The agenda for the U.S. FDA’s Cellular, Tissue, and Gene Therapies (CTGT) Advisory Committee meeting in February drew intense interest from numerous outside parties, some of whom spoke at the two-day, public meeting held in Gaithersburg, Md. For the first one-and-a-half days, committee members listened as experts from several universities and research foundations discussed the merits of using mitochondrial manipulation technologies in an effort to allow women with mitochondrial disease—an inherited disorder—to prevent passing on the disease to offspring. This procedure involves combining a healthy donor egg or zygote with genetic material from the mother. Some of the experts suggested the procedure could be used for general fertility treatments as well.

The Advisory Committee was tasked with exploring whether the procedure could move from animal research to human clinical trials. Ultimately, the Committee expressed concerns that while the procedure presents a potential option for reducing transmission of mitochondrial diseases, further study, including additional animal research, is warranted.

Gerald Shadel, PhD, Director, Pathology Research, Yale University, opened the education portion of the meeting by explaining the nature of mitochondrial genetics. This disease affects the mitochondria organelles within a person’s cells. Mitochondria play a vital role in energy conversion, including metabolism and respiration. Mitochondrial disease is maternally inherited, hence the research into altering the oocytes in women with mitochondrial disease.

Later that morning, Shoukhrat Mitalipov, PhD, Senior Scientist, Division of Reproductive and Developmental Sciences, Oregon Health and Science University, showcased the results of his team’s study of mitochondrial gene replacement using primate eggs. The team continues to monitor the health of the four primates born from this study.

Overseas, the United Kingdom is currently working on new regulations that would permit human clinical trials of pronuclear transfer strictly for reducing transmission of mitochondrial disease, according to Mary Herbert, PhD, Professor, Reproductive Biology, Newcastle University. This proposal would eventually reach Parliament for a vote.

“If it’s passed, detailed regulations would be agreed and adopted by the Human Fertilization and Embryological Authority that would allow them to issue a license…before they would grant a license, they would review the evidence that’s submitted to them,” she emphasized.

During the public comment portion of the meeting, presenters expressed concern about moving such trials from animals to humans, most voicing concern that while the procedure itself does not constitute genetic engineering, mitochondrial manipulation could serve as the “slippery slope” toward extensive modification of human genes in order for offspring to possess certain traits.

“If one kind of germline change is permitted, it does become more difficult to prevent modification of the nuclear genome,” said Marcy Darnovsky, PhD, Executive Director, Center for Genetics and Society.

Following the public comment period, Committee members spent considerable time discussing the concerns that a potential mitochondrial manipulation clinical trial would need to address. The Committee felt that while the research for mitochondrial manipulation was compelling, additional animal research is necessary. For a clinical trial to move forward, researchers would have to propose methods to control the manufacturing process and evaluate the final manipulated cells.

Evan Snyder, MD, PhD, Program Director and Professor Stem Cells and Regenerative Medicine Sanford/Burnham Medical Research Institute, and Chair of the Committee, stated in closing that portion of the meeting, that “there was probably not enough data in animals...to move on to human trials without answering a few additional questions.”

Early Phase Trials of Advanced Therapies Draw Debate

For the latter half of the second day, the Committee discussed the Draft Guidance for Industry: Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products. This draft guidance, issued in July 2013, is intended to assist in the development of early phase clinical trials of gene and cell therapy products that are regulated by CBER. Due to the unique characteristics of these products, early phase clinical trials for these products often differ from those for traditional pharmaceutical products.

The point of this meeting, said John Hyde, MD, Office of Cellular, Tissue and Gene Therapies, CBER, was to “at least raise the issues to the point where sponsors think to address them when they have a submission.”

The Committee drew consensus on a number of topics addressed in the guidance. First, for Phase I trials, use the set of patients that provides the greatest interpretability. While pediatric patients comprise a vulnerable population, they still should be considered for clinical trials, albeit with extra attention to dose finding studies and informed consent of the patients and their guardians. Panelists also agreed that the sections of the guidance concerning control groups are acceptable, and there is no need for specific guidelines for following up and monitoring; this needs to be done either on a case-by-case basis or determined by the type of cell or gene therapy used.

In addition, during the section of the meeting addressing additional comments, the Committee agreed that the definition of the appropriate dose for cell products is clear in the guidance document. Committee members also agreed that geriatric patients should be included in future trials. Geriatric populations share similarities with pediatric populations due to informed consent issues. There are also concerns about comorbidities within this population. Another Committee member then suggested that ways to accelerate trial design should be encouraged. This led to debate about allowing sponsors to share data so that there is less “reinventing the wheel” to avoid repeating steps known to be wrong by other sponsors. As far as how investigators can transition from Phase I to Phase II trials, a Committee member recommended putting together a paragraph or a couple of paragraphs at the end of the guidance addressing the steps that need to be taken before moving to Phase II.

All in all, the two-day meeting of the CTGT Advisory Committee included moments of scientific debate, public concern and consensus. Yet the lively discussions illustrated that the future of drug development lies in these products. Industry and regulatory agencies will need to continue working together to hammer out specific processes to develop advanced therapies in a safe and efficacious manner.

U.S. FDA Cellular, Tissue and Gene Therapies Advisory Committee

Evan Y. Snyder, MD, PhD (Chair)

Program Director and Professor Stem Cells and Regenerative Medicine

Sanford/Burnham Medical Research Institute

Gail Dapolito (Designated Federal Officer)

Center for Biologics Evaluation and Research

Food and Drug Administration

Tabassum Ahsan, PhD Assistant Professor

Department of Biomedical Engineering

Center for Stem Cell Research and Regenerative Medicine

Scott Bruder, MD, PhD (industry representative)

Chief Medical and Scientific Officer Stryker Corporation

William D. Bugbee, MD, Attending Orthopaedic Surgeon

Division of Orthopaedic Surgery, Scripps Clinic

Larry A. Couture, PhD, Senior Vice President

Center for Applied Technology Development, Beckman Research Institute of City of Hope

Timothy P. Cripe, MD, PhD, Professor

Division of Hematology/Oncology/Bone Marrow Transplantation, Nationwide Children’s Hospital

The Ohio State University Wexner College of Medicine

Linda A. Dahlgren, PhD, Associate Professor

Department of Large Animal Clinical Sciences, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University

Leisha A. Emens, MD, PhD, Associate Professor of Oncology

Johns Hopkins University School of Medicine

John D. Gearhart, PhD, James Effron University Professor

Institute for Regenerative Medicine, University of Pennsylvania School of Medicine

Steven A. Goldman, MD, PhD, Rykenboer Professor

Department of Neurology, Division of Cell and Gene Therapy, University of Rochester

Patrick Hwu, MD, Professor

Department of Melanoma Medical Oncology, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center

Stephen M. Rose, PhD (consumer representative) Chief Research Officer

Foundation Fighting Blindness]

Mei-Ling Ting Lee, PhD, Professor

Department of Epidemiology and Biostatistics Biostatistics and Risk Assessment Center, University of Maryland School of Public Health