IRBs might not have asked for it, but the National Institutes of Health (NIH) and the FDA have handed them a new responsibility when it comes to oversight of clinical trials involving human gene transfer.

NIH has transferred the responsibility for the initial assessment of the risk-benefit of human gene transfer applications from the NIH Recombinant DNA Advisory Committee (RAC) to the local IRBs and institutional biosafety committees (IBCs), says Joan Robbins, PhD, senior vice president of biosafety and gene therapy for WIRB-Copernicus Group in Princeton, NJ.

RAC is a federal advisory committee that gives the NIH director recommendations about basic and clinical research involving recombinant or synthetic nucleic acid molecules.

“What that means is IRBs and IBCs will now need to look at the gene therapy protocol and determine if it requires RAC review,” she explains. “They might say, ‘This is something we’re not concerned about and we’ve seen it before,’ and then the IRB will recommend that it is not given a full RAC review.”

Or if the IRB or IBC are concerned about the protocol, they can recommend that it is reviewed by the RAC, she adds.

The problem is that human gene transfer research is not an area that many IRBs have considerable experience in reviewing, Robbins says. So if they are presented with this type of study and are not accustomed to doing an evaluation of it, will they feel comfortable saying that it doesn’t require RAC review?

“Will a lot of less experienced IRBs say, ‘We don’t know a lot about this, so should we just recommend a RAC review?’” she says. “If they do that and it’s not appropriate, the NIH director can overrule them.”

IRBs and IBCs that review for the initial study site for gene therapy research will need to have a number of processes in place, Robbins says.

“They’ll have to have already implemented new processes to do what is essentially a pre-review,” she says. “NIH recommends that IRBs and IBCs augment their memberships with ad hoc experts. They may need expertise in everything from DNA plasmids to CAR T-cell, modified T-cells.”

The NIH Office of Science Policy published a Federal Register notice on March 22, 2016, about the revised procedures for reviewing gene transfer trials. The changes were effective as of April 27, 2016.

When the changes first were proposed there were not a lot of comments, Robbins notes.

“We reviewed the guidelines very carefully when they came out,” Robbins says. “We asked NIH to clarify some of the points that were not well defined, and we hope that further clarification will help us to steer through the process.”

The revised review process was intended to streamline the process for the RAC, but it does require that the IRB and IBC at the first trial site assess each protocol to determine whether it meets one or more of three criteria, according to the NIH’s RAC revisions fact sheet. The criteria are the following:

  • “The protocol uses a new vector, genetic material, or delivery methodology that represents a first-in-human experience, thus presenting an unknown risk; or
  • “The protocol relies on preclinical safety data that were obtained using a new preclinical model system of unknown and unconfirmed value; or
  • “The proposed vector, gene construct, or method of delivery is associated with possible toxicities that are not widely known and that may render it difficult for oversight bodies involved to evaluate the protocol rigorously.”

IRBs may find it difficult determining any of the three criteria, Robbins suggests.

For example, while it appears to be a simple matter to determine whether the research will be using a new vector or genetic material, this can land in a gray area: “Even defining if it’s new material is not that easy because there could be a complex hybrid,” Robbins says.

Also, it might be challenging to determine which preclinical model system has value.

“It’s very difficult to get model systems that actually do predict everything you would want them to predict in people,” Robbins says.

“There have been instances where preclinical studies have shown good safety profiles with nothing to worry about, and still when it comes to human testing some really serious adverse events occur,” she says.

Examples include Jesse Gelsinger’s death during a gene therapy study and the recent French drug study in which one volunteer died and several were injured.

“So I think it will be a little challenging for IRBs to necessarily know whether that criterion is met,” Robbins says.

“Another point is that the proposed vector or gene construct — if it’s associated with toxicity, which is not widely known — that it needs to be sent for RAC review,” she says. “But it’s really challenging to interpret what is widely known.”

As IRBs begin to absorb and handle this new responsibility, the key might be to prepare for the change and identify a broad range of experts who can help them assess each of the different kinds of gene transfer studies, Robbins suggests.

“They’ll need to have their process in place in order to do the pre-review,” she says.