and evaluation checkpoints designed to protect patients were followed. These milestones help to determine how safe and effective a vaccine will be, and whether or not the benefits are worth any potential risks.” (C)

“The U.S. Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) play complementary roles in establishing vaccine policy, and their differing roles can be a source of confusion for healthcare professionals, according to a new report.

“The most important point is to clarify the effort that is invested by so many people at FDA and CDC in determining safety (and) timing in terms of which vaccines are added to the schedule,” said Dr. H. Cody Meissner from Tufts Medical Center in Boston.

“The vaccine schedule is an exhaustively considered document and many factors go into deciding when a vaccine is added and the timing of the vaccine administration,” he told Reuters Health by email.

Dr. Meissner and colleagues explain the reasons for apparent differences between FDA-approved prescribing information and CDC recommendations for vaccine use in a paper online August 23 in Pediatrics.

The FDA’s Center for Biologics Evaluations and Research (CBER) is charged with regulating vaccines and ensuring the safety and effectiveness of vaccines that are available to the public.

After considering manufacturing data and results from animal studies and human clinical trials, CBER determines whether a vaccine is safe and effective for its intended use and, if so, ultimately approves prescribing information that includes indications and usage, dosage and administration, contraindications, and so on. This prescribing information is updated as needed.

Once a vaccine is approved by the FDA, the CDC’s Advisory Committee on Immunization Practices (ACIP) considers not only FDA-approved labeling, but also disease epidemiology, burden of disease, economic analyses and implementation issues in establishing how the vaccine should be used in the civilian population.

Only occasionally do these different roles lead to CDC recommendations that do not align perfectly with FDA-approved prescribing information.” (D)

Availability of safe and effective vaccines and adherence to national recommendations for immunization practices and vaccine use, including the recommended immunization schedules, are essential for the prevention and control of existing and emerging infectious diseases. The success of vaccines and public health vaccination programs in the United States is evidenced by the eradication of smallpox, the national elimination of polio, and historically low rates of measles, tetanus, diphtheria, rubella, and most other vaccine-preventable diseases.1

In the United States, the Center for Biologics Evaluations and Research (CBER) at the US Food and Drug Administration (FDA) regulates vaccines and ensures the safety and effectiveness of vaccines that are available to the public. The Centers for Disease Control and Prevention (CDC) makes recommendations for the use of FDA-licensed vaccines in the United States. Recommendations for vaccine use generally are consistent with FDA-approved prescribing information, which is commonly referred to as the “package insert.” However, differences between prescribing information and recommendations for vaccine use occur and may be a source of confusion for health care professionals. Our objective in this article is to explain how the roles of the FDA and CDC and the factors that are considered by the 2 agencies may lead to such differences.

The CBER is responsible for the regulatory oversight of vaccine development and the licensure of new vaccines in the United States. The CBER regulates vaccines under authorities that are derived from federal laws by applying specific regulations that address manufacturing consistency, clinical investigations, standards for safety and effectiveness, licensing, and product labeling. The CBER evaluates manufacturing data as well as data from animal studies and human clinical studies that are submitted to the CBER by the manufacturer in a biologics license application. The CBER’s evaluation includes a review of clinical studies for adherence to ethical and scientific quality standards, an inspection of clinical study sites, statistical analyses of primary data from clinical studies, a review of assay validation information, a review of detailed manufacturing information, and an inspection of manufacturing facilities. To be licensed, a vaccine must be safe and effective for its intended use. In making this determination, the FDA assesses whether the vaccine’s benefits outweigh its risks. In some cases, the CBER seeks advice from the Vaccines and Related Biological Products Advisory Committee, a federal advisory committee that consists of experts external to the FDA…

 The ACIP charter states that the committee should “provide advice and guidance to the director of the CDC regarding use of vaccines and related agents for effective control of vaccine-preventable diseases in the civilian population of the United States.”5 ACIP recommendations for the use of individual vaccines as well as the recommended childhood and adult immunization schedules become official when they are accepted by the CDC director and published in the CDC’s Morbidity and Mortality Weekly Report. Advice is provided for health care providers and public health officials regarding the use of licensed vaccines for different populations and circumstances. CDC recommendations are implemented by state immunization programs and may be used to develop school requirements for immunization. Recommendations for vaccine use are harmonized between the ACIP and liaison organizations, and, although rarely, recommendations from individual partner organizations may differ on the basis of variable interpretation of available data.

