Regenerative medicine cell therapies: numbers of units manufactured and patients treated between 1988 and 2010
2010; Future Medicine; Volume: 5; Issue: 3 Linguagem: Inglês
10.2217/rme.10.37
ISSN1746-076X
Autores Tópico(s)Biomedical Ethics and Regulation
ResumoRegenerative MedicineVol. 5, No. 3 ForewordFree AccessRegenerative medicine cell therapies: numbers of units manufactured and patients treated between 1988 and 2010Chris Mason and Elisa ManzottiChris Mason† Author for correspondenceAdvanced Centre for Biochemical Engineering, University College London, Roberts Building, Torrington Place, London, WC1E 7JE, UK. and Elisa ManzottiFuture Medicine Ltd, Unitec House, 2 Albert Place, Finchley Central, London, N3 1QB, UK. ; www.futuremedicine.com Published Online:10 May 2010https://doi.org/10.2217/rme.10.37AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail For over 20 years, the cell-based therapy industry has successfully manufactured products and cured patients [1,2]. Given the billions of dollars spent and many more requested, the common questions that we are all asked by governments, funding agencies and investment organizations are: 'how many units have been manufactured?' and 'how many patients have been treated?'. The challenge for us today is that mere arm waving is simply no longer acceptable. If we want their hard cash then we need to supply hard numbers. With the help of the leading providers of cell-based therapies and acknowledged experts we have collated the essential baseline data in order to robustly answer these two important questions.Regenerative medicine replaces or regenerates human cells, tissue or organs, to restore or establish normal function [3], therefore by definition, regenerative medicine is an opportunity for all the major therapeutic approaches including medical devices, small molecules, complex biological molecules as well as cell-based therapies [4]. However, there is no doubt that within regenerative medicine, the exciting paradigm shift is cell-based therapies. This is the step-change platform technology that is enabling the fourth pillar of healthcare – a sustainable new sector based on living cells as therapies [4]. Presently there are a great many misconceptions regarding the genuine achievements to date by our fledgling sector. The spectrum of stakeholder opinions ranges from near total inability to deliver a commercial product to estimates of annual sales in the billion dollar range [5,6]. The public believe we can either cure everything or nothing, the press is totally in the dark, politicians are confused and unregulated stem cell tourism is threatening legitimate business. The reason for this total chaos is a combination of the historical lack of an industry voice [7,8] combined with market reports that 'conveniently' interchange stem cell-based therapies with the all-encompassing term 'regenerative medicine'. Highly successful products such as the billion dollar per year recombinant human bone morphogenic protein (e.g., INFUSE®, Medtronic) are a very valid part of regenerative medicine and while having mechanisms of action that involve cells in vivo, they are not cell-based therapies but are products of conventional pharma and biotech. We need to urgently correct these misconceptions by providing our supporters and critics alike with unequivocal baseline data for cell-based therapies. We have articulated on many occasions that whilst cell therapies are just one of the four modalities for regenerative medicine, the converse is also true, regenerative medicine is just one medical indication for the cells as therapies industry ('Regen') [4,101]. Since this journal is exclusively focused on regenerative medicine, we have therefore endeavored to assemble accurate baseline data for the cell-based therapies that are the most relevant to regenerative medicine: permanent cell replacement therapies, transient cell therapies and tissue engineering. In order to establish a totally unambiguous baseline upon which to subsequently build and therefore to provide a dynamic tally of genuine progress in the regenerative medicine cell therapy sector, we have exclusively chosen to use data from products that have been successful when subjected to the stringent process of regulation including US FDA (and EMA equivalent) regulatory approval via Premarketing Approval Application (PMA), Biologic Licence Application (BLA) and Humanitarian Device Exemption (HDE). A suggested term for this category is 'cellular therapeutics' [Weber D, Biologics Consulting Group, Pers. Comm.]