A comprehensive literature scoping review of infection prevention and control methods for viral-mediated gene therapies.

Objective: This comprehensive literature scoping review outlines available infection prevention and control (IPC) methods for viral-mediated gene therapies and provides one IPC strategy for the healthcare setting based on a single-center recommendation. Methods: A team of experts in pharmacy, healthcare epidemiology, and biosafety with experience in viral-mediated gene therapy was assembled within a pediatric hospital to conduct a comprehensive literature scoping review. The comprehensive review included abstracts and full-text articles published since 2009 and utilized prespecified search terms of the five viral vectors of interest: adenovirus (AV), retrovirus (RV), adeno-associated virus (AAV), lentivirus (LV), and herpes simplex virus (HSV). Case reports, randomized controlled trials, and bench research studies were all included, while systematic reviews were excluded. Results: A total of 4473 case reports, randomized control trials, and benchtop research studies were identified using the defined search criteria. Chlorine compounds were found to inactivate AAV and AV, while alcohol-based disinfectants were ineffective. There was a relative paucity of studies investigating surface-based disinfection for HSV, however, alcohol-based disinfectants were effective in one study. Ultraviolent irradiation was also found to inactivate HSV in numerous studies. No studies investigated disinfection for LV and RV vectors. Conclusions: The need to define IPC methods is high due to the rapid emergence of viral-mediated gene therapies to treat rare diseases, but published clinical guidance remains scarce. In the absence of these data, our center recommends a 1:10 sodium hypochlorite solution in clinical and academic environments to ensure complete germicidal activity of viral-mediated gene therapies.

Clinical change 2 years from start of elexacaftor-tezacaftor-ivacaftor in severe cystic fibrosis.

RATIONALE: Limited published research is available on the impact of elexacaftor/tezacaftor/ivacaftor (ETI) beyond the initial few months postdrug initiation, especially for those who initiated therapy via individual investigational new drug application. The experiences of patients with cystic fibrosis (CF) experiencing severe lung disease were reviewed for significant improvements in clinical symptoms and quality of life. OBJECTIVES: To examine clinical outcomes 2 years post-ETI in patients with CF and advanced lung disease. METHODS: This single center institutional review board-approved, retrospective chart review assessed clinical markers (percent predicted forced expiratory volume in 1 s, weight, sweat chloride), quality of life and computed tomography scans in patients with advanced lung disease who met criteria for compassionate use/expanded access program due to high risk of death or transplant need within 2 years. RESULTS: Eighteen identified patients (ages 15-49 years) initiated drug between July and September 2019. Clinical markers indicated that therapy was well tolerated, not discontinued by any participant, and lab values did not indicate medical concern or discontinuation. Monitoring results indicated the safety of modulator therapy as there were no adverse clinical occurrences and all patients presented universal stabilization. There were no deaths and no transplants by the end of the study. CONCLUSIONS: This study focused on patients with CF eligible for modulator therapy and were initiated due to advanced lung disease. Initiation of modulator therapy was deemed safe and resulted in objective positive changes in nutrition, cough, FEV1 , subjective reports of clinical status, level of activity, and a reduction in burden of treatment.

Implementation and Patient Outcomes of a Pediatric COVID-19 Monoclonal Antibody Program.

