FDA comments on phase I clinical trials without vector biodistribution data

In the June issue of Nature Genetics, Haig Kazazian discussed calculations presented at a Recombinant DNA Advisory Committee (RAC) meeting held on 12 March 1999 on inadvertent germline alteration¹. He mentioned a proposed safety limit on genetic insertions, which was attributed to the Food and Drug Adminstration (FDA). We would like to clarify the FDA's policy. Rather than a specific limit, policy decisions about risks of genetic insertion are based on disease severity, age, life expectancy and reproductive status, as well as vector biology and animal safety data.

The FDA agrees with Kazazian that the natural rate of insertional mutations should be considered when developing regulations, and his presentation at the meeting was a key factor enabling a decision on policy to be reached. There are also other relevant factors to consider. Public reaction to a harmful germline mutation caused, even inadvertently, by gene therapy might differ from reaction to insertional mutations in nature. In addition, expression of therapeutic genes in inappropriate tissues or stages of development may have harmful consequences.

Germline alterations are a theoretical risk of somatic cell gene therapy that extends beyond consenting patients to unborn generations. Germline gene therapy² does not presently have societal endorsement^3,4. Previously, when cells were transduced by gene therapy vectors outside the body and used to treat serious diseases, inadvertent germline effects were not considered a significant risk. With direct administration of gene therapy vectors to patients, however, potential distribution to unintended tissues raises concern about effects on sperm or ova genomes. Concern is also heightened by extension of gene therapy to patients with milder conditions and greater reproductive potential.

The FDA determined that public discussion of inadvertent germline alteration was necessary to reach a consensus on policy. At the RAC meeting held in March, the FDA reviewed vector biodistribution data from pre-clinical studies, including unexpectedly persistent PCR signals in gonads http://www.nih.gov/od/orda/3-99sum.htm). RAC and public representatives concluded that a low risk of germline alteration was acceptable for some phase I trials. While PCR signals in gonads do not demonstrate that vector is in germ cells, further studies were recommended in such cases. Based on this public discussion, the FDA now allows certain therapies to enter initial clinical trials despite incomplete biodistribution data or detection of gonadal presence of the vector. Investigators are required, however, to address vector biodistribution and potential germline transmission during product development before licensure.