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General medicine
Early experience with the FDA’s regulatory review of novel gene therapies
  1. Jeremy Puthumana1,
  2. Alexander C Egilman2,
  3. Reshma Ramachandran3,
  4. Nida Naushad3,
  5. Nilay Shah4,
  6. Joseph Ross5
  1. 1Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
  2. 2Center for Outcomes Research and Evaluation, Yale New Haven Hospital, New Haven, Connecticut, USA
  3. 3Yale National Clinician Scholars Program, Yale School of Medicine, New Haven, Connecticut, USA
  4. 4Division of Health Care Delivery Research, Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota, USA
  5. 5Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
  1. Correspondence to Dr Jeremy Puthumana, Yale University School of Medicine, New Haven, Connecticut, USA; jeremy.puthumana{at}

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Recent advances in gene therapies offer novel therapeutic options for many diseases that are otherwise resistant to pharmacologic treatment. Through gene therapy, scientists now have the opportunity to replace disease-causing genes with healthy copies, inactivate genes functioning improperly and introduce genes into the body to help fight disease.1 As of 31 December 2020, the US Food and Drug Administration (FDA) has approved five gene therapies, and more than 900 are in clinical development.2 Based on an assessment of the current pipeline, the FDA predicts it will approve 10–20 gene therapy products per year by 2025.3 In anticipation of many more approvals in the coming years, the FDA recently released final guidance documents on the clinical development and manufacturing of gene therapy products.2 To facilitate the development of these therapies, the 21st Century Cures Act introduced a new expedited development programme, the regenerative medicine advanced therapy (RMAT) designation. This programme grants all the benefits of the breakthrough therapy designation, including rolling review and intensive FDA guidance on efficient drug development, along with an expanded range of options to fulfil postapproval commitments.4 As of 31 December 2020, the FDA has granted RMAT designation to 58 products.5

Although many laud these novel gene therapies as clinically transformative, there is growing concern about the high cost of these products, with list prices for one-time infusions ranging from $373 000 to as much as $2.1 million.6 In addition, gene therapies have been associated with serious safety risks including life-threatening immune responses and insertional mutagenesis-induced malignancies.7 As more gene therapies begin to enter the market, understanding the FDA’s past practices and standards in their review and approval of these products will help inform future regulatory decision-making, particularly upcoming approvals through the RMAT pathway, reimbursement decisions of payors, and the clinical …

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  • Contributors JP and JR drafted the manuscript. JP and ACE acquired and analysed the data. All authors participated in the conception and design of the study, interpretation of the data, critical revision of the article for important intellectual content and final approval of the version to be published.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests In the past 36 months, ACE and JR received research support through Yale University from the Laura and John Arnold Foundation for the Collaboration for Research Integrity and Transparency at Yale. ACE and JR currently receive support from the Food and Drug Administration (FDA) for the Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation (CERSI) program (U01FD005938). JR received research support through Yale University from Medtronic, Inc and the FDA to develop methods for postmarket surveillance of medical devices (U01FD004585) and from the Centers of Medicare and Medicaid Services to develop and maintain performance measures that are used for public reporting (HHSM-500-2013-13018I). JR currently receives research support through Yale University from Johnson and Johnson to develop methods of clinical trial data sharing, from the Medical Device Innovation Consortium as part of the National Evaluation System for Health Technology, from the Agency for Healthcare Research and Quality (R01HS022882), from the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH) (R01HS025164, R01HL144644), and from the Laura and John Arnold Foundation to establish the Good Pharma Scorecard at Bioethics International. In the past 36 months, NS has received research support through Mayo Clinic from the FDA to establish Yale-Mayo Clinic CERSI program (U01FD005938); the Centers of Medicare and Medicaid Innovation under the Transforming Clinical Practice Initiative; the Agency for Healthcare Research and Quality (R01HS025164; R01HS025402; R03HS025517; K12HS026379); the National Heart, Lung and Blood Institute of the NIH (R56HL130496; R01HL131535; R01HL151662); the National Science Foundation; and the Patient Centered Outcomes Research Institute to develop a Clinical Data Research Network (LHSNet). RR is an employee of the Veterans Health Administration, the views expressed in this article are that of the authors and do not necessarily reflect those of the US Department of Veteran Affairs or the US government.

  • Provenance and peer review Not commissioned; externally peer reviewed.