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Tuesday, December 27, 2011

2011 EMA Committee for Advanced Therapies (CAT) classification record. What can be learned?


What follows is the record of "classifications" done by the ATMP CAT in 2011 related to anything I would call "cell therapies". 

In my opinion there are a couple surprises. I'm surprised at the non-cardiac cells (MNCs, CD133s, and MSCs) for cardiac disease/repair being designated TEPs. I'm also surprised at the islets not being classified as an ATMP.

I've tapped into my European and/or regulatory colleagues to help explain those two as well as help us draw any other conclusions or observations we can make in terms of how the CAT is thinking based on the compendium of classifications we have to-date.  I'll post an update here when I have something useful.

In January, the following product was classified as a tissue engineered product - not combined:
  • Layer of autologous corneal epithelium containing stem cells intended for the treatment of extended corneal lesions

In April, the following product was classified as a tissue engineered product, combined: 
  • Allogeneic human fibroblasts cultured onto a biodegradable matrix, intended for use of conditions in the therapeutic area of dermatology

In May, the following product was classified as a somatic cell therapy medicinal product: 
  • Heterologous human adult liver-derived progenitor cells, intended for the treatment of inborn errors of liver metabolis

In July, the following product was classified as a Tissue Engineered Product, non-combined:
  • Suspension of allogeneic bone-marrow derived osteoblastic cells, intended for the treatment of non-union, delayed union or other fractures. 

In September, the following product was classified as a Tissue Engineered Product, non-combined:
  • Autologous mesenchymal stem cells (MSC), intended for the treatment of chronic heart failure symptoms by improvement in exercise capacity of NYHA class II and III chronic heart failure patients receiving standard therapy
     and the following product was not classified as an ATMP: 
  • Human islets of Langerhans, intended for: Post pancreatectomy for benign pancreatic pathologies (autologous); Treatment of severe forms of type 1 diabetes (Allogeneic)

In October, the following product was classified as a somatic cell therapy medicinal product: 
  • Autologous dendritic cell (DCs) immunotherapy consisting of autologous mature DCs coelectroporated with autologous RCC IVT RNA and synthetic CD40L IVT RNA, intended for the treatment of patients with advanced renal cell carcinoma

In November, the following products were classified as tissue-engineered products:
  • Concentrate of autologous bone marrow mononuclear cells (MNC), intended for improvement of heart function and quality of life in patients with chronic ischaemic heart disease and after MI.
  • CD 133+ Autologous bone marrow derived stem cells, intended for Improvement of heart function (LVEF) and quality of life in patients with chronic ischemic heart disease and after MI

In December, the following product was classified as somatic cell therapy medicinal product:
  • Autologous CD4+ T cells targeted to cells presenting class II restricted epitopes, intended forthe treatment of autoimmune diseases with MHC restricted specific immunity e.g. multiple sclerosis, type I diabetes or graft rejection.

Tuesday, December 20, 2011

Washing cryopreserved cells. An emerging need or disappearing process?


I’m not a fan of the allogeneic vs autologous business model debate because I don’t believe it’s a debate that rages other than at conference panel sessions.  Most investors, researchers, and executives recognize that there will almost certainly be room for both to succeed and that the winner in any particular indication will be largely determined by proven clinical efficacy over the standard of care and other available treatment alternatives.

Cryopreserved vs Fresh

The oft-touted primary commercial advantage of allogeneic cell therapy products over their autologous counterparts is the ability to inventory standardized products for later on-demand distribution and use.  This contributes to the ‘economies of scale’ advantage allogeneic products enjoy.  Certainly this is true.

Critics of the autologous business model cite the high cost of single-batch lot sizes and short shelf-life of autologous products- often shipped fresh - as the primary drivers of the high cost of these types of products and the variation in cell composition of therapeutic products derived from patient to patient.  Certainly also true.

Nonetheless, the two issues most involved in a debate comparing the business models are cost and price implications of the relative bioprocessing scalability and distribution costs of each model.  For sake of convenience it is most often assumed that allogeneic cell therapies are cryopreserved and autologous products are delivered fresh from the manufacturing site to the clinic for delivery to the donor-patient.  This is, of course, an over-simplification because it is not always true.    

