New Weapons Emerge in the Fight Against Respiratory Syncytial Virus (RSV)

Imagine your newborn baby has been hospitalized with a serious respiratory infection and is struggling to breathe. That’s a reality for thousands of US newborns and their parents every year during the respiratory syncytial virus (RSV) season. This common endemic virus doesn’t cause clinically significant disease in most children and adults, but it can cause serious respiratory disease in some newborns—particularly those born prematurely or with underlying conditions—and for older adults with weakened immune systems.

Unfortunately, until this year there were no vaccines available to prevent RSV infection. GlaxoSmithKline (GSK) and Pfizer both made history earlier this year with the approval of an RSV vaccine for older adults. On May 3, the US Food and Drug Administration (FDA) approved GSK’s Arexvy (the world’s first RSV vaccine for older adults), and on May 31, FDA approved Pfizer’s ABRYSVO™ RSV vaccine. In both cases, these vaccines were shown to significantly prevent lower respiratory tract infection caused by RSV in individuals 60 years of age or older. But what about infants and young children at risk for serious disease?

Every year in the United States nearly 600,000 infants and young children—mostly healthy, full‑term infants in their first year of life—will develop a lower respiratory tract infection from RSV, and up to 80,000 will be hospitalized.1,2 Some of these infants will require intensive care with oxygen and intravenous (IV) fluids, and a few of the most vulnerable infants—those born prematurely with underdeveloped lungs or with congenital heart disease—may die.

Synagis® (palivizumab)

Until now, the only option to prevent RSV infection was an anti-RSV antibody developed by MedImmune in the 1990s known as Synagis®. Synagis® (palivizumab) was approved in 1998, but only for use in high-risk infants like those described above. Synagis can be given during the 5-month RSV season, and it neutralizes the virus, thus reducing the risk of infection and serious respiratory disease. However, it requires 5 monthly intramuscular injections, and there was nothing available to prevent RSV infections in healthy, full-term infants.

But that all changed this week with the FDA approval of BEYFORTUS™ (nirsevimab) on July 17, which is indicated for the prevention of RSV lower respiratory tract disease in neonates and infants born during or entering their first RSV season, and in children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season. Nirsevimab is a potent RSV‑neutralizing antibody that can be given to an infant before or during the RSV season, and it has been engineered to have an extended half-life.

There will soon be two new weapons available in the US to protect infants and young children from RSV infection. The first is nirsevimab, which has been shown to provide ~75% protection from any medically attended RSV-associated lower respiratory tract infection for at least 5 months. Thus, a single shot can protect the infant for the entire RSV season. On June 8th, the Antimicrobial Drugs Advisory Committee unanimously endorsed approval of nirsevimab for all neonates and infants born during or entering their first RSV season. Importantly, there are no serious safety concerns with nirsevimab. A small number of infants who received the antibody had a minor rash or injection site reaction, as would be expected with a childhood vaccination, but there was no evidence of any serious risks associated with nirsevimab.

There will soon be two new weapons available in the US to protect infants and young children from RSV infection.

The second is a vaccine that can be given to the mother with the goal of boosting maternal antibodies against the virus, which are passed to the fetus through the placenta. Pfizer’s maternal vaccine ABRYSVO™ (the same formulation as the adult vaccine described above) was reviewed by the FDA Vaccines and Related Products Advisory Committee on May 18th and received a favorable recommendation. The maternal vaccine can be administered during the 2nd or 3rd trimester and provides the baby with about 80% protection from severe RSV lower respiratory tract infection for 3 to 4 months after birth. The advisory committee expressed some concern about the potential for the vaccine to increase the number of premature births but ultimately agreed that the benefits outweigh the risks. FDA will make a decision about the Pfizer vaccine in the near future.

Nirsevimab has the added benefit that it can provide protection regardless of when the baby is born. Nirsevimab can be given to the infant in the hospital, immediately after birth, or by a pediatrician just before the RSV season begins. That’s important because the RSV season in the United States typically occurs from October to March in most locations. So, if a mother who received the maternal vaccine gives birth in the Spring, her baby will no longer be protected when the next RSV season begins in October because of the waning of maternal antibodies present in the baby after 3 to 4 months. In such a case, the baby can be given nirsevimab in September or October and be protected for the full RSV season.

