A Biosafety Perspective on Operational Challenges in Cell and Gene Therapy Studies

A rapidly growing portion of clinical trials involve cell and gene therapy (CGT), or human gene transfer. These studies involve administration of living cells and/or genetically modified DNA or RNA to clinical trial participants. In 2022 to date, the Alliance for Regenerative Medicine has identified 2,093 active clinical trials in this category, testing products from 1,369 cell, gene, and tissue-engineering therapeutic developers.¹ Examples include: regenerative medicine products derived from pluripotent stem cells, immune effector cells engineered to express chimeric antigen receptors (e.g., CAR-T cells), genetically engineered oncolytic viruses, and viral vectors expressing therapeutic transgenes to treat inherited or acquired disease. Importantly, within the CGT category, certain operational considerations apply only to cellular therapies or only to gene transfer therapies, and some apply to both.

When research involves potentially infectious or transmissible agents, genetically modified DNA or RNA, or biological toxins, it should be evaluated for potential risk to research staff, the general public, and the environment. Biosafety is the field of practice dedicated to assessing and mitigating these risks, and biosafety oversight at many research centers is provided by an institutional biosafety committee (IBC). The NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules² are
issued by the National Institutes of Health (NIH) and mandate IBC approval for certain clinical trials prior to initiation. For research subject to the NIH guidelines, the approving IBC must be registered with the NIH, and each such IBC registration pertains to a unique institution or clinical trial site.

Historically, each NIH-registered IBC was administered by the respective research institution, usually the university or academic medical center, and the bulk of research under review by these committees was basic science or preclinical studies. More recently, biosafety oversight for many clinical trials has been provided by central commercial IBC service providers, who can manage the IBC registration for multiple sites selected for a multicenter trial, for example.

Whether or not IBC review is mandatory for a particular study, certain biosafety considerations are recommended in the interest of responsible conduct of research. In the sections ahead, we will summarize these considerations in terms of NIH requirements and best practice recommendations.

Study-level biosafety considerations for sponsors

The NIH guidelines require that IBC approvals be issued for each clinical trial site or institution. This means that there are no study-level approvals under the guidelines; nevertheless, there are many ways that clinical trial sponsors can facilitate best practices and efficient IBC approvals. If biosafety considerations are addressed in an investigational new drug (IND) application, they can inform preparation of study documents that are distributed to investigators and review committees. These documents may include the protocol, investigator’s brochure (IB), pharmacy manual (or administration manual/product handling instructions), and draft informed consent form (ICF).

Under the current version of the guidelines, IBCs are not required to review the ICF; however, institutional review boards (IRBs) and IBCs may collaborate to identify and address third-party risks to participants and close contacts or family members, and these considerations may affect IRB approval. Review and consultation with a biosafety professional during the drafting stage of these documents can enhance their utility and facilitate efficient site-level approvals. For example, where appropriate, protocols should include plans for shedding assessments in the schedule of events. Also, the IRB should realistically address potential third-party risks and summarize existing preclinical or clinical shedding data.

A key document for biosafety review in multicenter clinical trials is the sponsor pharmacy manual, or equivalent product handling instructions. The pharmacy manual provides an opportunity for the sponsor to instruct sites and investigators on the safe handling of study agents. The pharmacy manual can also help to inform the site selection and study start-up processes whenever special equipment, such as a biological safety cabinet (BSC) is required. Clinical trials of non-biohazardous drug products often involve the use of laminar flow hoods for drug preparation. However, laminar flow hoods are generally not approvable for preparation of biohazardous products. BSCs (e.g., Class II A2 BSCs) are designed to protect the sterility of the drug product and the safety of the clinical staff and are required for some but not all CGT research. IBCs consider biosafety requirements under both the NIH guidelines and the Biosafety in Microbiological and Biomedical Laboratories (BMBL) handbook.³ Depending on the study, drug preparation at a site may also be subject to rules relating to current good manufacturing practices (cGMP), US Pharmacopeia (USP) 797, or USP 800 requirements. Collaborative review by pharmacists and biosafety professionals during the drafting stage of the pharmacy manual can harmonize operating expectations and facilitate site regulatory submissions and clinical trial initiation.

