Transcription

Pettitt et al. Systematic Reviews (2017) 6:120DOI 10.1186/s13643-017-0517-4PROTOCOLOpen AccessAn assessment of the factors affecting thecommercialization of cell-basedtherapeutics: a systematic review protocolDavid Pettitt1,2, Zeeshaan Arshad3,4*, Benjamin Davies17, James Smith1,5, Anna French1, Doug Cole6, Kim Bure7,Sue Dopson8, David DiGiusto9, Jeff Karp10,11,12, Brock Reeve13, Richard Barker8, Georg Holländer2,14and David Brindley1,2,8,13,15,16AbstractBackground: Cellular-based therapies represent a platform technology within the rapidly expanding field ofregenerative medicine and are distinct from conventional therapeutics—offering a unique approach to managingwhat were once considered untreatable diseases. Despite a significant increase in basic science activity within thecell therapy arena, alongside a growing portfolio of cell therapy trials and promising investment, the translation ofcellular-based therapeutics from “bench to bedside” remains challenging, and the number of industry productsavailable for widespread clinical use remains comparatively low. This systematic review identifies unique intrinsicand extrinsic barriers in the cell-based therapy domain.Methods/design: Eight electronic databases will be searched, specifically Medline, EMBASE (OvidSP), BIOSIS & Web ofScience, 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 articleswill be subjected for review by two authors who will decide whether or not each article passes our inclusion/exclusioncriteria. Eligible papers will subsequently be reviewed, and key data extracted into a pre-designed data extractionscorecard. An assessment of the perceived impact of broad commercial barriers to the adoption of cell-based therapieswill 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 thereview. There is no PROSPERO registration number.Discussion: Through a systematic search and appraisal of available literature, this review will identify key challenges inthe commercialization pathway of cellular-based therapeutics and highlights significant barriers impeding successfulclinical adoption. This will aid in creating an adaptable, acceptable, and harmonized approach supported by appositeregulatory frameworks and pertinent expertise throughout the respective stages of the adoption cycle to facilitate theadoption of new products and technologies in the industry.Keywords: Cell-based therapies, Translational medicine, Commercialization, Clinical adoption* Correspondence: [email protected] of St. Andrews School of Medicine, University of St. Andrews, St.Andrews, UK4Docherty Gardens, Glenrothes KY7 5GA, UKFull list of author information is available at the end of the article The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication o/1.0/) applies to the data made available in this article, unless otherwise stated.

Pettitt et al. Systematic Reviews (2017) 6:120Review backgroundAs a key constituent of regenerative medicine, cellbased therapies are an exciting platform technologywith the prospect of potentially curing what wereonce considered untreatable diseases [1]. Defined bythe BSI (British Standards Institute) as “the therapeutic application of cells regardless of cell type orclinical indication” [2], they present a scientifically,commercially, and clinically important treatment modality. They are distinct from conventional pharmaceuticals, biologics, and medical devices through theircapacity to facilitate the de novo production of functional tissue [2] and potential ability to remedy, ratherthan ameliorate, a spectrum of medical and surgicaldiseases. Consequently, this has made them attractiveto a number of stakeholders, including healthcarepractitioners, industry, and investors—all of whom aredriving a paradigm shift away from conventional disease management [3].The cell therapy industry centers on the notion oftherapeutically utilizing cells across a multiplicity ofdisease indications, spanning diverse fields such asneurology, cardiology, and ophthalmology, and extending to both chronic and acute disease states [4, 5]. Despite its relative infancy, it has successfully establisheditself as a billion-dollar industry [3, 6], which is projected to grow—supported by an increasing number ofmarketable products, fiscal investment, and strongM&A (merger and acquisition) activity [7]. In 2014alone, venture capital investment into the biotech sector surpassed 9 billion (USD) [8] and transformed anindustry historically plagued by overly exuberant investments and multibillion-dollar losses [9] into a stableand sustainable market that appears attractive for bothfuture investment and long-term value.Page 2 of 6PurposeThis systematic review will critically examine key challenges in the commercialization pathway of cellular-basedtherapeutics and highlights