Together, these two interventions could dramatically reduce the burden of RSV infection in the United States. It is estimated that if every infant born in the United States received nirsevimab, it could prevent 300,000 RSV-related medical visits, 100,000 emergency room visits, and up to 60,000 hospitalizations every year. That would have a huge impact on busy pediatric emergency rooms and intensive care units that are often overwhelmed during the winter months due to RSV and influenza.

Together, these two interventions could dramatically reduce the burden of RSV infection in the United States.

The Long Road to RSV Prevention

It has been a long road to developing a broadly effective RSV-prevention strategy.3 The virus was first discovered in the 1950s, and the first trials of a formalin‑inactivated vaccine were conducted in the mid-1960s. However, that vaccine caused enhanced disease in some children who were later exposed to RSV and resulted in the death of two infants, which dramatically impeded subsequent vaccine development.

In the mid-1980s, the first studies demonstrating passive immunization with an antibody were completed; this led to the development of RSV-intravenous immunoglobulin (IVIG) and its approval in 1996. Next came the approval of palivizumab in 1998, an antibody that targets the RSV F fusion protein.

In 2013, the conformational mapping of the prefusion F protein by Jason McLellan and Barney Graham at the National Institutes of Health revolutionized the field.4 They identified important epitopes on the prefusion F protein, including Site 0, which is highly conserved and when targeted by antibodies can neutralize the virus so that it cannot infect cells. This ground-breaking research ultimately led to development of nirsevimab in 2014.

Timeline of the development of RSV prevention strategy for all infants.

The FDA approval of both vaccines and neutralizing antibodies against RSV in 2023 is another shining example of the power of biomedical research to address infectious diseases that pose a threat to human health. Although it took much longer to achieve this goal than anyone could have anticipated when the virus was first identified in 1958, science ultimately prevailed, thanks to the thousands of parents who were willing to enroll in clinical trials.

The FDA approval of both vaccines and neutralizing antibodies against RSV in 2023 is another shining example of the power of biomedical research to address infectious diseases that pose a threat to human health.


  1. Rainisch G, Adhikari B, Meltzer MI, Langley G. Estimating the impact of multiple immunization products on medically attended respiratory syncytial virus (RSV) infections in infants. Vaccine. 2020;38(2):251-257.
  2. McLaughlin JM, Khan F, Schmitt H-J, et al. Respiratory syncytial virus-associated hospitalization rates among US infants: a systematic review and meta-analysis. J Infect Dis. 2022;225(6):1100-1111.
  3. Villafana T, Falloon J, Griffin MP, et al. Passive and active immunization against respiratory syncytial virus for the young and old. Expert Rev Vaccines. 2017;16(7):1-13.
  4. McLellan JS, Chen M, Joyce MG, et al. Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus. Science. 2013;342:592-598.

Jeffrey S. Riegel, PhD
SVP, Scientific Communications, ProEd Regulatory
Jeff combines his scientific expertise in molecular biology and immunology with more than 25 years of global healthcare agency experience in guiding medical and regulatory communication strategies for biopharma companies. Jeff leads the scientific team at ProEd Regulatory, which helps clients prepare for FDA Advisory Committee meetings and other health authority interactions. Connect with Jeff on LinkedIn.

FDA Sets High Bar for Real-World Evidence in Rare Diseases

Real-world data (RWD) can be used to create historical control groups for clinical trials in rare diseases where a randomized controlled trial (RCT) is not feasible. But what happens when the US Food and Drug Administration (FDA) doesn’t accept it?

Since passage of the 21st Century Cures Act in 2016, FDA has promoted the use of real-world evidence (RWE) to increase the efficiency of clinical research. However, according to
FDA’s 2018 RWE framework, the use of RWE is primarily restricted to evaluating safety
(eg, monitoring postmarketing safety). It can only be used in limited circumstances to inform decisions about effectiveness.

When it comes to regulatory decisions about product effectiveness, FDA’s framework suggests that RWE can be used to support changes to labeling about product effectiveness, including adding or modifying an indication, such as a change in dose, dose regimen, or route of administration, adding a new population, or adding comparative effectiveness data.

So, where does that leave sponsors who want to compare the results of a single-arm clinical trial to a real-world historical control arm to demonstrate the effectiveness of a new product? Unfortunately, the FDA has set a very high bar.

