The Food and Drug Administration has authorized more than four dozen cell and gene therapy (CGT) products for use in the United States. But without standard national guidance on the safe handling of CGTs, health systems are relying on general recommendations and institutional experience to make these treatments available to patients.
“We’re trying to put our best foot forward, practice with what we know, and ... adjust our processes when we learn additional information,” said Anna Bieniek Wiener, manager of regulatory compliance, quality assurance, and medication safety for the pharmacy department at the Children’s Hospital of Philadelphia (CHOP).
CGTs are closely related and sometimes overlapping technologies. In general, cell therapies introduce altered forms of autologous or allogeneic cells into the patient to enhance cellular responses or replace abnormal cells. Gene therapies, instead of using whole cells, typically rely on adeno-associated virus (AAV) or other viral or nonviral vectors to introduce specific genes where needed.
In 2000, CHOP researchers developed an AAV vector for the successful delivery of gene therapy to treat hemophilia B. Today, the hospital offers a robust slate of commercially available gene-modifying treatments for pediatric patients.
“We have been in the game a little bit longer than many organizations. But we’re still continually learning,” Wiener said. She noted that the pharmacy department handles gene therapy products but hasn’t yet worked with cell therapies, though the infrastructure is in place to do so.
Wiener, who is a member of the Steering Committee for the ASHP Center for Next-Generation Therapeutics, supported the creation of a multidisciplinary process for evaluating biosafety risks associated with each gene therapy product considered for use at CHOP. She said the intent is to maximize safety without hindering care delivery.
“We think about things like pathogenicity, viability,” Wiener said of the multidisciplinary evaluation team’s work. “We think about the capacity to replicate, with the live agents. Toxicity of the transgene. And, most importantly, I think, in the realm of adeno-associated virus vector therapy, its immunogenicity.”
Wiener said the evaluation team relied largely on general guidance documents from the Centers for Disease Control and Prevention to establish safe handling practices for biohazardous CGTs. She said the group was careful not to designate CGTs as hazardous drugs as defined by the National Institute for Occupational Safety and Health (NIOSH). That definition, she said, is based on manufacturers’ special handling information and known drug toxicities but does not address the presence or toxicity of genetic material or concerns, such as immunogenicity, associated with viral vectors.
Wiener said physical requirements specified in United States Pharmacopeia Chapter <800> — negative pressure, a buffer room, and a biological safety cabinet — were adopted for spaces where CGTs are manipulated at CHOP.
She noted that teasing out the relevant information from various sources and applying it appropriately to gene therapies has been a challenge.
Elyse MacDonald, director of ambulatory operations and infusion and investigational drug services at Stanford Health Care in Palo Alto, California, voiced similar concerns about the lack of standard practices for working with CGTs.
“There is a gap in the literature,” she said. “We couldn’t find any other information out there that was pharmacy specific. There’s information out there more from a laboratory perspective. But we’re not a laboratory group; we’re a pharmacy group.”
MacDonald coauthored a case study, published last summer in AJHP, that describes how her health system developed pharmacy-specific standard operating procedures (SOPs) for the consistent and safe handling, compounding, and management of viral-vector-based gene therapies.
The case study describes a new institutional designation — biohazardous drugs — for use with some gene therapy products. Decisions about whether specific CGTs fall within this category are made during a risk assessment that includes clinicians and staff experts from the investigational drug and hematology-oncology services, medication safety and infection control committees, environmental health and safety, and other appropriate areas.
The risk determination underlies subsequent staff education, training, and policies for the use and handling of each CGT product. Pharmacy SOPs address labeling requirements, electronic medical record alerts, personal protective equipment recommendations, spill response and decontamination agents, and safety practices for compounding procedures.
MacDonald said the SOP project initially focused on staff in the investigational drug service (IDS) pharmacy who worked with CGTs. The scope expanded in recognition that as CGTs move from investigational to commercial use, a broader segment of the healthcare workforce needs practical guidance on working safely with these products.
“It was a pretty comprehensive process, to roll it out,” MacDonald said. “I think as you expand the stakeholder network, that’s where it gets challenging sometimes. But perseverance from our group really helped us move forward with implementing this project.”
Stanford’s pharmacy department compounds gene therapies designated as biohazardous drugs in a class II vertical flow biosafety cabinet dedicated for that purpose. Another department manages cell therapies.
“We do [biosafety level] 1 and 2, but we wouldn’t do any higher than at our institution — at least within the pharmacy — because we’re not equipped or set up to do that,” MacDonald noted.
The pharmacy department at CHOP has also set aside physical space and resources for working with CGTs.
“We have dedicated gene therapy rooms off our cleanroom suites that are intended for the sole handling of cell and gene therapies,” Wiener said.
Richard Dyke, director of pharmacy business operations for CHOP, said all safety recommendations needed for CGTs are incorporated into a work document for each product.
The work document also spells out administrative details, such as prior authorization requirements, how and where to place the order, and what phone number to call to escalate and resolve delivery issues.
“We do that for every gene therapy that we have operationalized at CHOP,” Dyke said.
He noted that the work document for delandistrogene moxeparvovec-rokl (Elevidys), an AAV-vector-based therapy for the treatment of Duchenne muscular dystrophy, runs about 25 pages.
Dyke emphasized that all medications used at the hospital, regardless of their cost or need for specialized handling, undergo a structured review and onboarding process.
But with gene therapies and other high-cost medications, he said, “the stakes are higher, and more people are interested in understanding the details.”
MacDonald, at Stanford, urged other hospitals, including small and rural sites that aren’t yet offering CGTs, to think about establishing a process for managing these therapies.
“People who need these medications aren’t solely located in an area where there’s an academic medical center, for example,” she said. “So for patient access, it would be great if availability could be expanded.”