Take, for instance, Opexa TherapeuticsToxavin which involves the cryopreservation of multiple doses (potentially representing several years) of treatment from a single patient apheresis.  This is in stark contrast with Dendreon’s Provenge which requires a new apheresis for each of three monthly treatments and a limited shelf-life of a fresh product of approximately 72 hours. One cannot avoid concluding that the likely cost implications of such a difference are bound to be significant considering the differences in upstream collection, processing, and distribution costs.

I want, however, in the last few paragraphs of this post to focus attention on a couple of aspects related to cryopreservation of cell therapeutics.  Firstly, as a digression, I am often left with the impression that executives and analysts alike often over-estimate the cost of shipping fresh products (with their temperature and time sensitivities) compared to the costs associated with shipping cryopreserved products which most often require heavy and bulky LN2 shippers as well as facilities and personnel experienced with receiving and handling cryopreserved products at regional repositories and local pharmacies.
Does the existence of cryoprotectant excipients dictate point-of-care cell washing?

Currently the short answer is “not necessarily”.  The primary point I want to address here, however, is related to the costs currently associated with balancing the excipient and processing requirements involved in cryopreserving, storing, and thawing cells on the one side with the need to have a product that is clinically safe, effective and well tolerated by the patient on the other side.  Companies developing cryopreserved cell therapies have three choices in this regard:
  1. Infuse the patient with a product that includes cryopreservant excipients (almost always including some levels of DMSO being the overwhelmingly dominant reagent) recognizing the impact on patient experience and infusion volumes (a more significant concern in bodily regions where capacity is small (e.g., heart) or potentially sensitive (e.g., brain). 
  2. Invest in developing an infusion-ready formulation that significantly minimizes the amount of excipients.  This may or may not involve a thaw or post-thaw dilution.  
  3. Commit to a process that involves point-of-care, post-thaw washing and re-concentration of the product to remove excipients and minimize the volume size of the product to be infused.
In terms of examples, we believe Mesoblast is currently in the first camp, Celgene has pursued the second strategy, and Athersys is an example of a company using the 3rd approach.  Each have a similar cell type and all three are pursuing some of the same indications. 

Some companies have worked hard to bring to market cryoprservant formulations that reduce the amount of DMSO (e.g., BioLife Solutions).  Some predict that in the near future DMSO-free cryoprservants will be a real fourth option (e.g, Essential Pharma's Cryo-Ess currently for Research Use Only). 

These products will have to be pioneered by some early-adopters before they are readily considered by the majority of players in a field which is oft-defined both by its dogged pursuit of precedent and reticence to be mold-breaking and innovative.

Stem cell transplanters are also faced with deciding between first and third course.  While different considerations and drivers apply to them vs companies developing s.351/ATMP products, they are still faced with the decision to wash or not.

What factors to consider in the “to wash or not wash” debate?

Of the many and somewhat differing factors to take into account, cell therapy developers and stem cell transplanters share a number of common considerations when deciding how to treat cryopreservants in the clinical setting:

  • Regulator’s general tolerance of DMSO in the final product formulation to-date.  Despite this record of tolerance, it is expected that for certain indications and/or for certain types of routes of administration, there may be significantly more regulatory scrutiny concerning injecting DMSO.  Indeed, DMSO is classified as a Class 3 (relatively low risk) solvent in ICH Q3C with a recommendation of 50 mg/day as upper threshold below which one does not need to ‘justify’ its presence.  The typical DMSO solutions used in cell therapy labs contain about 1 gram (not mg) per mL before dilution-- so if used at 10% in final product, this translates to 100 mg per mL. Therefore a 10 mL cell therapy product (at 10% DMSO) would contain 1000 mg (1 gram) of DMSO (20 times the ICH threshold).
It may be worth noting that apparent regulatory tolerance of the infusion of DMSO may be somewhat tied to the fact that most previous applications have involved the IV injection - allowing for excipients to e rapidly diluted in systemic circulation.  For cell therapies delivered some other way, potential toxicity may be a more significant concern.
  • Concentrations of 10-20% DMSO has been traditionally used since the dawn of stem cell transplantation with minor reports of allergic reactions (e.g., hives, itching or facial or glottal edema) and only rare reports of more serious anaphylactic/oid reactions. Side effects of DMSO include hypernatremia, fluid overload, dysgeusia (distorted taste), nausea, vomiting, elevated liver enzymes, hemolysis, renal failure, and allergic reaction.  DMSO toxicity is the most common complication of stem cell transplantation with symptoms including flushing, rash, chest tightness, nausea and vomiting, an cardiovascular instability (as outlined in the Circular of Information for the Use of Cellular Therapy Products).  Ruiz-DelGado recently reported dimethyl sulfoxide-induced toxicity in cord blood stem cell transplantation and reviewed the literature (Acta Haematol. 2009;122(1):1-5).  The authors reported the incidence of any cord blood infusion reaction ranging from 4% to 65%, with life-threatening infusion reactions occurring in up to 4.6% of patients. 
It is worth noting that  the FDA’s Pharmacovigilance Review Memo, related to the FDA’s recently approval of the New York Blood Centers BLA for its cord blood progenitor product named “Hemacord”, includes the following statement:  
Exposure to DMSO and Dextran-40, though not completely avoidable, can be limited by proper preparation before infusion of cord blood. Warnings and instructions for preparation (e.g. thawing, washing, dilution) should be included in the label.
  • Even for those patients who do not experience any toxicity, allergic, or anaphylactic/oid reaction, there is an undisputed and significant ‘garlic’ odor and taste experience by the patient as well as the issues related to having to consent around the infusion of such excipients.
  • One of the outstanding regulatory questions is to what extent regulators will consider point-of-care washing steps to be a final manufacturing step.  Closely related, but not necessarily intrinsically tied to this issue, is the question of whether a final release assay will be required to test a final product which was washed and re-concentrated post-thaw.
  • Finally, one is tempted to wonder whether to what extent regulatory opinion, commercial strategies, development pathways are influenced by what has been to-date a lack of commercially acceptable and viable technical solutions to post-thaw washing and re-concentration.

On this last note, Cell Therapy Group is working with Stem Cell Partners on bringing to market what we believe is potentially a simple, quick, cost-effective, easy-to-use density phase washing centrifugation device utilizing commercially available reagents and centrifuges – the EnsuraSep Cell Washer.  

Have a quick spin through the brief technology outline at and I would be happy to discuss it further with anyone interested.  

We are working on different configurations and sizes of that device for different applications. Stem Cell Partners is working with our clients to design custom canisters and reagent-formulations to meet their specific requirements.  Stem Cell Partners is also working on alternative centrifugation-based device that has a wider-capacity range. 

While we believe the Ensura-Sep Cell Washer may enable a simple and rapid washing and concentration of a cell suspension in a single centrifugation step, CTG is also working with other companies who are pursuing other solutions using different technologies such as filtration.

There is currently much expert divergence on the question of what role point-of-care cell washing/concentration may play in the future of cell therapies.  I invite any and all comments or feedback on this post either using the comment function here or in the discussion thread mentioned below in the LinkedIn Cell Therapy Industry Group.


Much thanks to a great discussion thread in the LinkedIn Cell Therapy Industry Group called “Clinical preparation of frozen cell therapy products” which inspired must of this content with a special nod to Jon RowleyReinout HesselinkEJ Read, Christopher Bravery, and Ali Mohamed.

Friday, December 16, 2011

Inactive and recently failed or terminated phase III or II/III cell therapy trials


Updated 20 December 2011

In the two previous posts I have outlined what I believe to be the active phase III and II/III cell therapy trials, as well as the cell therapy products to have 'recently' obtained formal regulatory market approval in some jurisdiction.

In the course of doing that work, I came across the following industry-sponsored phase III cell therapy trials which appear to be inactive and those which failed or were terminated.


