Bioprocess decision support tool for scalable manufacture of extracellular vesicles.

Newly recognized as natural nanocarriers that deliver biological information between cells, extracellular vesicles (EVs), including exosomes and microvesicles, provide unprecedented therapeutic opportunities. Large-scale and cost-effective manufacturing is imperative for EV products to meet commercial and clinical demands; successful translation requires careful decisions that minimize financial and technological risks. Here, we develop a decision support tool (DST) that computes the most cost-effective technologies for manufacturing EVs at different scales, by examining the costs of goods associated with using published protocols. The DST identifies costs of labor and consumables during EV harvest as key cost drivers, substantiating a need for larger-scale, higher-throughput, and automated technologies for harvesting EVs. Importantly, we highlight a lack of appropriate technologies for meeting clinical demands, and propose a potentially cost-effective solution. This DST can facilitate decision-making very early on in development and be used to predict, and better manage, the risk of process changes when commercializing EV products.

Bioprocessing automation in cell therapy manufacturing: Outcomes of special interest group automation workshop.

Phacilitate held a Special Interest Group workshop event in Edinburgh, UK, in May 2017. The event brought together leading stakeholders in the cell therapy bioprocessing field to identify present and future challenges and propose potential solutions to automation in cell therapy bioprocessing. Here, we review and summarize discussions from the event. Deep biological understanding of a product, its mechanism of action and indication pathogenesis underpin many factors relating to bioprocessing and automation. To fully exploit the opportunities of bioprocess automation, therapeutics developers must closely consider whether an automation strategy is applicable, how to design an 'automatable' bioprocess and how to implement process modifications with minimal disruption. Major decisions around bioprocess automation strategy should involve all relevant stakeholders; communication between technical and business strategy decision-makers is of particular importance. Developers should leverage automation to implement in-process testing, in turn applicable to process optimization, quality assurance (QA)/ quality control (QC), batch failure control, adaptive manufacturing and regulatory demands, but a lack of precedent and technical opportunities can complicate such efforts. Sparse standardization across product characterization, hardware components and software platforms is perceived to complicate efforts to implement automation. The use of advanced algorithmic approaches such as machine learning may have application to bioprocess and supply chain optimization. Automation can substantially de-risk the wider supply chain, including tracking and traceability, cryopreservation and thawing and logistics. The regulatory implications of automation are currently unclear because few hardware options exist and novel solutions require case-by-case validation, but automation can present attractive regulatory incentives.

A quantitative, multi-national and multi-stakeholder assessment of barriers to the adoption of cell therapies.

Cellular therapies, such as stem cell-based treatments, have been widely researched and numerous products and treatments have been developed. Despite this, there has been relatively limited use of these technologies in the healthcare sector. This study sought to investigate the perceived barriers to this more widespread adoption. An anonymous online questionnaire was developed, based on the findings of a pilot study. This was distributed to an audience of clinicians, researchers and commercial experts in 13 countries. The results were analysed for all respondents, and also sub-grouped by geographical region, and by profession of respondents. The results of the study showed that the most significant barrier was manufacturing, with other factors such as efficacy, regulation and cost-effectiveness being identified by the different groups. This study further demonstrates the need for these important issues to be addressed during the development of cellular therapies to enable more widespread adoption of these treatments.

An assessment of the factors affecting the commercialization of cell-based therapeutics: a systematic review protocol.

BACKGROUND: Cellular-based therapies represent a platform technology within the rapidly expanding field of regenerative medicine and are distinct from conventional therapeutics-offering a unique approach to managing what were once considered untreatable diseases. Despite a significant increase in basic science activity within the cell therapy arena, alongside a growing portfolio of cell therapy trials and promising investment, the translation of cellular-based therapeutics from "bench to bedside" remains challenging, and the number of industry products available for widespread clinical use remains comparatively low. This systematic review identifies unique intrinsic and extrinsic barriers in the cell-based therapy domain. METHODS/DESIGN: Eight electronic databases will be searched, specifically Medline, EMBASE (OvidSP), BIOSIS & Web of Science, Cochrane Library & HEED, EconLit (ProQuest), WHOLIS WHO Library Database, PAIS International (ProQuest), and Scopus. Addition to this gray literature was searched by manually reviewing relevant work. All identified articles will be subjected for review by two authors who will decide whether or not each article passes our inclusion/exclusion criteria. Eligible papers will subsequently be reviewed, and key data extracted into a pre-designed data extraction scorecard. An assessment of the perceived impact of broad commercial barriers to the adoption of cell-based therapies will be conducted. These broad categories will include manufacturing, regulation and intellectual property, reimbursement, clinical trials, clinical adoption, ethics, and business models. This will inform further discussion in the review. There is no PROSPERO registration number. DISCUSSION: Through a systematic search and appraisal of available literature, this review will identify key challenges in the commercialization pathway of cellular-based therapeutics and highlights significant barriers impeding successful clinical adoption. This will aid in creating an adaptable, acceptable, and harmonized approach supported by apposite regulatory frameworks and pertinent expertise throughout the respective stages of the adoption cycle to facilitate the adoption of new products and technologies in the industry.

