Systematic review protocol: An assessment of the post-approval challenges of autologous CAR-T therapy delivery

Introduction Following recent regulatory approvals of two chimeric antigen receptor T-cell (CAR-T) therapies, the field now faces a number of post-approval challenges. These challenges are in some respects defined and, in others, uncertain due to the nascence of the field. At present, information pertaining to such post-approval challenges are scattered in various previous reviews or raised in singular papers reporting experience in working with the therapy. This systematic review is designed to evaluate and summarise the post-approval challenges for robust delivery of CAR-T therapies to inform future work on the optimisation of CAR-T delivery to patients. Methods and analysis We will search Medline, EMBASE (OvidSP), BIOSIS & Web of Science, Cochrane Library, ICER database, NICE Evidence Search, CEA Registry, WHOLIS WHO Library and Scopus for studies published between 2014 and the present. In addition, a Google search for grey literature such as bioprocess blog posts, opinion pieces, press releases and listed companies involved in CAR-T development annual reports will be conducted. Two authors will independently screen the titles and abstracts identified from the search and accept or reject the studies according to the study inclusion criteria and any discrepancies will be discussed and resolved. The quality of the selected literature will be assessed using the Critical Appraisal Skills Programme(CASP) Systematic Review checklist and grey literature will be assessed using the Authority, Accuracy, Coverage, Objectivity, Date, Significance (AACODS) checklist. Data from eligible publications will be categorised using a flowchart and extracted using a data abstraction form. Qualitative and quantitative analysis of the post-approval challenges of CAR-T therapies will be conducted based on the results attained. Ethics and dissemination The executed study will be published in a peer-reviewed journal in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The findings from this review will be used to inform the development of an optimisation model for robust delivery of CAR-T therapies using a systems engineering approach. Trial registration number CRD42018109756

Systematic review protocol: an assessment of the post-approval challenges of autologous CAR-T therapy delivery

Following recent regulatory approvals of two chimeric antigen receptor T-cell (CAR-T) therapies, the field now faces a number of post-approval challenges. These challenges are in some respects defined and, in others, uncertain due to the nascence of the field. At present, information pertaining to such post-approval challenges are scattered in various previous reviews or raised in singular papers reporting experience in working with the therapy. This systematic review is designed to evaluate and summarise the post-approval challenges for robust delivery of CAR-T therapies to inform future work on the optimisation of CAR-T delivery to patients

Potential lifetime quality of life benefits of choroideremia gene therapy: projections from a clinically informed decision model

Background The first gene therapy for an inherited retinal dystrophy recently received market approval in the United States; multiple other gene therapies are in the clinical pipeline. Thus far, gene therapy has commanded prices in the range of USD 500,000 to over USD 1,000,000 for the one-time doses and have been indicated for highly orphan diseases where there is no other viable treatment option. To be adopted by healthcare systems, gene therapy will need to show clinical benefit in line with its increased costs. Before longitudinal patient studies are available, model-based estimations will be necessary to project the full clinical benefit of gene therapy. Methods To investigate the lifetime benefit of gene therapy for the retinal dystrophy choroideremia, we have built a Markov model of disease progression informed by clinical data of AAV.REP1 and voretigene neparvovec (Luxturna, Spark Therapeutics). Gene therapy patient benefit was estimated by quality-adjusted life years (QALYs) in three hypothetical disease severity patient groups. The severity of disease was defined by the combined effect of remaining retinal area and visual acuity and assigned corresponding health utility values. Results Early-stage patients treated with gene therapy were estimated to gain, in average, 14.30 QALYs over standard-of-care, mid-stage patients 6.22 QALYs, and late-stage patients 1.48 QALYs over untreated patients during their lifetime owing to treatment. Cost-effectiveness was not assessed as AAV.REP1 is still in clinical trials. Conclusions In young adults in the earlier stages of choroideremia, successful gene therapy is expected to provide a significant increase in health-related quality of life.</p

Potential lifetime quality of life benefits of choroideremia gene therapy: projections from a clinically informed decision model