. Whilst we fully appreciate that this rigid cutoff will underestimate the total scale of regenerative medicine cell-based therapies it does, however, provide a totally hype-free, robust baseline upon which to add other cell-based therapies with proven safety and efficacy. Since the majority of the companies are privately owned, the data have either been very kindly provided by the companies themselves or from estimates from leading authorities [6], and can be found in Table 1. Wherever possible we have attempted to cross-check data with other reputable sources including papers authored by the late Prof Michael Lysaght (Brown University, RI, USA) [2,5,6,9–13,102].Table 1 contains only data that we believe all would unanimously agree should be included since all have regulatory approval – FDA (and/or EMA equivalent) PMA, BLA and/or HDE. The list may be short but it immutably provides ample evidence of our genuine successes to date. There are, however, two more categories that need very careful consideration. The first is cell-based regenerative medicine treatments that are not subject to FDA (and/or EMA equivalent) regulatory authorization via either PMA or BLA. For this group perhaps 'regenerative medicine tissues' might be a good classification term – 'tissues' being defined as cellular or decellularized materials whose medical utility is inherent and thus do not require substantial ex vivo manipulation to make them medically useful [Suggestion by D Weber, Biologics Consulting Group, Pers. Comm.]. A good example is OsteoCel® Plus by NuVasive, which is regulated as a Human Cells, Tissues and Tissue-Based Product (HCT/P), as defined in the US FDA Title 21 Code of Federal Regulation Part 1271 [103]. According to this regulation, Osteocel Plus is restricted to homologous use for the repair, replacement or reconstruction of musculoskeletal defects. This route allows rapid access to the product by surgeons and their patients. The other important category is cell-based therapies that are provided routinely on a humanitarian basis (but not under an HDE), or via compassionate-use (rapid access) programs that allow a clinician to provide treatment for a given patient while the therapy is still under development. This issue of Regenerative Medicine contains an article on one of the leading examples, adult limbal stem cell therapy for corneal damage [14]. Other examples are included in Table 2. All the above 'cellular therapeutics' and 'regenerative medicine tissues' are produced either under good manufacturing practice (GMP) and/or good tissue practice (GTP).We estimate from the cumulative numbers of units manufactured and patients treated in Tables 1 & 2, as well as from discussions with senior industry experts, that the current value of the regenerative medicine cell therapy market is presently in the order of $100–200 million per annum. The largest contribution by far is from Apligraf® (Organogenesis). It is therefore highly interesting to note a comment from Geoff MacKay, CEO and President of Organogenesis that, "In the USA, on average, once every 2 minutes Monday to Friday a patient is treated with Apligraf." [Pers. Comm.].Since its inception, Regenerative Medicine has provided high-quality clinical translation and commercial reports, reviews and analysis [15–19]. Building quantitatively on this mainly qualitative foundation we plan to regularly update the baseline data for the regenerative medicine cell therapy field and therefore provide a 'gold standard' reference point for all the stakeholders as well as the public. We would therefore very much welcome comments, suggestions and appropriate data in order to keep this tally robust, up to date and most of all relevant. Today, with a minimum baseline of 675,000 therapeutic units manufactured and 323,000 patients treated, we are undoubtedly a credible new sector of advanced healthcare that is proud to stand up and be counted.Table 1. Regenerative medicine cell-based therapies with US FDA (and/or EMA equivalent) regulatory approval via Premarketing Approval Application (PMA), Biologic Licence Application (BLA) and/or Humanitarian Device Exemption (HDE)†.ProductCompanyBrief descriptionRegulatory approval