Corrigendum: A Quantitative Assessment of Factors Affecting the Technological Development and Adoption of Companion Diagnostics.

[This corrects the article on p. 357 in vol. 6, PMID: 26858745.].

Open Access Could Transform Drug Discovery: A Case Study of JQ1.

INTRODUCTION: The cost to develop a new drug from target discovery to market is a staggering $1.8 billion, largely due to the very high attrition rate of drug candidates and the lengthy transition times during development. Open access is an emerging model of open innovation that places no restriction on the use of information and has the potential to accelerate the development of new drugs. AREAS COVERED: To date, no quantitative assessment has yet taken place to determine the effects and viability of open access on the process of drug translation. This need is addressed within this study. The literature and intellectual property landscapes of the drug candidate JQ1, which was made available on an open access basis when discovered, and conventionally developed equivalents that were not are compared using the Web of Science and Thomson Innovation software, respectively. EXPERT OPINION: Results demonstrate that openly sharing the JQ1 molecule led to a greater uptake by a wider and more multi-disciplinary research community. A comparative analysis of the patent landscapes for each candidate also found that the broader scientific diaspora of the publically released JQ1 data enhanced innovation, evidenced by a greater number of downstream patents filed in relation to JQ1. The authors' findings counter the notion that open access drug discovery would leak commercial intellectual property. On the contrary, JQ1 serves as a test case to evidence that open access drug discovery can be an economic model that potentially improves efficiency and cost of drug discovery and its subsequent commercialization.

Enabling consistency in pluripotent stem cell-derived products for research and development and clinical applications through material standards.

There is a need for physical standards (reference materials) to ensure both reproducibility and consistency in the production of somatic cell types from human pluripotent stem cell (hPSC) sources. We have outlined the need for reference materials (RMs) in relation to the unique properties and concerns surrounding hPSC-derived products and suggest in-house approaches to RM generation relevant to basic research, drug screening, and therapeutic applications. hPSCs have an unparalleled potential as a source of somatic cells for drug screening, disease modeling, and therapeutic application. Undefined variation and product variability after differentiation to the lineage or cell type of interest impede efficient translation and can obscure the evaluation of clinical safety and efficacy. Moreover, in the absence of a consistent population, data generated from in vitro studies could be unreliable and irreproducible. Efforts to devise approaches and tools that facilitate improved consistency of hPSC-derived products, both as development tools and therapeutic products, will aid translation. Standards exist in both written and physical form; however, because many unknown factors persist in the field, premature written standards could inhibit rather than promote innovation and translation. We focused on the derivation of physical standard RMs. We outline the need for RMs and assess the approaches to in-house RM generation for hPSC-derived products, a critical tool for the analysis and control of product variation that can be applied by researchers and developers. We then explore potential routes for the generation of RMs, including both cellular and noncellular materials and novel methods that might provide valuable tools to measure and account for variation. Multiparametric techniques to identify "signatures" for therapeutically relevant cell types, such as neurons and cardiomyocytes that can be derived from hPSCs, would be of significant utility, although physical RMs will be required for clinical purposes.

Generating iPSCs: translating cell reprogramming science into scalable and robust biomanufacturing strategies.

Induced pluripotent stem cells (iPSCs) have the potential to transform drug discovery and healthcare in the 21(st) century. However, successful commercialization will require standardized manufacturing platforms. Here we highlight the need to define standardized practices for iPSC generation and processing and discuss current challenges to the robust manufacture of iPSC products.

A Quantitative Assessment of Factors Affecting the Technological Development and Adoption of Companion Diagnostics.

