A decade of marketing approval of gene and cell-based therapies in the United States, European Union and Japan: An evaluation of regulatory decision-making.

There is a widely held expectation of clinical advance with the development of gene and cell-based therapies (GCTs). Yet, establishing benefits and risks is highly uncertain. We examine differences in decision-making for GCT approval between jurisdictions by comparing regulatory assessment procedures in the United States (US), European Union (EU) and Japan. A cohort of 18 assessment procedures was analyzed by comparing product characteristics, evidentiary and non-evidentiary factors considered for approval and post-marketing risk management. Product characteristics are very heterogeneous and only three products are marketed in multiple jurisdictions. Almost half of all approved GCTs received an orphan designation. Overall, confirmatory evidence or indications of clinical benefit were evident in US and EU applications, whereas in Japan approval was solely granted based on non-confirmatory evidence. Due to scientific uncertainties and safety risks, substantial post-marketing risk management activities were requested in the EU and Japan. EU and Japanese authorities often took unmet medical needs into consideration in decision-making for approval. These observations underline the effects of implemented legislation in these two jurisdictions that facilitate an adaptive approach to licensing. In the US, the recent assessments of two chimeric antigen receptor-T cell (CAR-T) products are suggestive of a trend toward a more permissive approach for GCT approval under recent reforms, in contrast to a more binary decision-making approach for previous approvals. It indicates that all three regulatory agencies are currently willing to take risks by approving GCTs with scientific uncertainties and safety risks, urging them to pay accurate attention to post-marketing risk management.

Interview: commercial translation of cell-based therapies and regenerative medicine: learning by experience. Interview by Emily Culme-Seymour.

Dr Haseltine speaks to Emily Culme-Seymour, Assistant Commissioning Editor William A Haseltine, PhD has an active career in both Science and Business. He was a professor at Harvard Medical School and Harvard School of Public Health (MA, USA) from 1976 to 1993, where he was Founder and Chair of two academic research departments. He is well known for his pioneering work on cancer, HIV/AIDS and genomics. He has authored more than 200 manuscripts in peer-reviewed journals and is the author of several books. He is the founder of Human Genome Sciences, Inc. and served as the Chairman and CEO of the company until 2004. He is also the founder of several other successful biotechnology companies. William Haseltine is currently Chairman and President of ACCESS Health International, Inc., which supports access to affordable, high-quality health services in low, middle and high income countries, and Chairman of the Haseltine Foundation for Science and the Arts, which fosters a dialog between sciences and the arts. He is an Adjunct Professor at the Scripps Institute for Medical Research and the Institute of Chemical Engineering, the University of Mumbai, India. He is a member of the Advisory Board of the IE University, Madrid, the President's Council of the Cold Spring Harbor Laboratory, the Advisory Council for the Koch Institute of MIT, a member of the University Council Committee on technology transfer, Yale University, and is a Lifetime Governor of the New York Academy of Science (NY, USA). He is an honorary member of the Board of Trustees of the Brookings Institution, a member of the Board of Trustees of the Center for Emerging Markets of the Indian School of Business, a member of the Council on Foreign Relations, a member of the Board of AID for AIDS International, and a member of the Chairman's Circle of the Asia Society. He is a member of the Advisory Board of the Metropolitan Opera (NY, USA), the Chairman's Council of the Metropolitan Museum (NY, USA), the International Council of the Guggenheim Museum, the International Council of the Tate Modern, the Board of Directors of the Young Concert Artists, Inc. and the Youth Orchestra of the Americas.

Allogeneic haematopoietic stem cell transplantation: individualized stem cell and immune therapy of cancer.

The year 2009 marked the fiftieth anniversary of the first successful allogeneic haematopoietic stem cell transplant (HSCT). The field of HSCT has pioneered some of the most exciting areas of research today. HSCT was the original stem cell therapy, the first cancer immune therapy and the earliest example of individualized cancer therapy. In this Timeline article we review the history of the development of HSCT and major advances made in the past 50 years. We highlight accomplishments made by researchers who continue to strive to improve outcomes for patients and increase the availability of this potentially life-saving therapy for patients with otherwise incurable malignancies.

Looking into the future of cell-based therapy.

Recent research points to the future of regenerative medicine. In the past year, a handful of research groups have demonstrated that mature, adult cells could be "reprogrammed" to a very primitive, embryonic state via the forced expression of four genes (Oct-3/4, c-Myc, Klf4, and Sox2). These induced pluripotent cells (or iPS) share features with embryonic stem (ES) cells and generate tissues from all three embryonic germ layers (ectoderm, mesoderm, and endoderm). iPS cells are also capable of the ultimate demonstration of developmental potency, ie, when injected into an early mouse embryo, they contribute to the formation of an entire mouse including its germline. While the reprogramming of human fibroblasts into iPS cells remains to be seen, it is nevertheless difficult to overstate the value that this new research contributes to the field of regenerative medicine and its academic relative developmental biology. Herein, we attempt to bring these monumental works into greater focus and comment on how they work to shape the future of cellular therapies.

Remyelination of the central nervous system: a valuable contribution from the periphery.

The loss of myelin, a major element involved in the saltatory conduction of the electrical impulse of the nervous system, is a major target of current research. Serious long-term disabilities are observed in patients with demyelinating disease of the central nervous system, such as multiple sclerosis. New therapeutic strategies aimed at overcoming myelin damage and axonal loss focus on the repair potential of myelin-forming cells. This review examines the use of peripheral myelin-forming cells, the Schwann cells, to promote myelin repair.

Cell therapy--back on the up-curve. Interview with Paul Kemp by Elisa Manzotti.

Intercytex is an emerging healthcare company developing cell therapy products for the wound care and aesthetic medicine markets. The company, based in Cambridge, UK, commenced operations in 2000 and has raised over 31 million pounds in four private equity funding rounds. It is using its proprietary expertise in cell therapy to develop products that harness the innate ability of human cells to regenerate and repair the body. Here, founder and Chief Scientific Officer of Intercytex, Dr Paul Kemp, reflects on current status and future prospects for cell therapy with Regenerative Medicine's Elisa Manzotti. Dr Kemp was formerly Vice President of Research at Organogenesis, Inc. and has more than 17 years' experience in the commercial development of cell therapy. In this interview, Dr Kemp draws attention to a cycle that so often characterizes novel medical research: initial hype, a subsequent trough of disappointment and final emergence of viable technology. He explains how cell therapy is now emerging from the trough to become a rational, real and successful component of modern medicine.

Apheresis in donor and therapeutic settings: recruitments vs. possibilities--a multicenter study.

In our country, the first apheresis was performed in the late 1960s (by manual technique), and the first cell separator was used in 1979. The number of blood component collections performed from 1994 to 2004 was: 11,170 (total), i.e., 8540 (NBTI), 1180 (IT-MMA), 1050 (BTI of Novi Sad) and 400 (BTI Nis). The number of PBSC harvests during 1996-2004 was 386 for treatment of 272 patients. For treatment of myocardial infarction, "cell-therapy" by autologous stem cells was introduced in 2004 at the MMA. The results of PE treatments performed (7632 sessions) by our group for various immune-mediated and other disorders were generally beneficial, but the effect is not associated with bone marrow remission. TC procedures (total number=1279) resulted in a significant fall in the blood cell counts and hemorheological improvement, as well as the removal and replacement of abnormal red blood cells. Greater standardization of different apheresis protocols is required.