BACKGROUND: The severity and reach of the COVID-19 pandemic drove the development of various therapeutic approaches to combat SARS-CoV-2, including several neutralizing monoclonal antibody (mAb) therapies. A January 2021 pediatric consensus statement opposed routine use and recommended individualized risk assessments when considering COVID-19 mAb therapies in children and adolescents due to limited data. This report describes the implementation of a mAb referral process and the clinical outcomes of patients who received a mAb infusion in a pediatric hospital. METHODS: We developed a tiered allocation system based on underlying medical conditions and incorporated it into a standardized COVID-19 mAb referral and approval process. Demographics and clinical data were collected on all patients who received mAb therapy for treatment or post-exposure prophylaxis. Data recorded included sociodemographics, qualifying underlying medical conditions, clinical manifestations of infection, and overall course of treatment and disease. RESULTS: A total of 182 patients ≤21 years old received a COVID-19 mAb infusion between November 27, 2020 and January 26, 2022. Patient age ranged from 10 months to 21 years, with a median age of 15 years. In total, 7 patients (4%) had suspected adverse reactions during the infusion, and 15 (8%) patients required a COVID-19-related visit within 30 days of the mAb infusion. CONCLUSIONS: A tiered allocation process may provide the framework for the stratification and efficient distribution of mAb therapies. Future research must focus on the efficacy of these therapies in the pediatric population, standardized therapeutic prioritization, and the optimal timeframe for mAb delivery to prevent progression to severe disease.

Gene Replacement Therapy: A Primer for the Health-system Pharmacist.

PURPOSE: Comprehensive review of gene replacement therapy with guidance and expert opinion on handling and administration for pharmacists. SUMMARY: There are currently ∼2600 gene therapy clinical trials worldwide and 4 Food and Drug Administration (FDA)-approved gene therapy products available in the United States. Gene therapy and its handling are different from other drugs; however, there is a lack of guidance from the National Institutes of Health (NIH), FDA, Centers for Disease Control and Prevention (CDC), World Health Organization (WHO), and professional associations regarding their pharmaceutical application. Although the NIH stratifies the backbone biologicals of viral vectors in gene therapies into risk groups, incomplete information regarding minimization of exposure and reduction of risk exists. In the absence of defined guidance, individual institutions develop their own policies and procedures, which often differ and are often outdated. This review provides expert opinion on the role of pharmacists in institutional preparedness, as well as gene therapy handling and administration. A suggested infrastructural model for gene replacement therapy handling is described, including requisite equipment acquisition and standard operating procedure development. Personnel, patient, and caregiver education and training are discussed. CONCLUSION: Pharmacists have a key role in the proper handling and general management of gene replacement therapies, identifying risk level, establishing infrastructure, and developing adequate policies and protocols, particularly in the absence of consensus guidelines for the handling and transport of gene replacement therapies.

Biosafety Practices for In Vivo Viral-Mediated Gene Therapy in the Health Care Setting.

Introduction: Gene therapy encompasses a diverse array of genetically engineered products in biomedical research. As novel products continue to gain regulatory approval, institutions will be challenged by translating research processes into the clinical environment. This article will provide a summary of the 5 in vivo viral-based therapies that have been approved or are under review in the United States or European Union and discuss the development of biosafety handling practices in the clinical setting. Discussion: Commercially approved gene therapies utilize adeno-associated viral vectors, lentiviruses, and modified herpes simplex viruses for genetic manipulation. Health care personnel must understand the location of the genetic manipulation, ex vivo or in vivo, in order to develop safe work practices when handling the products. Occupational exposure to a viral agent could lead to risks of infection or acquired immunity. Institutions must merge biosafety and hazardous drug handling standards in order to develop safe handling procedures for clinical care. Conclusion: As biotechnology continues to advance, so will the challenges of incorporating novel therapies into the clinical setting. Health systems must educate themselves on the current recommendations and maintain competency of this evolving science to ensure the safety of patients, families, and staff in the clinical environment.

Safeguards for Using Viral Vector Systems in Human Gene Therapy: A Resource for Biosafety Professionals Mitigating Risks in Health Care Settings.