Regulatory “Fitness” in Rare Disease Clinical Trials

At a joint FDA-National Institutes of Health workshop in May 2022, titled “Regulatory Fitness in Rare Disease Clinical Trials,” Katie Donohue, Director of the Division of Rare Diseases and Medical Genetics in the Center for Drug Evaluation & Research, said that the challenges facing sponsors attempting a single-arm approach to develop a first therapy for a rare disease are so daunting that development programs only “work when you are very lucky.” In particular, she pointed out that single-arm studies are vulnerable to changes in rare disease natural history.

Changes in natural history, response assessment, and standard-of-care therapy can have a dramatic effect on time-to-event endpoints such as overall survival (OS). So, for a single-arm trial, FDA recommends concrete, confirmed endpoints “like an x-ray or blood test.”

These comments highlight the strong preference FDA has for RCTs, in general, and even for rare diseases, where it is often extremely challenging to conduct an RCT with sufficient statistical power to demonstrate effectiveness.

FDA Has Set the Bar Very High

FDA’s draft guidance, titled Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drug and Biological Products, acknowledges the potential utility of using RWD in interventional studies, including “to serve as a comparator arm in an external control trial.” However, the guidance focuses heavily on the use of RWD/RWE in non-interventional studies, such as observational cohort studies and case control studies that evaluate the safety and effectiveness of a product in routine medical practice and are not governed by a research protocol.

Although FDA is not opposed to the idea to using RWD to construct historical control groups also referred to as an external control arm – it is highly critical of that approach as the basis for regulatory approval of a novel drug.

Recently, Y-mAbs Therapeutics found this out the hard way. In collaboration with Memorial Sloan Kettering Cancer Center (MSKCC), Y-mAbs has developed a targeted radiolabeled antibody called 131I-omburtamab for the treatment of neuroblastoma that has metastasized to the central nervous system (CNS). This ultrarare pediatric indication affects only about 20 patients per year in the United States, and there are no approved therapies.

With traditional treatment approaches – surgery, radiotherapy (RT), and chemotherapy – most patients only survive a few months after diagnosis of CNS metastases. For about one third of patients who survive long enough to receive 2 or 3 treatment modalities, median survival is about 15 months. So, the clinical team at MSKCC, led by Dr. Nai-Kong Cheung and Dr. Kim Kramer, developed 131I-omburtamab, an anti-B7-H3 antibody, which they inject directly into the cerebrospinal fluid via an Ommaya catheter, as an adjunct to standard therapy. The goal is to eradicate residual tumor cells and increase the chance of achieving a cure.

The team at MSKCC has been studying the safety and effectiveness of 131I-omburtamab in this poor-prognosis patient population since 2004. In that timeframe, they have treated more than 100 children with CNS neuroblastoma, of whom about 40% have survived more than 8 years. Their treatment protocol demonstrated a median OS of 51 months, a milestone that clinical experts consider quite extraordinary.

Fast Forward to 2015

In 2015, Thomas Gad, whose daughter was successfully treated at MSKCC for CNS neuroblastoma, founded Y-mAbs Therapeutics to further develop 131I-omburtamab and get it approved in the US, so other children could have access to this potentially lifesaving drug.

To demonstrate the effectiveness of 131I-omburtamab, the company conducted its own single-arm multicenter trial in 50 patients, principally to confirm the results from the single-institution MSKCC trial and demonstrate objective responses to the drug. Given the rarity of this indication, an RCT was not feasible.

Y-mAbs then set out to obtain patient-level data from children with CNS neuroblastoma treated outside MSKCC and construct an external control arm for comparison with the MSKCC trial population. They succeeded in identifying only one suitable database, a neuroblastoma registry in Germany, and they were able to extract patient-level data from 120 patients who had a first recurrence of neuroblastoma in the brain. In collaboration with the FDA, Y-mAbs designed the comparative analysis using a propensity score model.

After carefully balancing the intensity of standard treatment with surgery, RT, and chemotherapy (modality group 2), the Y-mAbs biometrics team identified a cohort of 34 patients from the external control arm that they could compare to 89 patients in the MSKCC study. A comprehensive propensity score model that controlled for potential confounding factors demonstrated a 42% improvement in OS (hazard ratio = 0.58) compared with the external control arm. Sensitivity analyses showed a consistent treatment effect (hazard ratios ranged from 0.42 to 0.66) in favor of 131I-omburtamab.

Y-mAbs also went one step further, restricting the analysis to only patients in first recurrence, adjusting the index dates to control for immortal time bias, and removing patients from the external control arm treated prior to 1997. That analysis, which represents the best possible match between the populations, showed a 52% improvement in OS (Figure 1).