When it comes to site selection, there are a variety of considerations that specifically apply to CGT research. As mentioned, for gene transfer research, sites should either have an IBC registration with the NIH or be willing to become registered. Facilities and equipment required for a protocol should be specified in the respective pharmacy manual or equivalent, and prospective sites should be evaluated to see whether that equipment is available on site, or if purchasing, installation, and certification are required (all of which require time to complete). For cellular therapies, sites with demonstrable expertise in clinical operations may undergo a rigorous evaluation to become certified by the Foundation for Accreditation of Cellular Therapy (FACT).⁴ On the other hand, for many CGT products, it is possible with expert assistance to enable naïve sites to undertake advanced therapies research—an important consideration as sponsors seek to engage with underserved communities and diverse patient populations.

Biosafety considerations at the site level

For a site with limited experience in gene transfer clinical trials, preparing to conduct research with advanced therapy or gene transfer products may seem like a daunting challenge. IBC review ensures that proposed research activities are compliant with federal biosafety requirements. Clinical staff often report that working with an experienced biosafety professional helps them feel confident about their approach to CGT study start-up and execution.

For any site, the first step in securing IBC approval is to ensure that there is an IBC registered with the NIH for that site. For sites using a commercial IBC service, the registration is generally administered by the commercial service provider on behalf of the site. Once registered with NIH, the IBC may be maintained indefinitely, so a new registration for each new study is not required.

Once the NIH registration is filed, then site staff can begin working with the IBC to secure approval for the first protocol. In general, each clinical trial protocol requires separate IBC approval. In contrast to IRB reviews, which are focused on protecting clinical trial participants, IBC reviews are focused on protecting clinical staff, visitors, the public, and the environment. When reviewing a clinical trial, an IBC will consider numerous factors, including the proposed biosafety level (i.e., BSL-1 or BSL-2) for the research and the equipment, training, and procedures to be used in safe conduct of the research.

As mentioned, a key item of equipment for many (but not all) gene transfer procedures is a BSC, and the most used type is Class II A2. Many research pharmacies are already equipped with this type of cabinet for general use, even without gene transfer research experience. Class II A2 cabinets draw clean air from the surrounding environment via a HEPA filter and then blow clean, HEPA-filtered exhaust air back into the workspace. When properly used, this design will both protect the investigational product (IP) from contamination, and protect clinic staff from unintentional exposure to the gene transfer product. BSCs require certification by an expert inspector prior to initial use and at regular intervals after installation.

In general, IP preparation at clinical trial sites does not require rooms with special airflow or negative pressure to comply with biosafety requirements. However, in certain cases, sponsors or sites may determine that ducted evacuation of exhaust air is needed, in response to special requirements relating to cGMP standards or the use of volatile compounds. These designs may involve Class II B2 or Class III BSCs, which channel air into exhaust ducts. Designing facilities to maintain balanced airflow in the presence of ducted BSCs requires a very significant increase in expense and setup time compared to regular Class II A2 operations. Any such facility should be carefully designed in consultation with architects, HVAC engineers, and biosafety professionals to minimize expense and delays.

Sites preparing for IBC approval should ensure that there is a biosafety standard operating procedure (SOP) appropriate for each protocol under review. The SOP should clearly delineate how the IP is received, stored, transported, prepared, administered, and disposed of, in addition to describing planned response to spills, exposures, and other unexpected events. Spill response for an IP that may contain viral vectors, infectious agents, or bloodborne pathogens requires careful planning. It is important that staff trained on the SOP response are available to respond at any time that spills may occur.

It is also important to ensure that risk to patients and visitors not enrolled in the study is minimized, especially in clinical contexts such as cancer centers where many patients are likely to be immunocompromised. Depending on the study agent, it may be advisable to segregate enrolled participants from other patients, especially during dosing and infusion, when spills or accidental release of IP is most likely. Sites can benefit from planning ahead to identify infusion areas where participants can be kept separate during dosing.

Compliance and expectations

Clinical research with products containing genetically modified DNA and RNA is a rapidly growing area, and includes some of the most promising new advanced therapies. Most sites, even those with little or no experience in this area, can conduct these studies safely when they partner with experienced biosafety professionals. In many cases, the sites will be required to seek IBC approval, which not only ensures compliance with federal guidelines, but also helps ensure that investigators and staff understand best practices and expectations for safe and responsible conduct of gene transfer research.

Daniel Kavanagh, PhD, RAC, Senior Scientific Advisor, WCG

References

1. Regenerative Medicine: The Pipeline Momentum Builds; September 2022. https://alliancerm.org/sector-report/h1-2022-report/. Accessed 08SEP2022.
2. https://osp.od.nih.gov/wp-content/uploads/2019_NIH_Guidelines.htm
3. https://www.cdc.gov/labs/BMBL.html
4. https://www.factglobal.org