indication (year)Cumulative number of units manufactured up until 31st March 2010Cumulative number of patients treated up until 31st March 2010NotesApligraf®Organogenesis (USA)Bilayered skin substitute: epidermal layer formed by human keratinocytes dermal layer is composed of human fibroblasts in a bovine Type I collagen latticeVenous leg ulcers (FDA 1998)Diabetic foot ulcers (FDA 2001)Chronic ulcers and soft-tissue defects (Switzerland 2008)>300,000250,000Originally named Graftskin™Dermagraft®Advanced BioHealing (USA) (originally Advanced Tissue Sciences/Smith & Nephew)Cryopreserved human fibroblast-derived dermal substitute composed of fibroblasts, extracellular matrix and a bioabsorbable scaffoldTreatment of diabetic foot ulcers (FDA 2001)100,000 + >100,000 = >200,000 in total25,000 + >25,000 = >50,000 in totalBased on experts' estimates for Advanced Tissue Sciences/Smith & Nephew activity prior to acquisition in 2006.Advanced BioHealing since manufacturing recommenced in 2007Carticel®Genzyme (USA)Autologous cultured chondrocytes derived from in vitro expansion of chondrocytes harvested from the patient's normal femoral articular cartilageRepair of symptomatic cartilage defects of the femoral condyle, caused by acute or repetitive trauma, in patients with an inadequate response to prior repair procedure (FDA 1997)17,00017,000Commercial use since 1995TransCyte®Advanced BioHealing (USA) (originally Advanced Tissue Sciences/Smith & Nephew)Human fibroblast-derived temporary skin substituteTemporary wound covering for severe burns (FDA 1997)Originally named: Dermagraft-TC (Temporary Covering)15,000 bioreactors (two sheets per bioreactor) = Total 30,000 sheets4000Based on experts' estimates for Advanced Tissue Sciences/Smith & Nephew activity prior to acquisition in 2006.Currently AHB are not manufacturing/selling the productEpicel®Genzyme (USA) (originally BioSurface Technology)Cultured epidermal autograft – aseptically processed wound dressing composed of autologous keratinocytes grown in the presence of proliferation-arrested murine fibroblasts, hence a xenotransplantation productDeep dermal or full thickness burns comprising a total body surface area of greater than or equal to 30%Humanitarian Device Exemption (FDA 2007)127,50916531988: BioSurface Technology supplied Epicel for the treatment of serious burns.1994: Company acquired by Genzyme.The product had been considered a banked human tissue until 1996 when FDA announced that manipulated autologous cell-based products used for structural repair/reconstruction required regulatory oversightChondoCelectTiGenix (Belgium)Autologous cultured chondrocytes derived from in vitro expansion of chondrocytes harvested from the patient's normal articular cartilageRepair of single symptomatic cartilage defects of the femoral condyle of the knee in adults (EMA 2009)500500EU marketing authorization in October 2009 as the first Advanced Therapy Medicinal Product (ATMP)Numbers from clinical trials and compassionate use programs prior to marketing authorizationOrCel®Forticell (USA) (formally Ortec International)Bilayered cellular matrix: epidermal keratinocytes and dermal fibroblasts cultured in two separate layers deploying Type 1 bovine collagen spongeRecessive dystrophic epidermolysis bullosa hand reconstruction – patients with 'mitten deformity' as an adjunct to an autograftHumanitarian Device Exemption (FDA 2001)Donor site wounds – burns patients (FDA 2001)>200>2001998 initially designated a Humanitarian Use Device (HUD) i.e., device for conditions that affects 675,000>323,000 Notes: A suggested term for this category is 'cellular therapeutics' [Suggestion By D Weber, Biologics Consulting Group, Pers. Comm.].†A Humanitarian Device Exemption (HDE) is an application that is similar to a Premarket Approval Application (PMA) or Biologic Licence Application (BLA), but exempt from the effectiveness requirements of the Federal Food, Drug, and Cosmetic Act. FDA approval of an HDE authorizes the marketing of a Humanitarian Use Device (HUD).Historical context – Apligraf, Dermagraft, OrCel and Transcyte are PMAs, Epicel and OrCel are Humanitarian Device Exemption (HDE) and Carticel remains the only Biologic Licence Application (BLA) – most of the preceding list would be a BLA if submitted today [Bravery C, Consulting on Advanced Biologicals, Pers. Comm.].Table 2. Examples of cell-based