Figure 1.   Overall survival in patients in modality group 2 treated at first recurrence comparing index dates A vs D and excluding NB90 from external control arm

These data, along with supportive data from the multicenter trial, were the basis for the Y-mabs Biologics License Agreement filed in March 2022. However, after careful review of the data, FDA’s Oncology Division concluded that the external control arm is “not fit for purpose.” FDA argued that limitations of the data and multiple sources of potential bias resulted in a large degree of uncertainty regarding whether the observed OS difference was due to 131I‑omburtamab or differences between the populations, or a combination of these factors. FDA also had doubts about the objective response data.

FDA Oncologic Drugs Advisory Committee (ODAC) Meeting

At the ODAC meeting on October 28, 2022, the FDA presented its case that the 2 populations were not comparable, primarily because of differences in treatment intensity and era of therapy. They pointed out that none of the patients in the external control arm received craniospinal irradiation, a form of RT perceived to be more effective than the standard focal or whole-brain RT given to the German patients. However, there are no published studies to show that it is more effective in neuroblastoma. The FDA also presented evidence that clinical outcomes for CNS neuroblastoma have improved over time. Consequently, FDA restricted its analysis to only those patients in the external control arm who were treated from 2004 to 2015, the time period corresponding to the MSKCC study.

After adjusting for all these potential confounders, including immortal time bias, the FDA analysis showed a hazard ratio of 1.0, suggesting no OS benefit.

Ultimately, the committee voted unanimously that the Applicant had not provided sufficient evidence to conclude that 131I-omburtamab improves OS in the proposed indication. The committee wanted to see more data. Unfortunately, that may not be feasible.

This case sends a strong message regarding the rigor of data that FDA expects when establishing effectiveness based on a time-to-event endpoint in a single-arm trial with comparison to an external control arm, even in a rare disease where it exercises regulatory flexibility. The consequence of this ODAC decision means that sponsors will face a high bar when attempting to demonstrate that an external control arm is “fit for purpose.”

Jeff Riegel, PhD
SVP, Scientific Communications, ProEd Regulatory
Jeff combines his scientific expertise in molecular biology and immunology with more than 25 years of global healthcare agency experience guiding medical and regulatory communication strategies for biopharma companies. Jeff helps clients prepare for FDA Advisory Committee meetings and other health authority interactions. Connect with Jeff on LinkedIn.

COVID-19 Vaccines: When Will the Pandemic End?

As Pfizer, Moderna, and other pharma companies prepare to seek emergency authorization for their SARS-CoV-2 vaccines, the FDA has laid out a roadmap designed to ensure appropriate scientific rigor and help engender public trust. That plan was the subject of a special meeting of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) on October 22, 2020, where experts discussed 2 critical FDA guidance documents that provide a blueprint for development and approval of SARS-CoV-2 vaccines. That blueprint is at the center of a massive government effort to quickly and safely speed vaccines to the American public and bring the pandemic to an end.

Members of the VRBPAC, with expertise in infectious disease, epidemiology, and vaccine development, focused on issues around the FDA standards for safety and effectiveness that will support Emergency Use Authorization (EUA) of vaccine candidates. They discussed the need to continue the phase 3, randomized, placebo-controlled trials to completion after an EUA is granted. They considered how the vaccines will be rolled out to the American public, and they raised concerns about whether the public will embrace the vaccines and roll up their sleeves.

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The Target Product Profile—Your Blueprint for Drug Development

When utilized to its full potential, the Target Product Profile (TPP) is a dynamic, living document that ensures all stakeholders—clinical, regulatory, quality and manufacturing, commercial, market access, and medical affairs—are working from the same blueprint. Unfortunately, the TPP often has a bad rap within industry because many people think it is too rigid for today’s drug development environment. But often that reflects a failure to truly collaborate or a tendency to let the TPP get stale. To be effective, the TPP must be continually updated based on changes in the data and the competitive landscape. When companies take a balanced approach to developing the TPP and have a dynamic process that allows them to monitor and adapt it, as needed, they build agility into their drug development program that allows them to make critical go/no-go decisions or course corrections when necessary.

