By Melinda Young

In the two decades since Jesse Gelsinger died during a gene therapy clinical trial in September 1999, the clinical trial industry has treated gene therapy studies with additional caution.

Until now.

The balance is changing. The National Institutes of Health (NIH) is eliminating the Recombinant DNA Advisory Committee (RAC). After Gelsinger’s death, RAC was given enhanced oversight authority to improve checks and balances in research subject safety. (More information can be found at: https://go.nature.com/2tK5SlQ.)

Now, NIH has published new guidelines to streamline gene transfer research by eliminating RAC’s pre-review role and closing a national database of gene transfer studies. Titled Final Action Under the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines), the notice was published on April 26, 2019. (The guidance is available at: http://bit.ly/2Z0ROSX.)

These new guidelines for gene therapy research put more responsibility on IRBs for assessing gene transfer studies’ safety and have elicited 43 public comments — both for and against the changes. (The comments can be found at: http://bit.ly/2T4JnaO.)

The guidelines also eliminate pre-review at the federal level of any protocol for biosafety before new studies go to local biosafety committees, says Daniel Kavanagh, PhD, senior scientific advisor, gene therapy, WIRB-Copernicus Group (WCG) of Madison, WI.

The prior process was for principal investigators at the first clinical trial site to submit an Appendix M response to the Office of Science Policy (OSP) at NIH. Then, the NIH director would decide whether to refer the protocol to RAC as a pre-review step before it landed on the desks of IRBs, he explains.

“Up until 2016, RAC would review every protocol before it went forward,” Kavanagh adds. “All were registered in the federal database and sent back to the local institutional biosafety committee [IBC] for approval.”

Now, RAC is gone, and in its place is the Novel and Exceptional Technology and Research Advisory Committee (NExTRAC). The new entity will not review protocols, leaving that role to research sites’ ethics boards. (See story in this issue on how IRBs will need to change.)

The rationale for the change is that gene therapy studies are no longer novel and in need of additional oversight, notes Nancy M.P. King, JD, professor in the department of social sciences and health policy at Wake Forest School of Medicine in Winston-Salem, NC. King also is the co-director of the Center for Bioethics, Health, and Society and graduate program in bioethics.

“Gene transfer, or what is called gene addition now, doesn’t create enough novelty to sustain the RAC,” King says. “But gene editing has changed the landscape.”

King, a former RAC member, submitted a comment to NIH that opposed the change that would eliminate RAC’s authority.

“IBCs and IRBs still need guidance when reviewing gene transfer research protocols,” King wrote in her comment to NIH. “Simply ditching Appendix M might not be the best way to proceed.”

One of the underlying problems is that IBCs need more support than they receive, King says.

“IBCs have a very broad institutional mandate, and gene addition is only one small part of it,” she adds.

Whether IRBs and IBCs can handle the responsibility of reviewing gene transfer protocols without RAC’s help remains to be seen, she says.

“They probably are fine with gene addition research, but with all of this new genetic research, everybody needs more assistance,” King says. “NExTRAC is pretty far removed from advising IBCs.”

Many organizations and individuals commenting on the new NIH guidance said they were pleased to see NIH streamline oversight of gene transfer clinical research protocols and reduce duplication in reporting requirements.

For instance, the Immune Deficiency Foundation (IDF) submitted comments that applauded the change: “As the NIH and FDA noted in issuing this proposal, while such intense and overlapping oversight had its place, much has changed in recent years to justify a change that reduces regulatory burdens while still ensuring research participants are protected.”

NIH’s replacement of RAC with NExTRAC is the right change at the right time, says Donald B. Kohn, MD, distinguished professor of microbiology, immunology, molecular genetics and pediatrics, and molecular and medical pharmacology at the University of California, Los Angeles (UCLA). Kohn assisted IDF with writing the comments for NIH.

“I think it is time to eliminate the RAC reviewing every gene therapy protocol, as the FDA and local IRBs can monitor quality, safety concerns, etc.,” Kohn says. “But the RAC plays an important role as an open public forum to discuss issues of novel biosafety concerns, as it did when recombinant DNA technologies were first being developed.”

Another important change is that the Genetic Modification Clinical Research Information System (GeMCRIS) database will be eliminated.

“The database is going away,” Kavanagh says. “NIH stopped updating it last August with action by the NIH director, and by the fall of 2019, it will be taken offline.”

The result will be the loss of data that are valuable to some researchers and experts in the gene transfer research community.

“There are only a few of us specialists who found that database useful, and we will have downloaded everything before they take it offline,” Kavanagh says. “Everyone who cares has a copy on their computer, but it is a loss of information.”

Although research trials are listed on ClinicalTrials.gov, that database does not have as much information as did GeMCRIS, Kohn says.

“It is important to keep a complete registry of the numbers of patients getting various gene therapies while it is still an emerging treatment,” Kohn says.

With publicly-listed patient numbers, regulators and watchdog groups will know how many people could be impacted by safety issues and risks, he adds.

The premise behind the elimination of GeMCRIS is that gene therapy protocols are not different enough from other clinical research to justify having their own database, Kavanagh explains.

But there is risk: “Some gene transfer protocols are very high-risk in terms of potential harm to subjects, and some of them are moderate-risk in terms of potential harm to the public,” Kavanagh says.

“The IBC is mostly focused on whether there is risk the gene transfer agent will escape biocontainment and cause potential harm to people working in the clinic or in the general environment,” he adds. “IBCs also, until April 2019, had an overlapping responsibility with the IRB.”

Before the NIH changes, IBCs also assessed risk to clinical trial participants of gene transfer trials. They often had more gene therapy expertise on their committees, so IRBs benefited from their oversight.

“The FDA and NIH have decided that most IRBs have enough expertise available to assess these clinical trials without IBC assistance, in terms of risk to subjects,” Kavanagh says.

IRBs that review gene therapy studies will need access to expert advice, and they might not be able to rely on their institutions’ IBCs, as they have previously. IBCs still will review these studies, but solely for the purpose of determining occupational and public health risks.

“The IBC still reviews every protocol and still must issue an approval at every clinical trial site, but they’re not assessing risks to subjects,” Kavanagh explains. “They’re assessing risk to everyone else — to the clinical staff, the general public, and to the environment.”

The overlap of IBCs and IRBs assessing risk to subjects is gone. The change is in line with the Trump administration’s stated goals of reducing regulations.

“I have not seen public information that the change is tied into a larger regulatory strategy of the administration, but it is a response to feelings by clinical trials sponsors that there was too much duplicative oversight,” Kavanagh says. “Gene transfer work required more paperwork than other trials because of the large Appendix M document, and people trying to get their clinical trials started felt overly burdened.”

Some biosafety committees filed comments with NIH, saying the change was a step too far, Kavanagh adds.

While a number of comments to the NIH changes supported them, some individuals also expressed concern that oversight of gene therapy studies would be more lax and dangerous going forward.

For instance, Jesse Gelsinger’s father, Paul Gelsinger, wrote a comment to NIH about the change, asking the agency to not let history repeat itself.

“The death of innocence is something that we all must carry, and is an almost overwhelming burden,” Gelsinger wrote. “Everybody failed Jesse Gelsinger at every level, and all he wanted to do was help.”