Sponsors and CROs should seek expert advice on IBC oversight at an early stage of clinical trial planning, Dr Daniel Kavanagh, senior scientific advisor, gene therapy and IBC specialist, WCG, told BioPharma-Reporter.
He also stressed that while the current system of review of HGT clinical trials as required by the US National Institutes of Health (NIH) Guidelines is robust and useful, there are gaps that prevent a thorough evaluation of risks to public welfare.
Dr Kavanagh first outlined the type of studies run at sites inside or (in some cases) outside the US that would require an IBC evaluation.
“When it comes to an IBC review, we are concerned with gene therapy, such as viral vectors for gene replacement, and also mRNA vaccines, as well as genetically modified immune effector cells like CAR T cells or stem cells, essentially all HGT products as defined by the NIH.”
The IBC in the US is focused on protecting clinical staff, public health, and the environment from risks posed by gene transfer research. The committee reviews how an agent is shipped, received, stored, prepared, administered and disposed of.
“Some of these products contain agents that are capable of modifying the human chromosome or contain a live virus that could replicate, so accidental exposure as an occupational risk is something that has to be mitigated and that is one important purpose of the IBC,” explained Dr Kavanagh.
Along with IBCs, institutional review boards (IRBs) also have a critical role to play in approving and facilitating the initiation of such trials. They are responsible for protecting the rights of research participants in clinical trials, said the expert.
A basic requirement established many years ago, for NIH funded gene transfer research, whether that is focused on bench, animal, agricultural or clinical work, was that it must be reviewed by an IBC, and the original plan was that research was going to be happening in universities, and that they would be staffing those committees, he said.
“Around 20 years ago clinical research, specifically, started to be conducted outside the universities in hospitals and clinics, first in the US and then around the world, but those sites were not prepared to create their own committee of scientists to do these reviews, so WCG stepped in and created an external IBC service.
“External IBCs have been around for all these years because clinical trial sites need to conduct this research in compliance with the NIH guidelines, by having a committee that includes competent scientists but also local community members that are not affiliated with the institution, and that have knowledge of areas such as clinical research or environmental health.”
Challenges exist in relation to recruiting those local community representatives to take part in IBCs though.
“It depends on the location, of course. In San Francisco and Atlanta, it is easy to find qualified people who out of public mindedness or for a little stipend will be happy to join the committee. In less densely populated places like Wyoming or New Mexico, where there are patients who need to be recruited to trials, it may take a little longer to find suitable IBC members and that is occasionally an obstacle that clinical trial sponsors run into as an unpleasant surprise if they don’t plan ahead. We are pretty good at finding people but the more remote the area the longer it is going to take.
“It is also important for sponsors to take a look at their product, consult a biosafety professional in advance, and find out if their agent requires a review by an IBC. They also need to determine whether they are selecting clinical trial sites that are pre-registered with the NIH or using sites that require registration: they should find a partner early to get that done efficiently.”
The IBC review requires safe handling of the product, and that is defined within the NIH guidelines.
“In addition, the NIH guidelines call out a separate document called Biosafety in Microbiological and Biomedical Laboratories (BMBL), a joint publication of the CDC and the NIH, and that further outlines specific guidelines for handling of different classes of agents. So a sponsor needs to ensure it has product handling instructions – they are usually included in their pharmacy manual – that will pass muster when they come before an IBC and are assessed for their compliance with the NIH guidelines and the CDC handbook. It is prudent for sponsors to have that pharmacy manual reviewed in advance by a biosafety professional, an expert who can spot the potential deficits that would delay approval.”
There are now over 2,000 IBCs registered with the NIH, some by commercial entities like WCG and many by the institutions themselves, said Dr Kavanagh.
“Some of those registrations, though, are duplicates. In fact, the number of individual sites that are registered with the NIH isn’t that large and the number of potential sites is much larger. For a rare disease being treated at an academic medical center there is often not an issue as that site would have an IBC. But, for example, ophthalmologists around the world treating retinal diseases, a rapidly growing indication for gene therapy, they would have no knowledge of gene therapies. So such practitioners would frequently need to be educated about what gene therapy is and they would need to get registered. My team spends a considerable amount of time on that.”
Gaps in oversight
Dr Kavanagh highlighted how a revision of the NIH Guidelines in April 2019 altered federal oversight of HGT clinical research.
A notable change was the removal of the NIH Recombinant DNA Advisory Committee (RAC) from routine biosafety oversight of clinical and nonclinical research, he said.
Until 2016, every HGT trial subject to the NIH Guidelines had a prereview by the RAC, which were the national and world level experts in gene transfer and biosafety, before a trial ever came to the local committees. “That was very useful for helping local committees feel comfortable but it became very tedious and duplicative with hundreds of almost identical low-risk trials. There was a step-wise change in how the RAC did its reviews, and then the RAC was renamed and repurposed in 2019 and no longer conducts routine reviews of clinical trials.”
The former RAC is now known as the Novel and Exceptional Technology and Research Advisory Committee (NExTRAC) and deals with a broader array of scientific, safety and ethical issues associated with emerging biotechnologies, he continued.
The elimination of central federal biosafety assessment of HGT research was a loss for the research community, finds Dr Kavanagh. “The amount of biosafety review that now takes place is not always clear and not always public. The RAC meetings were public.”
Furthermore, before 2019, IBCs also reviewed risks to the trial participant. “So, the informed consent document had to be reviewed by both the IBCs and IRBs. Then the FDA and the NIH decided in 2018 that IRBs could review them on their own, and the IBCs did not have to evaluate such risk. I believe that there are new categories of agents that would continue to benefit from both reviews.”
And to illustrate that point, he outlined a potential biosafety threat in relation to some of the new types of oncolytic viruses being produced to kill cancer cells.
“These are live replicating viruses in most cases. They can be injected into the blood or into a tumor. They kill the tumor and they replicate. Sponsors are usually careful to make sure that the agent is unlikely to spread to other people. But that would have been formally reviewed by the IRB and the IBC under the old NIH rules.
“The question of how shedding should be reviewed by IRBs and IBCs deserves further scrutiny. The simple question of whether the virus is shed from the person receiving the treatment into the environment is an IBC concern and that is something an IBC must look at and they do. But how do you asses the risk to family members and close contacts? Is that also in the purview of the IRB? This is an active area under consideration by federal, commercial, and academic stakeholders.
“Another unsettled question is how third party risk should be described in informed consent documents.”
Dr Kavanagh suggests that IRBs and IBCs should start to collaborate more and perhaps NExTRAC should start to look at promising new therapies more closely, when there are live organisms involved.