To the Editor:

Patient and physician use of emergency approval from US Food and Drug Administration (FDA) for novel therapeutics, particularly in the area of gene-based products is thought of as a daunting—even impossible—task. However, with an appropriate clinical situation and product, we experienced the process to be highly efficient if the proper procedures and documents were provided. Herein we describe our experience and process for obtaining emergency use approval of an experimental gene-based xenograft vaccine.

Our process was initiated on behalf of a 56-year-old woman with retroperitoneal leiomyosarcoma who was at a life-threatening stage of her disease. She had been successfully palliated for several years after a series of surgical resections, chemotherapy, and experimental drug treatment. However, she recently demonstrated progression of her disease, and rapid action was thought to be necessary. Access to an experimental agent, transforming growth factor-β2 antisense granulocyte-macrophage colony-stimulating factor gene-modified autologous xenograft tumor cell TAG vaccine, was potentially able to be constructed via manufacturer, Gradalis Inc (Dallas, TX). We illustrate the processes utilized to permit emergency use treatment of this gene-based product.

A subject may qualify for a special exception to be filed with FDA under an Emergency Use Investigational New Drug (IND) application if either s/he does not meet the protocol eligibility criteria for an ongoing clinical trial or if no other standard or research therapies are available and the situation does not allow time for routine IND submission. Unlike a compassionate or single use IND, an emergency use IND is an expedited process that allows for product shipment to be approved before a full IND filing. Communication with FDA would be conducted by telephone or other rapid means. The FDA is highly responsive to requests; conversations with the FDA clinical reviewer provide guidance in properly preparing an acceptable submission.

A full IND filing is necessary after receiving verbal approval for an emergency use IND, including a product supply letter of authorization stating the rationale for requesting the exception and the intent to supply the agent/drug. This is followed by the submission of necessary documents: submission of the emergency use IND; brief clinical history; proposed treatment plan; drug supply reference statement; informed consent statement; investigator qualification statement; FSA form 1571; contact telephone number and facsimile number.

The investigator must ensure that institutional review board review is conducted and approved before commencing treatment. Studies utilizing gene-based products have two additional review boards overseeing the conduct of a trial: the recombinant advisory committee and the Institutional Biosafety Committee (IBC). In addition to the protocol, the Recombinant DNA Advisory Committee requires that appendix M must be completed along with a scientific abstract and a nontechnical abstract. Appendix M is comprised of a series of questions that must be answered regarding the design and submission of the protocol. Appendix M outlines the items necessary for recombinant advisory committee review (appendix M I-A), including the potential safety risks imposed on individuals handling the product and product management. The IBC is a local body responsible for reviewing and approving recombinant DNA research and potentially biohazardous projects. The IBC sets containment levels in accordance with the National Institutes of Health guidelines and those of the Centers for Disease Control and Prevention.

On the day of vaccine delivery, the subject unfortunately, declined in clinical status, and it was determined that the vaccine delivery would have no chance of benefit so it was not administered.

In conclusion, the emergency use IND process is readily accessible even when considering experimental gene transfer products. Although the clinical course of their diseases may not allow all the index patients to benefit from this process, those that do justify the effort.

The actual time sequence for our emergency use IND approval process is shown in Table 1.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: John Nemunaitis, Gradalis Inc (U) Consultant or Advisory Role: None Stock Ownership: Phillip B. Maples, Gradalis Inc; John Nemunaitis, Gradalis Inc Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None