Introduction: Health care workers who work daily with human body fluids and hazardous drugs are among those at the highest risk of occupational exposure to these agents. The Occupational Safety and Health Administration's (OSHA) Bloodborne Pathogens Standard (29 CFR 1910.1030) prescribes safeguards to protect workers against health hazards related to bloodborne pathogens. Similarly, the United States Pharmacopeia General Chapter 800 (USP <800>), a standard first published in February 2016 and implementation required by December 2019, addresses the occupational exposure risks of health care workers at organizations working with hazardous drugs. With emerging technologies in the field of gene therapy, these occupational exposure risks to health care workers now extend beyond those associated with bloodborne pathogens and hazardous drugs and now include recombinant DNA. The fifth edition of the Biosafety in Microbiological and Biomedical Laboratories (BMBL) and the National Institutes of Health Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines) mostly govern work with biohazardous agents and recombinant DNA in a laboratory research setting. When gene therapy products are utilized in a hospital environment, health care workers have very few resources to identify and reduce the risks associated with product use during and after the administration of treatments. Methods: At the Abigail Wexner Research Institute at Nationwide Children's Hospital, a comprehensive gap analysis was executed between the research and health care environment to develop a program for risk mitigation. The BMBL, NIH Guidelines, World Health Organization Biosafety Manual, OSHA Bloodborne Pathogens Standard, and USP <800> were used to develop a framework for the gap analysis process. Results: The standards and guidelines for working with viral vector systems in a research laboratory environment were adapted to develop a program that will mitigate the risks to health care workers involved in the preparation, transportation, and administration of gene therapies as well as subsequent patient care activities. The gap analysis identified significant differences in technical language used in daily operations, work environment, training and education, disinfection practices, and policy development between research and health care settings. These differences informed decisions and helped the organization develop a collaborative framework for risk mitigation when a gene therapy product enters the health care setting. Discussion: With continuing advances in the field of gene therapy, the oversight structure needs to evolve for the health care setting. To deliver the best outcomes to the patients of these therapies, researchers, Institutional Biosafety Committees, and health care workers need to collaborate on training programs to safeguard the public trust in the use of this technology both in clinical trials and as FDA-approved therapeutics.

A practical approach to assess the hazardous exposure potential of investigational drugs.

PURPOSE: A method to evaluate the hazardous exposure potential of investigational drugs was developed in order to comply with hazardous drug handling standards. SUMMARY: New nationwide standards require health-system pharmacies to recognize potential occupational risks and protect employees from any hazardous exposure. United States Pharmacopeia general chapter 800 (USP<800>) provides recommendations on handling precautions for commercial hazardous drugs. Recommendations for investigational drugs are less clear, with USP<800> suggesting more widespread protections when information is deemed insufficient to assess the risk. The investigational drug services pharmacy at a freestanding pediatric hospital developed a method to evaluate the hazardous potential of investigational drugs in order to determine the likelihood that a drug held an occupational handling risk. The goal of the project was to ensure compliance with hazardous drug handling standards and provide adequate employee protection while minimizing the financial burden on the health-system pharmacy. CONCLUSION: Investigational drugs that meet any of 4 defined criteria should be subject to hazardous drug handling precautions until adequate safety data are available.

Viral-mediated gene therapy and genetically modified therapeutics: A primer on biosafety handling for the health-system pharmacist.

PURPOSE: The guidance documents applicable to the manipulation of viral vectors in a health-system pharmacy are reviewed to provide recommendations for occupational safe drug handling. SUMMARY: Biosafety handling principles should be drawn from 2 guidance documents essential in the manipulation of biological material: Biosafety in Microbiological and Biomedical Laboratories, 5th Edition. and the National Institute of Health's NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines). Incorporating the biosafety guidance of these 2 documents into the pharmaceutical standards of United States Pharmacopeia chapter 800, "Hazardous Drugs-Handling in Healthcare Settings," will assist in the establishment of viral gene therapy handling guidelines in a health-system pharmacy. CONCLUSION: Novel gene therapies and genetically modified therapeutic products will expose health-system pharmacists to classes of medications with unique biological handling requirements. Occupational safety data on the handling of these medications will be limited. The health-system pharmacy will need to rely on published biosafety recommendations to evaluate the infectious and genotoxic risks of these products while determining the necessary containment strategies to ensure safe work practice.