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09/07/2018

RACeing to Deregulate: Can We Afford Less Oversight of Gene Transfer Research?

by Craig Klugman, Ph.D.

 “As gene therapy continues to change, so must the federal framework set up to oversee it.”-Francis Collins & Scott Gottlieb

In one of his first acts of office, Trump ordered executive agencies to reduce regulations. Supporters believed this would remove obstacles to innovation and bringing new products to market faster. Critics believed that this move would diminish health and safety protections, putting the public at potential risk. The NIH heard this message loud and clear as it has proposed reducing, and in some cases eliminating, regulations governing gene therapy experiments.

In case you have any doubt of the motivation, check out the NIH “admin” blog on its own website: “From Emerging to Emerged: Streamlining Gene Therapy Oversight.”Francis Collins, NIH Director echoes this reasoning in his NIH letter when he states: “With the evolution of the field of gene therapy, duplication in reviews and paperwork have sometimes occurred without a commensurate increase in protecting participant safety.”

In a New England Journal of Medicineeditorial, Collins and FDA commissioner, Scott Gottlieb, argue for this new position. They claim eliminating the review is important because “Though still more needs to be learned about the safety and efficacy of current technologies, many promising new approaches are on the horizon.” They conclude that DNA research has gone mainstream and is no longer “unique and unpredictable.” The letter tells us “we don’t know, but don’t worry.” Who wants to stand in the way of progress, which is another way of saying there is a lot of money to be made in this arena and the government should move aside.

Art by Craig Klugman

While Collins cites the lack of evidence that having NIH and FDA review of this research as protecting subjects, he may forget that lack of data is not proof. After all, how can you prove how many lives were saved, how many illness prevented because you took precautions? Increased scrutiny began after the death of Jesse Gelsingerin 1999. Gelsinger was a healthy 18-year-old born with ornithine transcarbamoylase (OTC) deficiency—his body cannot eliminate ammonia. The disease is rare, affecting 1 out of 40,000 births and if not detected, half die by age 1 month and the other half before age 5. However, with newborn testing, a special diet can minimize the damage. Although he had no symptoms on his diet, Gelsinger volunteered for a gene transfer experiment to help others. He was given in infusion of a corrected gene and 4 days later, he was dead. Although the final lawsuit is sealed, part of the issue was that the informed consent document did not mention serious side effects experienced by other subjects.

The proposed changes are to theregulations focus on the function of the NIH’s Recombinant DNA Advisory Group (RAC) and to the responsibilitiesof local Institutional Biosafety Committees (IBCs). In 1974, the NIH created the RAC to provide guidance on research into DNA. The group was charged to advise the NIH director and Secretary of DHHS, “Publicly reviewing human gene transfer clinical trial data”; providing advice on biosafety; and examining broad scientific, social, and ethics issues related to gene transfer and recombinant DNA research. However, in 2017, NIH Director Francis Collins signed a revised charter for the group which eliminated many of thesefunctions. The proposed new regulations take the reductions further.

Soon, the RAC will report only to the NIH director, will no longer review individual protocols, and will no longer review annual reports and adverse event filings. The former are administrative and mission changes but the latter removes a level of scientific review of protocols before they are carried out. Since they also need to have FDA approval before a process could be approved for market, this was seen as two steps—a regulatory overburden: “In changes proposed on August 17, 2018, in the Federal Register, the NIH and the FDA seek to reduce the duplicative oversight burden by further limiting the role of the NIH and RAC in assessing gene-therapy protocols and reviewing their safety information.”

The other change is in the function of IBCs. Their responsibility of reviewing and approving protocols; and reviewing biosafety protocols will not change. However, they will no longer look at any aspect of human subjects involvement (such as informed consent documents). IBCs also will no longer have continuing oversight of projects after the gene transfer to patients. Basically, now they have to follow up with subjects. Under the new guidelines their oversight work ends right after the last subject receives a final dose of the experimental agent. In a surprise piece, they do get one additional power: They now have to ensure that projects are “consistent with FDA’s current guidance on individual patient expanded access to investigational drugs.” Yes, right-to-try has been brought to gene therapy research.

While regulations and processes should not normally exist to frustrate researchers or to slow down (e.g.  when working with technologies that might have irreversible changes to the greater environment or the human species). This change assumes that gene transfer is generally safe and needs no more oversight than a new drug. But an adverse event from a drug trial, at its worst, would lead to the death of a subject or their permanent physical or mental maiming (very bad outcomes to be avoided): The potential damage is limited to the individual. If a rogue gene got out of the lab/a body/a species, it could effect every human being on the planet and perhaps many other life forms as well. Thus, the scale of potential harm is a exponentially larger. Also, to stop a drug from harming people, you stop distributing the drug. To stop a gene that has jumped to other individuals or species you…. We lack the words and ideas because your choice is to locate and quarantine every organism potentially affected (which is unlikely to work) or you destroy all life forms in a given quarantined geographic area to ensure no further spread. A rogue gene cannot easily be contained.

We have no proof that this nightmare scenario will happen. We also have limited data showing that these methods are perfectly safe. We do have some scientists claiming theyhave data showing that in agriculture, modified genes have “jumped the species barrier.” A UK report says we should not worryabout this because it happens in nature all of the time. The point made in a minority opinion, is that’s the problem—this transfer happens all of the time and we do not yet have the technology to know all of the effects that a change in a gene can have in an organism.

Even though the pace of development of gene therapy has been impressive with greater potential, there is enough historical precedent and enough potential widescale risk to suggest an additional layer of basic, scientific review is wise. We should not let a fervor for streamlining the government get in the way of sound scientific thinking. This is a situation where being more conservative in approach is desirable—a bit of paperwork is certainly worth saving lives or even entire species. What can we do about this? We can let our voices be heard. Although there is not a great track record of public comments on proposed regulatory changes being read, you can add your voice. The public open comment period is open until October 16, 2018. Click here and let the NIH know.

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