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The Importance of Hazard Communications in Clinical Trials Involving Genetic Engineering

Recombinant DNA technologies and genetically modified biological agents are being adapted for a wide scope of therapeutic applications, and their use is becoming increasingly common in clinical trials.

These types of investigational products (IPs) can present extraordinary hazards potentially unfamiliar to the clinical personnel responsible for handling these IPs.

The standard policies and procedures for safe handling of other types of hazards, such as antineoplastic drugs and infectious material, may not accommodate the specific risks posed by recombinant therapeutics.

This gap in hazard communication and safe handling practices training is bridged with an institutional biosafety committee (IBC) standard operating procedure (SOP) addressing specific risks. This blog describes why hazard communications are necessary and what an effective SOP should include.

Why Do You Need an SOP About IP Hazards?

When working with an unfamiliar IP, clinical personnel are likely looking for answers to three main questions:

Genetically engineered products often require additional safety practices to ensure the infectious agents do not endanger participants, study staff, or the broader environment where such agents are administered. Because these therapies often use live viral vectors, there is the risk of accidental transmission that is not encountered with non-biological drugs and therapeutics.

Communicating the Specific Hazards of IPs Involving Genetic Engineering

The health consequences from an exposure depend primarily on the virulence of the biological agent (or organism) and whether the agent can replicate.

Bundling IPs of the same risk classification into one SOP version provides standardization and consistency for clinics participating in multiple clinical trials using recombinant therapeutics. For example, a site conducting only protocols involving mRNA may be able to leverage a generic SOP covering any mRNA protocol at that site.

This means site personnel do not have to review and sign a new SOP each time they submit a new mRNA protocol.

The following information includes common elements to consider in site hazard communications and use of this “bundling” approach to simplify things for stakeholders (this is the approach Advarra’s IBC has taken).

Replication-incompetent Agents

Many viral vectors used in clinical trials today are genetically engineered with safeguards to render them replication-incompetent.

Whether an mRNA therapeutic or a replication-incompetent viral vector, IPs in this class can be safely handled using similar risk mitigation strategies, and one SOP can be applicable to most, if not all.

These types of agents are classified as self-limiting, because the amount of agent potentially shedding or distributing systemically from the site of exposure cannot exceed, and is likely inferior to, the original amount exposed. Thus, the likelihood of transmitting (or spreading) the agent to others is highly unlikely.

Synthetic mRNA-based therapeutics used in clinical research today also fall into this self-limiting class of recombinant therapeutics. These IPs pose the lowest risk amongst all recombinant IPs. However, “replication-incompetent” does not mean these IPs are without risk altogether. Low-grade side effects are common for most mRNA-based IPs.

For a healthy individual, occupational exposure side effects would likely mimic, to a lesser degree, those experienced by study subjects receiving full doses of the IP. These side effects most commonly are low-grade reactions localized to the injection site.

However, some individuals may have pre-existing immune-related conditions, making them vulnerable to more severe reactions upon IP exposure, such as systemic allergic reactions requiring medical treatment.

Clinical personnel need to understand these risks and how risks are differentiated between healthy and vulnerable individuals.

Replication-competent Agents

On the other side of the risk spectrum, live replication-competent viruses are being developed as therapies for solid tumors. Known as oncolytic viruses, these are engineered to restrict replication and spread of the virus to within the tumor tissue, but the safeguards engineered for this purpose are not absolute (unlike those used to make viruses replication-incompetent).

Due to their unique complexities, oncolytic viruses normally require specific SOPs to communicate the risks and appropriate safe handling practices specific to oncolytic viruses, and also succinctly describe the nuances responsible for their exceptional risk.

Depending on the genetic modifications of the oncolytic virus, exposure may result in an infection or disease with symptoms mimicking those from an infection by the native parent virus. The SOP should list these symptoms and any available prophylaxis for post-exposure treatment.

This SOP should also advise persons who are immunocompromised or taking immune suppressive medications against handling the investigational product, as they could be particularly vulnerable to disease resulting from exposure. Since the risk posed to a pregnancy and unborn fetus is typically unknown, pregnant women may also be advised as such.

If a vaccine is available, clinical personnel working with the IP should consider vaccination status. That should be in the SOP as well.

The IBC’s Role in Developing Hazard Communications

In its review, the IBC derives these safe product handling answers using a risk assessment. The IBC’s risk assessment considers the biological properties inherent to the investigational product, as well as aspects specific to the clinical protocol (such as modes for preparation and administration).

In addition to these questions, the IBC also assesses the probability of the IP being shed into the environment, the risk such a release poses to the environment, the adequacy of the clinic’s facilities for working with the IP, and the competency and training of the principal investigator (PI) and clinical personnel who will work with the IP.

All this information is distilled into a concise hazard communication, which can be incorporated into a site’s standard SOP and training materials for the PI and clinical personnel. These communications and SOPs are typically specific to an investigational product (or class of investigational products) rather than a specific clinical trial protocol.

Benefits and Limitations of Bundling Common Hazard Communications

As mentioned above, in its risk assessment, the IBC considers aspects specific to the clinical protocol, which may be independent of the IP. The mode of administration to participants can significantly impact the protocol’s risk evaluation.

The one-size-fits-all approach mentioned above for SOPs covering self-limiting or replication-incompetent IPs applies for only the most common modes of administration, such as intramuscular or intravenous.

If, for example, a protocol requires the IP to be nebulized for administration into the lung, all persons in the room during administration will be at risk of exposure from inhalation. In this case, a protocol-specific SOP with exceptional exposure mitigation measures would be required. These measures could include use of respiratory protection for all persons in the room, restricting the room to only required personnel, and disinfecting all surfaces following administration.

The Importance of Hazard Communications in Clinical Trials

Recombinant therapeutics evaluated in humans are unlikely to be highly virulent because they are intentionally and carefully developed that way. However, some degree of virulence and risk is acceptable, depending on the disease and subject population being treated.

NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules require IBCs ensure hazards are appropriately communicated to those potentially impacted, and study staff receive training on appropriate safe handling practices. Most clinical research clinics do not have the type of administrative resources in place to maintain a registered IBC with the NIH. This is why using an externally administered IBC is paramount for the development of medical recombinant therapeutics.

The risk of these IPs to enrolled study subjects, who ostensibly receive full doses of the IP, are mitigated by the protocol’s defined exclusion criteria. Vulnerable individuals who may react adversely to the study treatment are not eligible to participate in the trial, which minimizes the possibility of adverse events occurring in these individuals.

Further, enrolled study subjects are informed of the known and anticipated risks of the IP in the informed consent form (ICF) they are required to review and sign prior to enrollment. Thus, mechanisms are already in place for hazard communication and training for enrolled study subjects.

However, no such formal communication or training requirement exists for clinical personnel with potential for exposure. A formal hazard communication or IBC SOP fills this gap by effectively providing the hazard communication and training clinical personnel deserve.

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