Background The first gene therapy for an inherited retinal dystrophy recently received market approval in the United States; multiple other gene therapies are in the clinical pipeline. Thus far, gene therapy has commanded prices in the range of USD 500,000 to over USD 1,000,000 for the one-time doses and have been indicated for highly orphan diseases where there is no other viable treatment option. To be adopted by healthcare systems, gene therapy will need to show clinical benefit in line with its increased costs. Before longitudinal patient studies are available, model-based estimations will be necessary to project the full clinical benefit of gene therapy. Methods To investigate the lifetime benefit of gene therapy for the retinal dystrophy choroideremia, we have built a Markov model of disease progression informed by clinical data of AAV.REP1 and voretigene neparvovec (Luxturna, Spark Therapeutics). Gene therapy patient benefit was estimated by quality-adjusted life years (QALYs) in three hypothetical disease severity patient groups. The severity of disease was defined by the combined effect of remaining retinal area and visual acuity and assigned corresponding health utility values. Results Early-stage patients treated with gene therapy were estimated to gain, in average, 14.30 QALYs over standard-of-care, mid-stage patients 6.22 QALYs, and late-stage patients 1.48 QALYs over untreated patients during their lifetime owing to treatment. Cost-effectiveness was not assessed as AAV.REP1 is still in clinical trials. Conclusions In young adults in the earlier stages of choroideremia, successful gene therapy is expected to provide a significant increase in health-related quality of life.</p

Regulatory considerations for gene therapy products in the US, EU, and Japan

Developers of gene therapy products (GTPs) must adhere to additional regulation beyond that of traditional small-molecule therapeutics, due to the unique mechanism-of-action of GTPs and the subsequent novel risks arisen. We have provided herein a summary of the regulatory structure under which GTPs fall in the United States, the European Union, and Japan, and a comprehensive overview of the regulatory guidance applicable to the developer of GTP. Understanding the regulatory requirements for seeking GTP market approval in these major jurisdictions is crucial for an effective and expedient path to market. The novel challenges facing GTP developers is highlighted by a case study of alipogene tiparvovec (Glybera)

Adipose-derived stem cells in aesthetic surgery: a mixed methods evaluation of the current clinical trial, intellectual property, and regulatory landscape

Background: Adipose tissue, which can be readily harvested via a number of liposuction techniques, offers an easily accessible and abundant source of adipose-derived stem cells (ASCs). Consequently, ASCs have become an increasingly popular reconstructive option and a novel means of aesthetic soft tissue augmentation. Objectives: This paper examines recent advances in the aesthetic surgery field, extending beyond traditional review formats to incorporate a comprehensive analysis of current clinical trials, adoption status, and the commercialization pathway. Methods: Keyword searches were carried out on clinical trial databases to search for trials using ASCs for aesthetic indications. An intellectual property landscape was created using commercial software (Thomson Reuters Thomson Innovation, New York, NY). Analysis of who is claiming what in respect of ASC use in aesthetic surgery for commercial purposes was analyzed by reviewing the patent landscape in relation to these techniques. Key international regulatory guidelines were also summarized. Results: Completed clinical trials lacked robust controls, employed small sample sizes, and lacked long-term follow-up data. Ongoing clinical trials still do not address such issues. In recent years, claims to intellectual property ownership have increased in the “aesthetic stem cell” domain, reflecting commercial interest in the area. However, significant translational barriers remain including regulatory challenges and ethical considerations. Conclusions: Further rigorous randomized controlled trials are required to delineate long-term clinical efficacy and safety. Providers should consider the introduction of patient reported outcome metrics to facilitate clinical adoption. Robust regulatory and ethical policies concerning stem cells and aesthetic surgery should be devised to discourage further growth of “stem cell tourism.

Regulatory considerations for gene therapy products in the US, EU, and Japan

Developers of gene therapy products (GTPs) must adhere to additional regulation beyond that of traditional small-molecule therapeutics, due to the unique mechanism-of-action of GTPs and the subsequent novel risks arisen. We have provided herein a summary of the regulatory structure under which GTPs fall in the United States, the European Union, and Japan, and a comprehensive overview of the regulatory guidance applicable to the developer of GTP. Understanding the regulatory requirements for seeking GTP market approval in these major jurisdictions is crucial for an effective and expedient path to market. The novel challenges facing GTP developers is highlighted by a case study of alipogene tiparvovec (Glybera)

Adipose-derived stem cells in aesthetic surgery: a mixed methods evaluation of the current clinical trial, intellectual property, and regulatory landscape