Rapid innovation in (epi)genetics and biomarker sciences is driving a new drug development and product development pathway, with the personalized medicine era dominated by biologic therapeutics and companion diagnostics. Companion diagnostics (CDx) are tests and assays that detect biomarkers and specific mutations to elucidate disease pathways, stratify patient populations, and target drug therapies. CDx can substantially influence the development and regulatory approval for certain high-risk biologics. However, despite the increasingly important role of companion diagnostics in the realization of personalized medicine, in the USA, there are only 23 Food and Drug Administration (FDA) approved companion diagnostics on the market for 11 unique indications. Personalized medicines have great potential, yet their use is currently constrained. A major factor for this may lie in the increased complexity of the companion diagnostic and corresponding therapeutic development and adoption pathways. Understanding the market dynamics of companion diagnostic/therapeutic (CDx/Rx) pairs is important to further development and adoption of personalized medicine. Therefore, data collected on a variety of factors may highlight incentives or disincentives driving the development of companion diagnostics. Statistical analysis for 36 hypotheses resulted in two significant relationships and 34 non-significant relationships. The sensitivity of the companion diagnostic was the only factor that significantly correlated with the price of the companion diagnostic. This result indicates that while there is regulatory pressure for the diagnostic and pharmaceutical industry to collaborate and co-develop companion diagnostics for the approval of personalized therapeutics, there seems to be a lack of parallel economic collaboration to incentivize development of companion diagnostics.

Quantitative assessment of barriers to the clinical development and adoption of cellular therapies: A pilot study.

There has been a large increase in basic science activity in cell therapy and a growing portfolio of cell therapy trials. However, the number of industry products available for widespread clinical use does not match this magnitude of activity. We hypothesize that the paucity of engagement with the clinical community is a key contributor to the lack of commercially successful cell therapy products. To investigate this, we launched a pilot study to survey clinicians from five specialities and to determine what they believe to be the most significant barriers to cellular therapy clinical development and adoption. Our study shows that the main concerns among this group are cost-effectiveness, efficacy, reimbursement, and regulation. Addressing these concerns can best be achieved by ensuring that future clinical trials are conducted to adequately answer the questions of both regulators and the broader clinical community.

Global strategic partnerships in regenerative medicine.

The approach to research and development in biomedical science is changing. Increasingly, academia and industry seek to collaborate, and share resources and expertise, by establishing partnerships. Here, we explore the co-development partnership landscape in the field of regenerative medicine, focusing on agreements involving one or more private entities. A majority of the largest biopharmaceutical companies have announced strategic partnerships with a specific regenerative medicine focus, signifying the growth and widening appeal of this emerging sector.

CASMI TSCC launch event, Paris, France, July 2013: an assessment of the key barriers to the commercialization and clinical adoption of pluripotent stem cell therapies.

The high incidence of unmet medical needs in combination with the rising burden of chronic diseases, linked to an increasingly aging population, necessitates new approaches to therapeutic intervention. One potential class of health care innovation that may offer an alternative approach to addressing current shortfalls is stem cell therapies. The CASMI Translational Stem Cell Consortium (CTSCC) was formed to elucidate the key hurdles to the commercialization and clinical adoption of stem cell technologies, with a particular focus on pluripotent stem cell (PSC) technologies. As a global pre-competitive academic-industry consortium, the CTSCC unites thought leaders from a range of sectors and technical specialties in defining and discovering solutions to roadblocks that will impede the field. Targeted toward stakeholder requirements at the delivery end of the translational spectrum, the CTSCC aims to provide mechanisms for multidirectional dialogue and to produce academically rigorous and commercially practicable research outputs to accelerate industry progress. On the 30th and 31st of July, 2013, the CASMI Translational Stem Cell Consortium (CTSCC) held a launch event at the Saint James Club, Paris, France.

The implementation of novel collaborative structures for the identification and resolution of barriers to pluripotent stem cell translation.

Increased global connectivity has catalyzed technological development in almost all industries, in part through the facilitation of novel collaborative structures. Notably, open innovation and crowd-sourcing-of expertise and/or funding-has tremendous potential to increase the efficiency with which biomedical ecosystems interact to deliver safe, efficacious and affordable therapies to patients. Consequently, such practices offer tremendous potential in advancing development of cellular therapies. In this vein, the CASMI Translational Stem Cell Consortium (CTSCC) was formed to unite global thought-leaders, producing academically rigorous and commercially practicable solutions to a range of challenges in pluripotent stem cell translation. Critically, the CTSCC research agenda is defined through continuous consultation with its international funding and research partners. Herein, initial findings for all research focus areas are presented to inform global product development strategies, and to stimulate continued industry interaction around biomanufacturing, strategic partnerships, standards, regulation and intellectual property and clinical adoption.