Daria G. Husni

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The European Commission, the Heads of Medicines Agencies (HMA), and the European Medicines Agency (EMA) issued recommendations on July 17, 2023 for actions to prevent shortages of antibiotics (e.g., amoxicillin, amoxicillin/clavulanic acid, penicillin V, azithromycin, clarithromycin, ceftriaxone, cefotaxime and piperacillin-tazobactam) crucial in the treatment of respiratory infections . The recommendations were made to help prevent infections next winter in the European Union and were developed by the Executive Steering Group on Shortages and Safety in Medicinal Products (MSSG). The recommendations will be followed up on by the European Commission.

These recommendations reflect a new mandate for EMA (Regulation on EMA’s Reinforced Role (Regulation (EU) 2022/123)) which gives EMA new responsibilities on preventing critical medicine shortage crises. These responsibilities include monitoring events such as medicine shortages that may cause public health emergencies, reporting shortages to EU countries and coordinating responses with said countries, monitoring the supply and demand of medicinal products, and setting up two groups (MSSG and the Executive Steering Group on Shortages of Medical Devices).

EMA and the European Health Emergency Preparedness and Response Authority (HERA) will work with marketing authorization holders to ensure first and second-line antibiotics for respiratory infections will match demand. EMA and HERA recommended that marketing authorization holders increase production on these key antibiotics and take early action in the autumn and winter season to give sufficient time to manufacturers. EMA and the Commission, along with Member States, reminded stakeholders to order medicines as normal and to not stockpile medications. They also urged medical professionals to only prescribe antibiotics for bacterial infections in order to avoid antimicrobial resistance. Citizen awareness-raising initiatives were also recommended.

“Based on the data received we are working to ensure that we are better prepared for the upcoming winter season,” said Professor Karl Broich, chair of the HMA. “These early projections will allow the European medicines regulatory network to work with stakeholders to take measures in advance and prevent potential shortages for patients in the upcoming winter season.”

Going forward, EMA and HERA will continue to monitor supply and demand of key antibiotics throughout the rest of the year. “It is important that manufacturers take early action, ahead of the winter season, so that they can ramp up manufacturing capacity where necessary,” said Emer Cooke, EMA’s executive director in a EMA press release. A HERA Board meeting with representatives of the EU Member States’ Ministries of Health, the Commission, and the industry took place on July 20, 2023 to further discuss the issue and agree on future steps.

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These recommendations will keep key antibiotics for respiratory infections available when they are needed most.

EU Takes Steps to Prevent Antibiotic Shortages Next Winter

FDA published a draft guidance document on July 13, 2023 outlining recommendations for manufacturing of products related to human cellular therapy or gene therapy (CGT). Recommendations included product compatibility and manufacturing changes regarding investigational and licensed CGT products. The draft guidance document reflected FDA’s current view on “management and reporting of manufacturing changes for CGT products based on a lifecycle approach, and comparability studies to assess the effect of manufacturing changes on product quality.”

The guidance specifically talks about considerations for the management of manufacturing changes related to risk management, stability and delivery device compatibility, nonclinical studies, and clinical students. It then covers regulatory reporting of manufacturing changes. This included chemistry, manufacturing, controls (CMC) changes requiring a new Investigational New Drug Application (IND) submission, and reporting manufacturing changes to an IND and to a Biologics License Application (BLA). Comparability assessment and reporting are also discussed, touching on risk assessment, analytical comparability study design, analytical methods, results, and statistics. There is also a section for special considerations for tissue-engineered medical products.

Due to the complexity of CGT products and the unique factors present in manufacturing and control of CGT products, making changes to their management and manufacturing may be more of a challenge than for other biological products. While product manufacturers may seek to make a manufacturing chance for many reasons, it is important that the risks to product quality be properly assessed beforehand. The guidance states, “Risk assessment should be performed for all types of manufacturing changes, regardless of the stage of product development. If a risk assessment indicates that a manufacturing change has the potential to adversely affect product quality, comparability studies should be performed to evaluate the impact of the proposed manufacturing change.”

Sponsors and applicants of CGT products were recommended to discuss significant manufacturing changes with FDA’s Center for Biologics Evaluation and Research, especially if the changes would take place in later stages of the product lifecycle.

The document’s recommendations outline what studies and reports are required for changes to cell and gene therapy manufacturing.

FDA Publishes Draft Guidance on Human Cellular and Gene Therapy Products

On July 17, 2023, FDA approved nirsevimab-alip for newborns and infants born during or entering their first season of Respiratory Syncytial Virus (RSV), and children up to 24 months during their second RSV season who are vulnerable to severe RSV disease. Nirsevimab-alip—brand name Beyfortus—is a monoclonal antibody (mAB) that is administered as a single intramuscularly injection before or during the RSV season, according to FDA. One dose may prevent RSV during the entire season.

To support the safety and effectiveness of nirsevimab-alip, three clinical trials were conducted (Trials 03, 04, and 05). Efficacy was measured by the occurrence of RSV lower respiratory tract infection (MA RSV LRTI) during a period of 150 days after nirsevimab-alip injection. 

—a randomized, double-blind, and placebo-controlled multicenter clinical trial—included 1453 preterm infants born during or entering their first RSV season. Nirsevimab-alip reduced the risk of MA RSV LRTI by around 70% relative to placebo. 

 analyzed 1490 term and late preterm infants, and nirsevimab-alip reduced the risk of MA RSV LRTI by around 75% relative to placebo. 

—a randomized, double-blind, active (palivizumab)-controlled, multicenter trial—supported the use of nirsevimab-alip “in children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season. The trial enrolled 925 preterm infants and infants with chronic lung disease of prematurity or congenital heart disease.”

Nirsevimab-alip’s potential side effects include rash and injection site reactions. Infants and children with a history of serious reactions to its active ingredients or excipients should not take nirsevimab-alip. FDA cautioned that nirsevimab-alip “comes with warnings and precautions about serious hypersensitivity reactions, including anaphylaxis, which have been observed with other human IgG1 monoclonal antibodies.” Use of nirsevimab-alip in infants and children with clinically significant bleeding disorders should be done with caution.

“RSV can cause serious disease in infants and some children and results in a large number of emergency department and physician office visits each year,” said John Farley, M.D., M.P.H., director of the Office of Infectious Diseases in FDA’s Center for Drug Evaluation and Research, in an FDA press release. “Today’s approval addresses the great need for products to help reduce the impact of RSV disease on children, families and the health care system.”

RSV is a virus with the potential to cause acute respiratory infection in all age groups. Most infants and young children experience mild cold-like symptoms, but some infants (particularly if it is their first infection) develop lower respiratory tract diseases such as pneumonia and bronchiolitis. These diseases cause swelling on small airway passages in the lungs and often lead to trips to the physician or ER. RSV poses the highest risk to premature infants, and those with chronic lung disease of prematurity or significant congenital heart disease. RSV circulation is seasonal in most of the United States, starting in the fall and peaking in the winter, and is transmitted through close contact with someone who is infected, according to FDA.

The new drug may help vulnerable children resist RSV in the coming fall and winter season.