significant barriers impedingsuccessful clinical adoption. This will help formulate anadaptable and harmonized approach to commercializationthat is aligned with appropriate regulatory frameworks,whilst providing evidence-based recommendations for theadoption cycle. Ultimately, this will help expedite theavailability of efficacious medical treatments to patientswith high, unmet clinical needs.Previous reviews and rationaleAlthough most cell therapies are currently in pre-launchdiscovery phases (see Fig. 1), a number of products haveachieved success across EU (European Union), US(United States), and global marketplaces. However, despite a promising global demand and favorable investment, the translation of cellular-based therapeutics from“bench to bedside” remains challenging. Difficulties pertaining to healthcare translation are nothing new—the2006 Cooksey Report [10] identified two major translational gaps in health research, namely translating basicscience and clinical research into ideas and products,and subsequently introducing these into clinical practice—both of which are relatable to cell therapies. Translational difficulties, and in particular, the clinicaladoption of a therapeutic agent, encompass a complexseries of processes and relationships between heterogeneous stakeholder groups.There are a number of review published that look toassess barriers to the development of cell-based therapies. An example is a study conducted by Dodson et al.(2015), who retrospectively analyzed the development ofseven cell-based therapies [11]. They concluded thatFig. 1 The current regenerative medicine landscape. Compiled using Thomson Reuters Cortellis competitive intelligence software. Gene therapycandidates currently lead the Discovery phase, whilst most Launched drugs comprise tissue-engineered products (including skin substitutes). MSC:mesenchymal stem cell, AAV: adeno-associated virus

Pettitt et al. Systematic Reviews (2017) 6:120funding, regulation, lack of scientific understanding, reimbursement, and manufacturing are key areas dampening the development of such technology. To the best ofour knowledge, however, no systematic evaluation has beenconducted to assess the barriers to the commercializationof cell-based therapies. This is a need addressed within thisstudy and is essential to remove bias that may exist whenevaluating isolated technologies. Qualitative studies havebeen previously conducted will also lay the foundation forour pilot data extraction sheet.Methods/designThis systematic review will be reported following thePreferred Reporting Items for Systematic Reviews andMeta-Analyses (PRISMA) guidelines [12]. Because thisreview will only use publically available information, anethics review board approval will not be required.Page 3 of 6Table 2 Database search summaryDatabaseResults(n )Selected(n )MEDLINE (OvidSP)14562EMBASE (OvidSP)1580194Cochrane Library & HEED1040EconLit (ProQuest)29629BIOSIS & Web of Science (Thomson Reuters)15937WHOLIS, WHO Library Database120PAIS International, ProQuest128Scopus1181147Gray literature/hand search–31Subtotal (n )3489(3520 inc gray)508Duplicates146Total362Eligibility criteriaEnglish language manuscripts published within the last5 years will be included in this review. Inclusion and exclusion criteria to be used are listed in Table 1.Search strategy and search term developmentA review of the literature will be conducted to identify published studies from the following bibliographic databases: Ovid MEDLINE, Ovid EMBASE,Cochrane Library, EconLit, BIOSIS, WHOLIS, PAISInternational, and Scopus. Due to social sciencework within the area, a manual review of relevantjournals will also be carried out.The search strategy will be developed using keywords and controlled vocabulary terms (e.g., NationalLibrary of Medicine’s Medical Subject Headings).Additional papers will be obtained through the use ofcitation-tracking software, pursuing bibliographicalreferences of papers electronically identified in thedatabase searches and through further exploration ofgray literature (Tables 2 and 3).Key data regarding electronic database and ThomsonReuters Cortellis searches is provided below.The above electronic databases were first accessed on17 November 2015.Table 1 Inclusion and exclusion criteriaInclusion criteriaExclusion criteria Published within the last 5 years English language publications Addressed regenerative medicineso Autologous or allogeneic Identified potential challenges inthe commercialization or clinicaladoption process Exclusive focus on manufacturing Technical papers examiningisolation techniques, drug deliverysystems or bioprocessing practices Non-human or veterinary focus Conference abstracts Book chapters Competing interests—sponsoredby manufacturerKey words and medical subheadings:Subheadings: cell therapy; biomedical technology assessment; cost benefit analysis; financial management;economic aspect; commercial phenomena; biological therapy; cell therapy; cost; healthcare cost; stem cell; regenerative medicineKey words: commercialization; cell therapy; reimbursement; barrier; regenerative medicineThomson Reuters Cortellis Competitive IntelligenceSoftware:This software will be searched to identify cell therapyproducts from 01/01/2010 to 01/05/2016 (access date:01/05/2016). Identified products will be stratified byphase, i.e., launched (in market) or in discovery phase.Key search terms: cell therapy; gene therapy (limited toAAV and lentivirus); mesenchymal stem cellStudy selectionTwo independent reviewers will screen manuscript titlesand abstracts for relevance, and full text papers will beobtained for further citations deemed potentially appropriate. Reviewer discrepancies will be discussed untilconsensus is reached. Full text papers will then beassessed for eligibility according to predefined inclusionand exclusion criteria (as listed in Table 1).Eligible papers will be subsequently reviewed and keydata extracted into a pre-designed data extraction scorecard. An overview of the methodology can be seen inFig. 2 below:SynthesisThe data synthesis and extraction scorecard will be categorized into eight key domains, which are outlinedbelow:

Pettitt et al. Systematic Reviews (2017) 6:120Page 4 of 6Table 3 MeSH termsSubjectheadingConcept 1Concept 2Concept 3Concept 4Clinical adoptionMeSH: Technologyassessment, Biomedical,Cost-Benefit AnalysisCell-based therapeuticsMeSH: Cell- and Tissue-BasedTherapy, MeSH: biologicaltherapy, MeSH: RegenerativeMedicineConventional therapeutics MeSH:Therapeutics, Drug Therapy,Enzyme therapy, MolecularTargeted Therapy,Immunotherapy, Transplantation,Monoclonal Antibodies, Vaccines,biosimilars, small-molecule drugsEmergingBarrierstechnologies MeSH:technologyassessment,Biomedical, High-CostTechnologyBiologics, gene therapy,regenerative medicines, celland tissue-based therapy,stem cells, tissueengineeringMedicines, pharmacologicalagents, organ transplant,monoclonal, vaccineTranslational medicalresearchKeywords Clinical adoption,implementation,technology assessment,appraisal, .ManufacturingRegulation and intellectual propertyReimbursementClinical TrialsClinical AdoptionEthicsBusiness modelsOtherSuch domains were identified as being key through briefreview of the literature in the area. Each domain will befurther subcategorized into important components, e.g.,within the Manufacturing domain, subcategories willFig. 2 Systematic review methodological overviewConcept 5include Scalability, Automation, and Supply Chain. Thetabulated scorecard serves to:i. Facilitate the assignment of a perceived impact and/or importance scoreii. Serve as a record of frequency for which a barrier/domain was mentioned in a manuscriptThe data synthesis and extraction scorecard will bepiloted on a sample of 23 manuscripts and completed bytwo independent reviewers. The pilot sample will be acquired from the 83 records identified by stratifying themaccording to highest impact factor journal (n 13) and

Pettitt et al. Systematic Reviews (2017) 6:120Page 5 of 6number of paper citations (n 10). The scorecard willsubsequently be applied to all 83 identified records andcompleted by two independent reviewers. The IRR(inter-rater reliability) will be calculated following analysis.The data synthesis and extraction scorecard will scoreeach paper on the perceived impact and importance of acited factor, as seen below in Table 4.The excerpt above displays a linear scale ranging fromEssential to Negligible, which is accompanied by anumerical value (see parenthesis). The scorecard willalso facilitate the documentation of additional information, including publication details (e.g., year, journal,country of publication), cell-based therapy characteristics (e.g., therapeutic indication, autologous vs. allogeneic, cell type), generalizability (e.g., if nature of findingsare limited to a particular region by the regulatory system described), and sources of funding and potentialconflicts of interest. An additional free text box will beincluded for “other” challenges or barriers identified inthe reviewed manuscripts that did not fall into one ofthe predetermined domains or subcategories.A PRISMA-P file is included as Additional file 1.There is no PROSPERO registration number.DiscussionThis systematic review will critically examine key challenges in the commercialization pathway of cellularbased therapeutics and highlights significant barriersimpeding successful clinical adoption. This will helpformulate an adaptable and harmonized approach tocommercialization that is aligned with appropriateregulatory frameworks, whilst providing