By using the TPP to ensure everyone is on the same page, drug developers can avoid costly delays when, for example, manufacturing isn’t ready to scale up to commercial production when the phase 3 data comes in ahead of schedule. Keeping a close eye on the evolving therapeutic landscape helps the development team anticipate what data will be needed to support labeling claims that may serve as a key differentiator from the competition and provide added value in the marketplace. So let’s look at how a dynamic TPP—one that is proactively updated—can help achieve the critical success factors introduced in the last installment. Continue reading

Mapping a Successful Path to Label Optimization

Bringing a drug to market is a long and expensive process. An analysis by the Tufts Center for the Study of Drug Development estimated the total cost of development from discovery to commercialization at $2.6 billion over the course of about 10 years (based primarily on big pharma companies). This represents more than a 10‑fold increase since the 1970s, when a drug could be developed from bench to bedside for less than $200 million (Figure 1).1 Others estimate the cost to commercialize a drug to be much lower (< $1 billion when they consider small biotech companies),2 yet it is generally accepted that the cost of drug development is on the rise. A major driver of those rising costs is the money spent on drug candidates that never make it to market because of safety concerns or lack of efficacy. The bottom line is that there is no room for costly mistakes, miscalculations, or inefficiencies in the drug development process.
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Making Sense of FDA’s Expedited Drug Approval Pathways and Designations – for the Non-Regulatory Professional

blog header linkedin - FDA Approval v6 blog sizeOne of the fundamental responsibilities of the US Food and Drug Administration (FDA) is to approve effective medicines for people who need them, while upholding high standards for safety. That mission also demands that the FDA work efficiently and not delay approval of life-saving medical advances. Today, the FDA is reviewing applications for approval of new medicines faster than ever, and that’s a welcome change from the status quo 25 years ago. In the era from 1962 (immediately following the thalidomide recall) to the early 1990s, FDA review times for a New Drug Application (NDA) or Biologic License Agreement (BLA) were often measured in years rather than months. In 1993, the standard review time (from NDA or BLA submission to decision) for a new molecular or biologic entity (parlance for a drug not previously approved for any other use) was about 28 months,1 and in some cases, approvals were delayed for many years.

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Implications of ICMJE’s Data Sharing Proposal

ProEd-ICMJE-Data-Sharing-Proposal-PostOn January 20, members of the International Committee of Medical Journal Editors (ICMJE) announced a proposal that would require the authors of clinical trial publications to share the deidentified individual patient data that support their published results within 6 months of publication. Announced in an editorial published simultaneously in multiple medical journals, this proposal is based on the belief that authors have an “ethical obligation to responsibly share data generated by interventional clinical trials.” It also reflects the broader agenda of the ICMJE to foster greater transparency and reduce the potential for bias. This new requirement will likely go into effect in 2016 and will affect any clinical trial that enrolls patients beginning 1 year after ICMJE adopts the requirement.

This proposal makes a lot of sense in the interest of transparency, but what does it mean for clinical investigators involved in research and the companies that sponsor that research? To quote the ICMJE authors, “enabling responsible data sharing is a major endeavor that will affect the fabric of how clinical trials are planned and conducted and how their data are used.” Continue reading

President Obama’s Cancer Moonshot 2020 Initiative: How Big Is the Challenge?

Apollo rocket blasting offWhen President Obama’s White House Task Force meets for the first time this week, it faces a lofty charge: “Let’s make America the country that cures cancer once and for all.” His proposed Cancer Moonshot 2020 initiative will provide much needed funding for research, will encourage collaboration between industry and academia, and will undoubtedly lead to important advances in our understanding of cancer and how to treat it.

Although this initiative is noble and well intentioned, calling for a “cure for cancer” oversimplifies the challenge and is based on an outdated understanding of the disease.

The public needs to understand that cancer is not one disease; it’s hundreds of different diseases, and it’s more complex than anyone imagined back in 1971 when President Nixon first declared war on cancer. Those involved in cancer research know that conquering cancer, in all its varied forms, is truly a global endeavor that will require a sustained commitment for decades to come. While a challenge to be the “country that cures cancer” stirs our patriotic spirit and conviction that American biomedical know-how can render cancer irrelevant in our lifetime, the reality is that meaningful progress will require international collaboration.

Are we, as a nation, prepared to take on that challenge and lead such a charge? The President has taken the first step, appointing Vice President Joe Biden to lead the White House Task Force. But now the difficult work begins. Can we balance competing priorities and sustain both our political will and financial commitment for the many years that such an effort will undoubtedly take? Continue reading