NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (Final Guidelines)

The Policy

What it does

Modifies standards for review, registration and submission of protocols regarding human gene transfer clinical research.


Final changes to National Institutes of Health Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines) are made in the following areas, as recommended by the Institute of Medicine (announced via Federal Register notice 81 FR 15315):

  • Criteria for selecting protocols for in-depth review and public discussion by the NIH Recombinant DNA Advisory Committee (RAC),
  • Process by which human gene transfer protocols (protocols) are reviewed and registered with the NIH, and
  • Streamlining of the NIH protocol submission requirements.

RAC will no longer review all human gene transfer protocols. Instead, it will review only those that come to it through one of two systems:

Process 1

  • Requested by an oversight body (Institutional Biosafety Committee or Institutional Review Board) that determines the protocol would significantly benefit from RAC review; AND
  • Meets one or more of the following criteria:
    1. Represents a first time use in humans and because of that presents an unknown risk.
    2. Relies on preclinical safety data obtained using a model that is not yet known to be correct enough to rely upon for the purposes of clinical research safety decisions.
    3. Is associated with possible toxicities that are not widely known and that may render it difficult for oversight bodies to rigorously evaluate.

Process 2

  • Initiated by the NIH Director, which:
    • Reflect one of the three criteria above, and
    • Provide a clear and obvious benefit to the science community or the public, or the protocol otherwise raises significant scientific societal or ethical concerns.

All human gene transfer protocols will continue to be registered with the NIH. Researchers will submit documentation on protocols to an institution’s Institutional Review Board or Institutional Biosafety Committee (“local oversight bodies”) and the NIH.

Two separate registration processes exist and use is dependent on whether RAC review is deemed necessary, but in no event shall research participants be enrolled in a protocol until registration has been completed.

Only a subset of the information currently required will be necessary for protocol registration under this final action, and will pertain to:


<p>Research with recombinant DNA technologies began in the 1970s. In 1972, two teams of scientists first published papers regarding recombinant DNA technologies, which elicited myriad biosafety, biosecurity and ethical concerns and resulted in a temporary moratorium on all recombinant DNA research. The RAC, originally called the Recombinant DNA Molecule Program Advisory Committee, was created by the NIH to respond to concerns within and outside of the science community. Oversight and regulations of recombinant DNA (and later, synthetic biology) have continued through the decades and today.&nbsp; A timeline of the history and policy decisions made regarding recombinant DNA is available <a href="">here</a>.</p>

<p>When human gene transfer was a relatively new experimental approach, regulators were concerned about the potential risks and ethical implications. This regulatory action would streamline research and development of new drugs and therapies that employ established human gene transfer approaches and reserve historical regulatory oversight by the RAC for new techniques with unknown risk profiles.</p>

The Science

Science Synopsis

Recombinant DNA, or rDNA, is defined as hybrid DNA from two or more sources that can replicate in a living cell. Usually, DNA from one source (foreign DNA) is inserted into an organism, or host, which contains its own DNA (the second source.) Synthetic DNA is foreign DNA that is chemically generated in a laboratory and is not derived from a living organism, but can function alongside and replicate with naturally occurring DNA.

Foreign DNA carrying one or more genes can be delivered to human cells directly, using physical or mechanical methods, or with the use of carriers called vectors. Deactivated viruses are often used as vectors, because they can infect the cell and deliver the gene. The viruses are modified so that they can't cause disease. Some viral vectors are derived from retroviruses that can insert themselves into the host genome. Other viral vectors, like adenoviruses, can deliver the new gene to the nucleus but do not incorporate it into the host genome. Whether delivered directly or with the use of a vector, the host cell treats the new gene as its own DNA and transcribes and translates it into proteins to be used by the organism. In this way, a functioning copy of a specific gene can be delivered to cells of people that carry non-functional or dysfunctional versions of that gene.

Human gene transfer is the intentional transfer into human clinical patients or research participants of recombinant or synthetic DNA.  The full listing of currently approved Human Gene Transfer Protocols as of November 2015 may be found here

The Debate

Endorsements & Opposition

As of April 7th, 2016, no endorsements or oppositional statements have been published. A summary of public comments considered in this rule are available here