The first gene therapy trial was run more than thirty years ago. The earliest studies showed that gene therapy could have very serious health risks, such as toxicity, inflammation, and cancer. Since then, researchers have studied the mechanisms and developed improved techniques that are less likely to cause dangerous immune reactions or cancer. Because gene therapy techniques are relatively new, some risks may be unpredictable; however, medical researchers, institutions, and regulatory agencies are working to ensure that gene therapy research, clinical trials, and approved treatments are as safe as possible.

Comprehensive federal laws, regulations, and guidelines help protect people who participate in research studies (called clinical trials). The U.S. Food and Drug Administration (FDA) regulates all gene therapy products in the United States and oversees research in this area. Researchers who wish to test an approach in a clinical trial must first obtain permission from the FDA. The FDA has the authority to reject or suspend clinical trials that are suspected of being unsafe for participants.

The National Institutes of Health (NIH) also plays an important role in ensuring the safety of gene therapy research. NIH provides guidelines for investigators and institutions (such as universities and hospitals) to follow when conducting clinical trials with gene therapy. These guidelines state that clinical trials at institutions receiving NIH funding for this type of research must be registered with the NIH Office of Biotechnology Activities. The protocol, or plan, for each clinical trial is then reviewed by the NIH Recombinant DNA Advisory Committee (RAC) to determine whether it raises medical, ethical, or safety issues that warrant further discussion at a RAC public meeting.

An Institutional Review Board (IRB) and an Institutional Biosafety Committee (IBC) must approve each gene therapy clinical trial before it can be carried out. An IRB is a committee of scientific and medical advisors and consumers that reviews all research within an institution. An IBC is a group that reviews and approves an institution's potentially hazardous research studies. Multiple levels of evaluation and oversight ensure that safety concerns are a top priority in the planning and carrying out of gene therapy research. 

The clinical trial process occurs in three phases. Phase I studies determine if a treatment is safe for people and identify its side effects. Phase II studies determine if the treatment is effective, meaning whether it works. Phase III studies compare the new treatment to the current treatments available. Doctors want to know whether the new treatment works better or has fewer side effects than the standard treatment. The FDA reviews the results of the clinical trial. If it determines that the benefits of the new treatment outweigh the side effects, it approves the therapy, and doctors can use it to treat a disorder. 

Successful clinical trials have led to the approval of a small number of gene therapies, including therapies to treat inherited disorders like spinal muscular atrophy and Leber congenital amaurosis.