Since 2011, evidence-based recommendations from the CDC have been developed in part by the use of the Grading of Recommendations Assessment, Development, and Evaluation approach to assess the quality of evidence regarding the predicted benefit and potential harm, to provide transparency in the development of recommendations and to determine the strength of the recommendation.15–17 Additionally, in February 2018, the ACIP adopted an Evidence to Recommendations Framework to increase the transparency of the Grading of Recommendations Assessment, Development, and Evaluation process during the recommendation development phase (Morbidity and Mortality Weekly Report to be published). The CDC may consider a wider range of data on vaccine safety and effectiveness compared with data that are submitted to and considered by the CBER in making regulatory decisions…” (E)

“The U.S. FDA and CDC each convene advisory committees comprised of independent experts to provide advice and recommendations on a broad range of public health issues, including drug approvals.

The FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) and the CDC’s Advisory Committee on Immunization Practices (ACIP) are two of these panels.

In some instances, FDA will ask its VRBPAC members to vote on whether a vaccine should be approved, and for which population. If the agency does approve the vaccine in question, the CDC will ask its ACIP committee to vote on how it should best be administered to Americans. In both committees, a simple majority vote will become the panel’s recommendation.

In the case of Pfizer’s COVID-19 booster, VRBPAC endorsed a narrower guideline than originally requested by the drugmaker. The CDC’s advisers narrowed their recommendation further.

WHO SERVES ON THE ADVISORY COMMITTEES?

ACIP’s 15 members are mostly doctors who have expertise in how to best administer vaccines, including the timing and target populations. Candidates are nominated or can nominate themselves. Members are reimbursed for travel expenses and can receive an optional honorarium of $250 for each day the committee meets.

The membership of FDA’s VRBPAC also mostly consists of doctors, many of whom specialize in infectious diseases. Candidates with minimal conflicts of interest can apply or be nominated to the FDA. Members of FDA advisory committees receive travel and per diem costs if they are accrued.

CAN THE AGENCIES DISREGARD ADVISORY COMMITTEE ADVICE?

Yes. While both agencies generally end up in agreement with the recommendations reached by their outside advisers they are not binding. The ultimate responsibility for making the final decisions rests with the heads of the respective agencies.

“This was a scientific close call. In that situation, it was my call to make,” CDC Director Rochelle Walensky said of her decision for a broader booster rollout after weighing the advisory panel’s recommendations.

Some scientists said Walensky was justified in insisting on additional protection for frontline workers, such as nurses and doctors caring for COVID-19 patients. Others questioned whether the broad definition of high-risk jobs opened the door to a wider use of boosters than necessary, particularly in young men who may be at higher risk of rare heart inflammation following the shots.” (F)

“All approved indications for vaccines must be supported by substantial evidence of effectiveness.2 From a regulatory perspective, the most direct evidence of vaccine effectiveness is obtained from randomized controlled clinical trials in which the protective efficacy of the vaccine in preventing clinical disease is evaluated. Often, both clinical efficacy data and immunologic response data contribute to the evaluation of vaccine effectiveness. In general, regarding diseases for which there is a scientifically well-established immunologic marker that predicts protection and that can be measured reliably in a validated assay, immunologic response data provide sufficient evidence of effectiveness without the need for disease end point clinical efficacy trials. The FDA also may consider data from certain observational studies to support vaccine effectiveness. In general, the CBER expects that the demonstration of effectiveness is based on adequate and well-controlled clinical studies. The CBER considers the following characteristics to determine if studies are adequate and well-controlled: prespecification of objectives and analysis methods; study designs that permit a valid comparison of a group that is receiving an investigational vaccine with a control group to provide a quantitative assessment of the vaccine’s effect; methods of assigning participants to study groups to minimize bias and ensure comparability with regard to pertinent variables other than the vaccine (eg, randomization); measures to minimize bias on the part of the study participants, observers, and data analysts (eg, blinding); and an extent to which methods of the assessment of the vaccine’s response are well-defined and reliable.3” (G)

“The U.S. Food and Drug Administration on Friday approved the emergency use of a smaller dose of Pfizer’s coronavirus vaccine for children ages 5 to 11, paving the way for 28 million kids across the country to get their shots…

Earlier in the week, the FDA’s vaccine advisory panel voted to recommend the approval. The vote was nearly unanimous at 17-0, with one abstention.

Despite the vote count, some panel members noted at the time that they struggled with the decision.

“This is a much tougher one, I think, than we had expected coming into it,” panel member Dr. Eric Rubin, editor-in-chief of the New England Journal of Medicine, said during the meeting, NBC News reported. “The data show that the vaccine works and it’s pretty safe … [yet] we’re worried about a side effect that we can’t measure yet,” he said, referring to a heart condition called myocarditis that has cropped up in rare cases in some younger recipients of COVID vaccines.

Another panel member questioned whether the vaccinations were needed at all for these youngest Americans.

“It just seems to me that in some ways, we’re vaccinating children to protect the adults, and it should be the other way around,” committee member Dr. James Hildreth, president and CEO of Meharry Medical College in Tennessee, told NBC. “I do believe that children at highest risk do need to be vaccinated. But vaccinating all of the children … that seems a bit … much for me.”