Background: Adipose tissue, which can be readily harvested via a number of liposuction techniques, offers an easily accessible and abundant source of adipose-derived stem cells (ASCs). Consequently, ASCs have become an increasingly popular reconstructive option and a novel means of aesthetic soft tissue augmentation. Objectives: This paper examines recent advances in the aesthetic surgery field, extending beyond traditional review formats to incorporate a comprehensive analysis of current clinical trials, adoption status, and the commercialization pathway. Methods: Keyword searches were carried out on clinical trial databases to search for trials using ASCs for aesthetic indications. An intellectual property landscape was created using commercial software (Thomson Reuters Thomson Innovation, New York, NY). Analysis of who is claiming what in respect of ASC use in aesthetic surgery for commercial purposes was analyzed by reviewing the patent landscape in relation to these techniques. Key international regulatory guidelines were also summarized. Results: Completed clinical trials lacked robust controls, employed small sample sizes, and lacked long-term follow-up data. Ongoing clinical trials still do not address such issues. In recent years, claims to intellectual property ownership have increased in the “aesthetic stem cell” domain, reflecting commercial interest in the area. However, significant translational barriers remain including regulatory challenges and ethical considerations. Conclusions: Further rigorous randomized controlled trials are required to delineate long-term clinical efficacy and safety. Providers should consider the introduction of patient reported outcome metrics to facilitate clinical adoption. Robust regulatory and ethical policies concerning stem cells and aesthetic surgery should be devised to discourage further growth of “stem cell tourism.

Digital technology in somatic and gene therapy trials of paediatric patients with ocular diseases: a systematic scoping review protocol

Background Pharmacogenomics suggests that diseases with similar symptomatic presentations often have varying genetic causes, affecting an individual patient’s response to a specific therapeutic strategy. Gene therapies and somatic cell therapies offer unique therapeutic pathways for ocular diseases and often depend on increased understanding of the genotype-phenotype relationship in disease presentation and progression. While demand for personalised medicine is increasing and the required molecular tools are available, its adoption within paediatric ophthalmology remains to be maximised in the post-genomic era. To address the individual hurdles encountered in the field of genomic-related clinical trials and facilitate the uptake of personalised medicine, we propose to conduct a review that will examine and identify the digital technologies used to facilitate data analysis in somatic and gene therapy trials in paediatric patients with ocular diseases. Objectives To present an outline of HIT/ICT resources used in somatic and gene therapy clinical trials in children with ocular diseases. This review will enable authors to identify challenges and provide recommendations facilitating the uptake of genetic and somatic therapies as therapeutic tools in paediatric ophthalmology. The review will also determine whether conducting a systematic review will be beneficial. Results Database searches will be initiated in September 2018. We expect to complete the review in December 2018. Conclusions Based on review findings, the authors will summarise methods used for facilitating IT integration in personalised medicine. Additionally, it will identify further research gaps and determine whether conduction of further reviews will be beneficial

Adipose-Derived Stem Cells in Aesthetic Surgery: A Mixed Methods Evaluation of the Current Clinical Trial, Intellectual Property, and Regulatory Landscape

Background: Adipose tissue, which can be readily harvested via a number of liposuction techniques, offers an easily accessible and abundant source of adipose-derived stem cells (ASCs). Consequently, ASCs have become an increasingly popular reconstructive option and a novel means of aesthetic soft tissue augmentation. Objectives: This paper examines recent advances in the aesthetic surgery field, extending beyond traditional review formats to incorporate a comprehensive analysis of current clinical trials, adoption status, and the commercialization pathway. Methods: Keyword searches were carried out on clinical trial databases to search for trials using ASCs for aesthetic indications. An intellectual property landscape was created using commercial software (Thomson Reuters Thomson Innovation, New York, NY). Analysis of who is claiming what in respect of ASC use in aesthetic surgery for commercial purposes was analyzed by reviewing the patent landscape in relation to these techniques. Key international regulatory guidelines were also summarized. Results: Completed clinical trials lacked robust controls, employed small sample sizes, and lacked long-term follow-up data. Ongoing clinical trials still do not address such issues. In recent years, claims to intellectual property ownership have increased in the "aesthetic stem cell" domain, reflecting commercial interest in the area. However, significant translational barriers remain including regulatory challenges and ethical considerations. Conclusions: Further rigorous randomized controlled trials are required to delineate long-term clinical efficacy and safety. Providers should consider the introduction of patient reported outcome metrics to facilitate clinical adoption. Robust regulatory and ethical policies concerning stem cells and aesthetic surgery should be devised to discourage further growth of "stem cell tourism.