evidence-basedrecommendations for the adoption cycle. Ultimately,this will help expedite the availability of efficaciousmedical treatments to patients with high, unmet clinicalneeds.A number of limitations will be inherent to this study.Notably, the assignment of an impact score is subjectiveand open to reviewer interpretation. Publication bias is alsoinherent to the academic literature and it is plausible thatmore important or challenging commercialization barriersare more widely discussed and, consequently, published.Challenges are also experience-dependent. Cell therapydevelopers may therefore have a greater degree of real-worldexperience with the initial phases of commercialization, e.g.,manufacturing or seeking regulatory approval withTable 4 Data synthesis and extraction scorecard excerptPerceived impact and importanceEssential (4)Major (3)Moderate (2)Negligible (1)Imperative barrier,definitiveconsiderationHigh priority,keyconsiderationLower valueor narrowerimpactLow priority orrelevance to field,minimal impactdemonstrable clinical trial data, in comparison to the latter phases, such as clinical adoption or reimbursement.Due to the rapid evolution of the regenerative medicine field, it was deemed appropriate to only include papers published in the last 5 years. It is however likelythat a number of studies published at the beginning ofthis period are now outdated. It may also be possiblethat a number of relevant studies published prior to thistime period contain valid arguments for ongoingcommercialization challenges and may have beenmissed. The study was also limited to English languagepublications, which may have resulted in research findings, particularly from South East Asian nations withnovel regulatory mechanisms, being excluded. Such limitations can be mitigated in future research that employsmore extensive inclusion criteria and regularly re-visitskey literature sources.Additional fileAdditional file 1: PRISMA-P (Preferred Reporting Items for Systematicreview and Meta-Analysis Protocols) 2015 checklist: recommended itemsto address in a systematic review protocol*. (DOC 81 kb)AbbreviationsIRR: Inter-rater reliability; PRISMA: Preferred Reporting Items for SystematicReviews and Meta-AnalysesAcknowledgementsNot applicableFundingWe express sincere thanks to the following organizations that havecontributed to the CASMI Translational Stem Cell Consortium (CTSCC) asfunding and events partners, without whom the consortium and thebenefits it will bring to stem cell translation would be constrained: GEHealthcare, the Center for Commercialization of Regenerative Medicine(CCRM), Sartorius Stedim Biotech (formerly TAP Biosystems), Lonza, theCalifornia Institute for Regenerative Medicine (CIRM), the Strategies forEngineered Negligible Senescence (SENS) Research Foundation, UK CellTherapy Catapult, NIH Centre for Regenerative Medicine, the New York StemCell Foundation (NYSCF), ThermoFisher Scientific, Eisai, Medipost (US),Medipost (Korea), Celgene, Roche and Oxford Biomedica. Author Brindleygratefully acknowledges personal funding from the Oxford MusculoskeletalNational Institute for Health Research (NIHR) the Saïd Foundation, and theSENS Research Foundation. Authors Pettitt and Smith gratefully acknowledgesupport from the CASMI Translational Stem Cell Consortium (CTSCC).Funders had no role within the study.Availability of data and materialsThe datasets during and/or analyzed during the current study are availablefrom the corresponding author on reasonable request.Authors’ contributionsDP was responsible for the study design, data collection/analysis, and draftof the manuscript. BD was responsible for the study design, data collection/analysis, and draft of the manuscript. JS was responsible for the study design,data collection/analysis, and draft of the manuscript. AF was responsible forthe study design, data collection/analysis, and draft of the manuscript. DCwas responsible for the study design, data collection/analysis, and draft ofthe manuscript. KB was responsible for the study design, data collection/analysis, and draft of the manuscript. SD was responsible for the studydesign, data collection/analysis, and draft of the manuscript. DD wasresponsible for the study design, data collection/analysis, and draft of the