Panel member Dr. Paul Offit, a vaccine researcher at Children’s Hospital of Philadelphia, said, “It’s always nerve-racking, I think, when you’re asked to make a decision for millions of children based on studies of only a few thousand children.”

But he stressed that the potential threat from a pediatric infection with COVID-19 is real.

“The question is, when do you know enough?” Offit added. “And I think we certainly know that there are many children between 5 and 11 years of age who are susceptible to this disease who could very well be sick and are hospitalized or die from it.”

Panel member Dr. Amanda Cohn, chief medical officer at the U.S. Centers for Disease Control and Prevention, saw the decision similarly.

“When I look at this question, it is pretty clear to me that the benefits do outweigh the risk, when I hear about children who are being put in the ICU, who are having long-term outcomes after their COVID, and children are dying,” Cohn said. “We vaccinate routinely against a couple of vaccine-preventable diseases for which far fewer deaths and hospitalizations and ICU admissions occur.”” (H)

“Some people want the FDA to speed up. Others want it to be more cautious. All of this can be head-spinning for anyone who just wants the agency to do whatever actually works to get us out of this horrendous pandemic. If one thing has defined America’s vaccination rollout, it’s exactly these competing pressures. There’s a fundamental tension between the right to get access to a drug people are desperate for and the right to protection from dangerous failures of quality. The first demands speed; the second requires time…

…For many people, the reflexive position remains: Get vaccines into arms. If the FDA doesn’t hurry up, it is killing Americans. But imagine the cost of the agency taking a controversial safety shortcut. For full FDA approval to bring all the benefits it could, people need to trust that such approval means something.

We have good reason to be cautious about both assumptions. Let’s start with the FDA. The agency’s full approval is more than just a formality. Yes, the vaccines are a tremendous success. But although early, publicly available data have now been thoroughly scrutinized, the agency has access to enormous amounts of more recent information that needs to be combed over for any surprises or signs of possible undetected issues. On a press call about the approval announcement, Peter Marks, the director of the FDA’s Center for Biologics Evaluation and Research, said that the agency reviewed hundreds of thousands of pages of new data from Pfizer. Even for an agency as well resourced as the FDA, thorough analysis and consideration of so much information is a heavy lift, especially for multiple vaccines at once…

We’ve gotten used to the emergency-use-authorization world. We can’t predict for sure what open season on marketing for the vaccines will be like. Some things may be simpler, but others may get more complicated. What is certain: We need widespread confidence on efficacy, safety, and the reliability of vaccine quality. The FDA’s job is to make sure that confidence is well placed and difficult to undermine. Even when it seems as though the agency is lumbering along, a perception that corners were cut under pressure would only make things worse.” (I)

• A.FDA advisory panel recommends Pfizer vaccine for kids ages 5 to 11, by JOE NEEL, https://www.npr.org/sections/health-shots/2021/10/26/1049372524/fda-panel-recommends-pfizer-vaccine-for-kids-ages-5-to-11
• B.Vaccine Development, Testing, and Regulation. By Paul Offit, https://ftp.historyofvaccines.org/content/articles/vaccine-development-testing-and-regulation
• C.How were researchers able to develop COVID-19 vaccines so quickly?, By Alison Caldwell, https://news.uchicago.edu/story/how-were-researchers-able-develop-covid-19-vaccines-so-quickly
• D.FDA, CDC Play Complementary Roles in Vaccine Policy-Making, By Will Boggs, https://www.hmpgloballearningnetwork.com/site/pln/content/fda-cdc-play-complementary-roles-vaccine-policy-making
• E.Understanding FDA-Approved Labeling and CDC Recommendations for Use of Vaccines, by H. Cody Meissner, Karen Farizo, Douglas Pratt, Larry K. Pickering and Amanda C. Cohn, https://pediatrics.aappublications.org/content/142/3/e20180780
• F.EXPLAINER-What is the role of outside advisers to the U.S. FDA and CDC in vaccine decisions?, by Michael Erman, https://finance.yahoo.com/news/explainer-role-outside-advisers-u-211642784.html?guccounter=1
• G.Understanding FDA-Approved Labeling and CDC Recommendations for Use of Vaccines, by H. Cody Meissner, Karen Farizo, Douglas Pratt, Larry K. Pickering and Amanda C. Cohn, https://pediatrics.aappublications.org/content/142/3/e20180780
• H.FDA Approves Pfizer COVID Vaccine for Kids 5-11, By Dennis Thompson and Robin Foster, https://www.usnews.com/news/health-news/articles/2021-10-29/fda-approves-pfizer-covid-vaccine-for-kids-5-11
• I.The FDA Really Did Have to Take This Long, By Hilda Bastian, https://www.theatlantic.com/science/archive/2021/08/fda-pfizer-vaccine-full-approval/619870/
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