Guest Column | August 15, 2018

Surveying The U.S. Regulatory Landscape For Cell And Gene Therapies

By Kate Cook, Greenleaf Health


FDA has defined human gene therapy products as all products that mediate their effects by transcription or translation of transferred genetic material or by specifically altering host (human) genetic sequences. The first clinical trial of a gene therapy to treat severe combined immunodeficiency disease began in 1990. The journey to commercial marketing of gene therapy products has been a long one, finally leading to FDA approval in the past year of three biological products using gene therapy technologies:

  • Kymriah (tisagenlecleucel): Novartis Pharmaceuticals Corporation; a cancer immunotherapy that directs genetically modified autologous T-cells to target leukemia cells that have a specific antigen (CD19) on the surface (Aug. 30, 2017)
  • Yescarta (axicabtagene ciloleucel): Kite Pharma, Inc.; a cancer immunotherapy that directs genetically modified autologous T-cells to target large B-cell lymphoma cells (Oct. 18, 2017)
  • Luxturna (voretigene neparvovec): Spark Therapeutics, Inc.,;the first gene therapy for a rare genetic disease, biallelic RPE65 mutation-associated retinal dystrophy; Luxturna uses a naturally occurring adeno-associated virus, which has been modified using recombinant DNA techniques, as a vehicle to deliver the normal human RPE65 gene to the retinal cells to restore vision (Dec. 19, 2017)

There may be many more approvals on the horizon. In a Dec. 19, 2017 media call addressing the Luxturna approval, FDA Commissioner Scott Gottlieb stated:

To give you just one example related to the agency's current approval action, there are more than 600 active investigational new drug applications related to gene therapy products.

And researchers at the Massachusetts Institute of Technology estimate that about 40 gene therapies might win approval by 2022 from a current pipeline of 932 development candidates. They estimate that about 45 percent of these relate to treatments for cancer. I can't confirm their estimate, but I can affirm that we're at the early stages of a transformation in medical care as a consequence of these and other transformative platforms.

On July 11, 2018, the FDA issued six draft guidances addressing gene therapy product development issues (click on each title for a summary of the corresponding draft guidance):

These six draft guidance documents are only the latest policy communications in this area. The FDA has been issuing guidance documents addressing gene therapy development issues for approximately 20 years — a remarkable dedication of agency resources to a product area that did not have a licensed product until 2017. The six documents join other existing documents, with the oldest issued in 1998:

  • Guidance: Recommendations for Microbial Vectors Used for Gene Therapy (September 2016)
  • Draft Guidance: Assay Development for Immunogenicity Testing of Therapeutic Proteins (April 2016)
  • Guidance: Design and Analysis of Shedding Studies for Virus or Bacteria-Based Gene Therapy and Oncolytic Products (August 2015)
  • Guidance: Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products (June 2015)
  • Guidance: Determining the Need for and Content of Environmental Assessments for Gene Therapies, Vectored Vaccines, and Related Recombinant Viral or Microbial Products (March 2015)
  • Guidance: Preclinical Assessment of Investigational Cellular and Gene Therapy Products (November 2013)
  • Guidance: Potency Tests for Cellular and Gene Therapy Products (June 2011)
  • Guidance: Guidance for Human Somatic Cell Therapy and Gene Therapy (March 1998)

Suite Of Disease-Specific Guidances To Come

Two of the recently issued draft guidance documents represent the first of the “suite of disease-specific guidance documents on the development of specific gene therapy products” that Dr. Gottlieb promised in his Dec. 19 media call.  They may be all that we see in 2018, though, since the FDA does not list additional gene therapy guidances on the CBER Guidance Agenda for calendar year 2018.  

The retinal disorders and hemophilia guidances likely came first because the FDA has the most experience with those programs. Recognizing that sponsors often treat even draft guidances as binding rules -- even though the top of each page bears the legend “Contains Nonbinding Recommendations” — the FDA tries to assure that FDA guidance documents are based on carefully developed knowledge of the issues. We may have to wait for the FDA’s knowledge development before we see additional disease specific guidance documents.

The Knowledge Base Supporting FDA Guidances

The FDA should know what it is talking about when it issues a guidance document. Regulators gain knowledge as they review regulatory submissions and discuss issues with the product sponsors. An FDA official currently sits as a nonvoting member of the Recombinant DNA Advisory Committee, the advisory committee convened by the NIH Office of Science Policy that provides recommendations to the NIH director related to basic and clinical research involving recombinant or synthetic nucleic acid molecules. FDA officials may participate in university programs as visiting scientists, such as at the UCSF-Stanford Center for Excellence in Regulatory Science and Innovation.  The FDA will occasionally seek input in public meetings or workshops on questions of interest or concern, such as the conduct of first-in-human clinical trials in young pediatric patients. The FDA sought advice from the Cellular, Tissue and Gene Therapies Advisory Committee before approving Kymriah and Luxturna.

The FDA’s laboratory research in regulatory science supports FDA guidance documents. FDA scientists in the Center for Biologics Evaluation and Research (CBER) are conducting research into gene therapy regulatory science issues.  In a Sept. 7, 2016 presentation to the Cellular, Tissue and Gene Therapies Advisory Committee, Raj Puri, the director of the Division of Cellular and Gene Therapies in CBER’s Office of Tissues and Advanced Therapies, described his office’s research programs. These include research programs related directly to gene therapy regulatory questions, addressing issues such as viral vectors, immune response and modulation, genomics, transgenics, and gene editing.  In his slides presented to the committee, Dr. Puri noted that by supporting this research, CBER “fosters a cadre of Research Reviewer scientists.” These research reviewers “perform regulatory review and participate in the development of policy and guidance documents to promote product development and patient safety” and “help sponsors solve product development problems to advance products to the marketplace.” 

International Harmonization

International harmonization is an important goal for the FDA’s gene therapy regulatory program. The FDA works with the International Council on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), the International Pharmaceutical Regulators Forum (IPRF), and the International Medical Device Regulators Forum. The agency participates through confidential exchanges with counterpart regulatory agencies during guidance and policy development, such as dedicated cluster discussions with the European Medicines Agency. The IPRF’s Cell Therapy Working Group and Gene Therapy Working Group bring together international regulators to discuss emerging regulatory issues.

Guidances Must Reflect Current Science

Sponsors, patients, and other members of the public have an opportunity to comment on draft guidances. The FDA has requested comments on the six new draft documents by Oct. 10, 2018. Comments provided by that date will be taken into consideration when the final guidance is issued. 

Scientific knowledge accrues and changes. Guidance documents based on outdated policy and outdated scientific knowledge can misdirect sponsors and lead to inefficiencies in product development — and delays in patient access to potential cures. This means that FDA guidances should be up to date when issued and kept up to date throughout their life on the FDA website. Notably, three of the draft guidances issued on July 11 (those addressing CMC issues, replication competent retroviruses, and long-term follow-up) were updates of previously issued documents, which indicates that the FDA is aware of its responsibility.    

About The Author:

Kate Cook is executive VP of drug and biological products at Greenleaf Health, Inc.  She joined Greenleaf after a long career at the FDA, including 15 years in the Office of Chief Counsel, five years in the Office of the Center Director at the FDA’s Center for Biologics Evaluation and Research, and one and a half as associate director for regulations and policy at the FDA’s Center for Devices and Radiological Health. You can contact her at