Pettitt et al. Systematic Reviews (2017) 6:120manuscript. JK was responsible for the study design, data collection/analysis,and draft of the manuscript. BR was responsible for the study design, datacollection/analysis, and draft of the manuscript. RB was responsible for thestudy design, data collection/analysis, and draft of the manuscript. Allauthors read and approved the final version of the manuscript.Authors’ informationNot applicableCompeting interestsThis article represents the authors’ individual opinions and may notnecessarily represent the viewpoints of their employers. Brindley is astockholder in Translation Ventures Ltd. (Charlbury, Oxfordshire, UK) and IPAsset Ventures Ltd. (Oxford, Oxfordshire, UK), companies that among otherservices provide cell therapy biomanufacturing, regulatory, and financialadvice to pharmaceutical clients. Smith is a consultant with IP Asset VenturesLtd. Brindley also is subject to the CFA Institute’s codes, standards, andguidelines, so he must stress that this piece is provided for academic interestonly and must not be construed in any way as an investmentrecommendation. Additionally, at time of publication, Brindley and theorganizations with which he is affiliated may or may not have agreed and/orpending funding commitments from the organizations named herein.Page 6 of 66.Brindley DA, Davie NL, Sahlman WA, Bonfiglio GA, Culme-Seymour EJ, ReeveBC, et al. Promising Growth and Investment in the Cell Therapy Industryduring the First Quarter of 2012. Cell Stem Cell. 2012;10:492–6.7. Booth BL. This time may be different. Nat Biotechnol. 2016;34:25–30.8. Huggett B. Biotech’s wellspring—a survey of the health of the private sectorin 2014. Nat Biotechnol. 2015;33:470–7.9. Brindley DA, Reeve BC, Sahlman WA, Bonfiglio GA, Davie NL, CulmeSeymour EJ, et al. The Impact of Market Volatility on the Cell TherapyIndustry. Cell Stem Cell. 2011;9:397–401.10. HM Treasury e-CT. Cooksey Review. http://webarchive.nationalarchives.gov.uk/ /http:/www.hm-treasury.gov.uk/cooksey review index.htm. Accessed 8Aug 2015.11. Dodson BP, Levine AD. Challenges in the translation and commercializationof cell therapies. BMC Biotechnol. 2015;15:70.12. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al.The PRISMA statement for reporting systematic reviews and meta-analysesof studies that evaluate healthcare interventions: explanation andelaboration. BMJ. 2009;339:b2700.Consent for publicationNot applicableEthical approval and consent to participateNot applicablePublisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1The Oxford – UCL Centre for the Advancement of Sustainable MedicalInnovation (CASMI), The University of Oxford, Oxford, UK. 2Department ofPaediatrics, University of Oxford, Oxford, UK. 3University of St. AndrewsSchool of Medicine, University of St. Andrews, St. Andrews, UK. 4DochertyGardens, Glenrothes KY7 5GA, UK. 5Nuffield Department of Orthopedics,Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford,UK. 6Flagship Ventures, Cambridge, USA. 7Sartorius Stedim, Göttingen,Germany. 8Said Business School, University of Oxford, Oxford, UK. 9Division ofCell Transplantation and Regenerative Medicine, University of Stanford,Stanford, USA. 10Harvard Medical School, Harvard University, Boston, USA.11Brigham and Women’s Hospital, Boston, USA. 12Harvard-MIT Division ofHealth Sciences and Technology, Cambridge, USA. 13Harvard Stem CellInstitute, Cambridge, USA. 14Department of Biomedicine, University of Baseland Basel University Children’s Hospital, Basel, Switzerland. 15Centre forBehavioral Medicine, UCL School of Pharmacy, University College London,London, UK. 16USCF-Stanford Center of Excellence in Regulatory Science andInnovation (CERSI), Stanford, USA. 17Orthopedic Surgery Departement,University of Cambridge, Cambridge, UK.Received: 1 September 2016 Accepted: 9 June 2017References1. Caplan AI, West MD. Progressive Approval: A Proposal for a New RegulatoryPathway for Regenerative Medicine. Stem Cells Transl Med. 2014;3:560–3.2. Culme-Seymour EJ, Davie NL, Brindley DA, Edwards-Parton S, Mason C. Adecade of cell therapy clinical trials (2000-2010). Regen Med. 2012;7:455–62.3. Mason C, Brindley DA, Culme-Seymour EJ, Davie NL. Cell therapy industry:billion dollar global business with unlimited potential. Regen Med. 2011;6:265–72.4. Mount NM, Ward SJ, Kefalas P, Hyllner J. Cell-based therapy technologyclassifications and translational challenges. Philos Trans R Soc Lond B BiolSci. 2015;370:20150017.5. Martell K, Trounson A, Baum E. Stem Cell Therapies in Clinical Trials:Workshop on Best Practices and the Need for Harmonization. Cell Stem Cell.2010;7:451–4.Submit your next manuscript to BioMed Centraland we will help you at every step: We accept pre-submission inquiries Our selector tool helps you to find the most relevant journal We provide round the clock customer support Convenient online submission Thorough peer review Inclusion in PubMed and all major indexing services Maximum visibility for your researchSubmit your manuscript atwww.biomedcentral.com/submit

Thomson Reuters Cortellis Competitive Intelligence Software: This software will be searched to identify cell therapy products from 01/01/2010 to 01/05/2016 (access date: 01/05/2016). Identified products will be stratified by phase, i.e., launched (in market) or in discovery phase.