Ethics and Oversight in Recombinant Genetic Research

By Michael Young

In 1972, biochemist Paul Berg and his student Janet Mertz published groundbreaking details of their first successful attempt at devising a procedure to cleave separate pieces of DNA and recombine them into a single novel molecule.  These innovations, dubbed recombinant DNA (rDNA) technology, spurred a flurry of concerns from members of the scientific community who worried about the safety, risks and potential drawbacks of creating recombinant DNA molecules.  Motivated by these concerns, the NIH established the Recombinant DNA Molecule Program Advisory Committee (RAC) in 1974.  The RAC was charged with the mission of overseeing research and implementation of rDNA technologies, with a particular focus on proposals involving the transfer of recombinant or synthetic DNA into humans (i.e., human gene transfer).

Last week, after nearly 40 years of providing an additional layer of oversight to this class of research, the RAC received recommendations from an independent Institute of Medicine (IOM) committee that was convened to assess “whether the current oversight of individual gene transfer protocols by the Recombinant DNA Advisory Committee (RAC) continues to be necessary.”

The committee’s report calls for significant changes to the prevailing structures of rDNA research regulation and oversight, and represents a victory for many gene transfer researchers who have challenged RAC regulations. Many researchers have opposed special RAC oversight on grounds that it is often inefficient, redundant, and may unnecessarily delay the movement of vital therapeutics from bench to bedside, especially given pre-existing requirements for proposals to be reviewed both by the FDA and by internal institutional review boards.

Echoing some of these concerns, the IOM Committee’s report concludes that

“the time for modernization has arrived..the NIH should consider developing a process—using the RAC as a model—to rigorously review human subject research that is so novel, and carries significant unknown risks, that the normal regulatory apparatus lacks the capacity to conduct an adequate review. Until such a process is developed and agreed upon, the RAC should continue to review individual gene transfer protocols but should use new, more focused criteria in order to direct its resources to exceptional cases that warrant special oversight.”

In support of these recommendations, the report contends that

“[w]hereas the field of gene transfer research was characterized in its early years by considerable uncertainty and concern about theoretical risks—on the part of the public as well as the scientific community—this field has matured to a state in which some of the early concerns about risk, and uncertainty overall, have been minimized. With the experience of more than 40 years of gene transfer trials and nearly seventeen hundred currently approved clinical trials; much has been learned about potential adverse events and how to ensure the safety of research participants. The committee concluded that many gene transfer clinical trials pose acceptable risks and are fast becoming an established modality of modern medicine.

       Although gene transfer research continues to raise important scientific, social, and ethical questions, not all gene transfer research is unique, and the time has arrived to develop an oversight process that has matured along with the science.”

These recommendations provide constructive guidance to the RAC, whose current structure indeed has been largely outpaced by scientific progress. Nonetheless, the recommendations raise a host of unanswered questions about the RAC’s future and about the oversight of human subjects research more generally.  Instead of categorically focusing on on rDNA research proposals, the IOM committee envisions the establishment of a process for reviewing any human subject research that is “so novel, and carries significant unknown risks, that the normal regulatory apparatus lacks the capacity to conduct an adequate review.”  This suggestion leaves opaque the key issues of how to determine each research proposal’s novelty; how to assess degrees of “unknown” risk; and how to evaluate the adequacy of the normal regulatory apparatus relative to these variables.

As the NIH considers its response to the IOM Committee’s recommendations, how these issues will play out remains to be answered. Whatever the outcome, these recommendations reveal a critical need for broader discussion about the ideal roles of existing regulatory bodies in overseeing human subjects research as genomic science marches ever forward.

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