regenerative medicine treatments that are not subject to US FDA (and/or EMA equivalent) regulatory approval via Premarketing Approval Application (PMA) or Biologic Licence Application (BLA)† and cell-based products/services that are routinely provided on a humanitarian basis (but not under an Humanitarian Device Exemption [HDE]) or via compassionate use (rapid access) programs.ProductOrganizationBrief descriptionIndicationCumulative number of units manufactured up until 31st March 2010Cumulative number of patients treated up until 31st March 2010NotesOsteocel® PlusNuVasive (USA) (originally Osiris Therapeutics)Allogeneic bone matrix containing viable mesenchymal stem cellsRegulated as a Human Cells, Tissues and Tissue-Based Product (HCT/P) – US FDA Title 21 Code of Federal Regulation Part 1271 – restricted to homologous use for the repair, replacement or reconstruction of musculoskeletal defects35,00035,000Marketed in the USA since 2005 as Osteocel (Osiris Therapeutics) and Trinity (Blackstone Medical) prior to NuVasive introducing Osteocel Plus.Sold to NuVasive in 2008.Undergoing clinical trials in USA since 2009 for degenerative disc disease.Numbers are for Osteocel product familyReCell®Avita Medical (UK) (formally Clinical Cell Culture)Point of care autologous cell harvesting, processing and delivery technology. Initially marketed only for small wounds ( 1500>1500Avita Medical are no longer marketing CellSpray as ReCell provides faster, lower cost and more effective coverageLimbal stem cell therapyL V Prasad Eye Institute (India)Autologous or closely related donor limbal cells on amniotic membraneLimbal stem cell deficiency mainly due to chemical burns710710Commenced 2001. Success rate 70% at 1 year 50–55% at 3–4 yearsLimbal stem cell therapyGraziella Pellegrini/Michele De Luca currently at University of Modena and Reggio Emilia (Italy). Treatments carried out at a number of locations with different collaborators all deploying the Pellegrini/De Luca core technologyAutologous cultured confluent epithelium transferred to a fibrin gel for transplantationLimbal stem cell deficiency mainly chemical burns252212Commenced 1998. Some patients had both eyes transplanted (bilateral lesions) and some needed two transplants on the same eye to complete corneal reconstruction. Overall success rate of 68% on total 212 patients. 76.6% on 112 patients at 10 yearsMyskin™Altrika (UK) (originally CellTran)Layer of autologous cultured keratinocytes on a flexible medical-grade silicone coated with a chemically controlled plasma polymer filmBurns, chronic ulcers and graft donor sites>1000105Available since November 2003Total >42,000>41,000 Note: †A suggested term for this category is 'Regenerative medicine tissues' – tissues being defined as cellular or decellularized materials whose medical utility is inherent and thus do not require substantial ex vivo manipulation to make them medically useful [Suggestion by D Weber, Biologics Consulting Group, Pers. Comm.].tbs: Total body surface area.AcknowledgementsWe would like to thank the following for either directly providing their company's data (when possible) and/or advice, suggestions and comments: Dorairajan Balasubramania, L V Prasad Eye Institute; Gil Beyen, TiGenix; Christopher Bravery, Consulting on Advanced Biologicals; Julie Daniels, UCL/Moorfields Eye Hospital; William Dolphin, Avita Medical; David Haddow, Altrika; Paul Kemp, Intercytex; Tyler Lipschultz, NuVasive; Michele De Luca, University of Modena and Reggio Emilia; Geoff MacKay, Organogenesis; Jonathan Mansbridge, Tecellact; Nick Medcalf, Smith & Nephew; Randal Mills, Osiris Therapeutics; Gary du Moulin, Genzyme; Graziella Pellegrini, University of Modena and Reggio Emilia; Virender Sangwan, L V Prasad Eye Institute; David Smith, Lonza Walkersville; Alex Speechley, Altrika; Dean Tozer, Advanced BioHealing; Geeta Vemuganti, L V Prasad Eye Institute; Darin Weber, Biologics Consulting Group.C Mason and E Manzotti are both Principle Investigators on the British Regen Industry Tool Set (BRITS) project funded by the Technology Strategy Board under their Regenerative Medicine Program: Value Systems and Business Modeling.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. 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This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download
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