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T 12: Special Safety Considerations for Gene Therapy Products in Global Clinical Development

Poster Presenter

      Radius Davenport

      • Vice President Regulatory Affairs
      • Radius Health
        United States


Transfer of recombinant DNA to patients poses specific safety challenges that must be appropriately monitored and mitigated by health authorities, ethics committees, other regulatory bodies and the sponsor. The various types of regulatory bodies, and monitoring and mitigation plans are discussed.


ORAL PRESENTATION SCHEDULED: Session 1B at 12:00 - 12:10 PM

A review of regulatory guidance and legislation from regulatory bodies in North America, Europe and World Health Organization were reviewed. Guidance and legislation were included from FDA, EMA and ICH.


At that National level the Committee for Advanced Therapies (CAT) is a scientific body that reviews Advanced Therapy Medicinal Products (ATMPs) in Europe. The approval of Clinical Trial Applications (CTA) for ATMPs is under the remit of European National Competent Authorities (NCA). If the gene therapy is particularly complex, the product may also be reviewed by the CAT. In the US the Recombinant DNA Advisory Committee (RAC) within the National Institutes of Health reviews gene therapy studies in addition to the FDA reviewing the protocol under the Investigational New Drug Application (IND). At the clinical site level many countries have committees that must approve the study separately from the ethics committee (e.g., Institutional Biosafety Committee in the US; environmental approvals in Netherlands and UK). To assist with the IBC and environmental approvals an Environmental Risk Assessment (ERA) document prepared by the Sponsor may be provided to the site. The risk group (RG) classification and appropriate Biosafety Level (BSL) or Containment Level (CL) in which the product should be used should be defined in the ERA document. Gene therapy trials pose specific considerations for the subject with regard to standard clinical trial procedures or documents. For example, the Informed Consent form should inform patients that they may be followed-up long after the study and that an autopsy will be requested at the time of their death. Gene therapy products pose a theoretical risk for cancer and reproduction. A well-developed safety management plan and independent data monitoring committee should be utilized. Clear pregnancy prevention and reporting and long-term follow-up (LTFU) plans should be detailed in the protocol. The type of LTFU program will depend on the type of vector used, propensity to integrate into the host genome and other factors affecting the risk for developing delayed adverse events.


Gene therapy, an advanced therapy medicinal products (ATMP), is part of one of the fastest growing sectors in the pharmaceutical industry offering great hope to patients. However, transfer of recombinant nucleic acid sequences to patients poses specific safety challenges that must be appropriately monitored and mitigated. Global clinical development of gene therapy products poses particular safety challenges that that must be monitored and mitigated by various stakeholders: 1) National level by Regulatory bodies and Central Ethics Committees; and (2) Site level by Institutional Review Boards, Institutional Biosafety Committees, Local Ethics Committees and other country specific environmental review committees. In the EU the CAT may or may not be involved in the assessment of the clinical study by the National Competent Authority or Central Ethics Committee (CEC). If a gene therapy product is particularly complex, the NCA or the CEC may request a review by the CAT, which may extend the review timelines. In contrast, the RAC is not an advisory board for the FDA but provides a separate, independent and more public review of the gene therapy protocol. A well-developed Environmental Risk Assessment document prepared by the Sponsor that is provided to clinical sites can help facilitate completion of documentation for the site specific environmental approvals (e.g. IBC). Other Sponsor documentation that are critical to ensuring unique aspects of safety related to gene therapy clinical trials include the Informed Consent form, Safety Management Plan, Risk Management Plan, Pregnancy Prevention and Reporting Plan and Long-Term Follow-Up Plan. The type of safety monitoring during and after the clinical study is dependent on preclinical and clinical observations as well as theoretical risks such as reproductive and mutagenesis. Gene therapy has the potential to fill an unmet medical need in many therapeutic areas and with careful planning and execution can be safely developed.

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