  •     Aastrom              BRCs
  •     Aldagen              ALD-101
  •     Arblast               AMT-301
  •     Avax                  Mvax
  •     Vioheart             Myocell    
  •     HepaLife Tech      HepaMate
  •     KeraCure             KeraPac
  •     Northwest Bio      DCVax-Prostate
  •     t2cure                 BMCs
  •     TVAX                  TV-Brain
  •     TVAX                  TV-Kidney-1


  •     ABH (now Shire)        Dermgraft
  •     Cellerix                    Cx401

I don't imagine this is an exhaustive list but as I have encouraged in previous posts, I welcome feedback as to errors, corrections, or omissions.   I'm using the 2009-11 time-frame here.  I'll update the post accordingly.

Friday, December 9, 2011

Recently approved cell therapy products


Following is a list of cell therapy product approved in 2012:

Medipost                                      Cartistem                         S. Korea
Anterogen                                     Cupistem                         S. Korea

Following is a list of cell therapy products approved recently (2010-11):  

  •  Dendreon                           Provenge                           US
  •  FCB-Pharmicell                 Hearticellgram-AMI         S.  Korea
  •  Fibrocell Sciences              Laviv                                  US
  •  Living Cell Technologies    DIABECELL                     Russia

 Honorable mention goes to TiGenix' ChondroCelect approved in late 2009 representing the first EMA approval of an ATMP:

  • TiGenix                              ChondroCelect                   EU

Late-stage industry-sponsored cell therapy trials


Updated 22 August 2012 (originally posted December 2011)

At Cell Therapy Group, we track cell therapy industry activity globally but  particularly activity related to the clinical development and commercialization of cell based therapeutic products globally.

Below is a synopsis of the pivotal, phase 3 or 2/3 industry-sponsored cell therapy trials we are currently tracking globally.  

There is a database behind this that includes more data fields like therapeutic category, cell/tissue source, cell type, expansion, indication, expected completion date, clinical trial site locations, etc. 

Industry-sponsored pivotal, phase 3 or 2/3 trials*
    *active or expected to be active in 2012 

  • Ixmyelocel-T
  • Arcelis - AGS-003
Avita Medical
  • ReCell
  • ACT34-CMI
Bone Therapeutics           
Cardio3 Biosciences         
  • C-CURE
Cell Medica                     
  • adoptive cellular therapy
CellSeed France               
  • CAOMECS (Cultured Autologous Oral Mucosal Epithelial Cell-Sheet)
  • co.don chondrosphere
Cook Myosite                  
  • AMDC
  • ADRCs
DePuy Mitek
  • CAIS
ERYtech Pharma              
GamidaCell - Teva           
  • StemEx
Harvest Technologies       
  • SmartPReP 2 BMAC
  • HP802-247
  • NeoCart
  • Immunecell-LC
  • IES13 (Urocell?)
ISTO Technologies            
  • DeNovo ET
JW Creagene
  • CreaVax-RCC
Kiaidis Pharma                
  • ATIR
  • CureXcell
  • Revascor    
  • CliniMACS CD34 Selection System
  • TK
Newlink Genetics             
  • HyperAcute Pancreas
  • Biocell Natural Killer Mixture
Northwest Biotherapeutics
  • DCVax-L
  • Lucanix
  • Osteocel Plus
  • Prochymal
  • Heartcellgram-AMI
Prima Biomed                  
  • Cvac
Sanofi (Genzyme)
  • MACI
  • DVAC/Pca
Tigenix (Cellerix)
  • Cx601
The Hawkins Foundation (in collaboration with Depuy Mitek
  • CAIS
  • amniotic membrane

Some of the products listed above are in more than one clinical trial - different regions and/or different indications.

In total we are tracking 48 industry sponsored, active (or expected to be active 2012) cell therapy trials in pivotal, ph III or II/III expected to involve over 11,000 patients.  Some of the products listed above are the subject of multiple trials.

The 50 trials are sponsored by 40 companies.  The trials roughly break down as follows:
    • 59% are autologous
    • 45% are allogeneic
    • Two are gene-modified allogeneic
    • One involves autologous and allogeneic cells (we counted it for both)
    • 30% for oncology or related indications
    • 13% for cardiac-related indications
    • 13% for non-cardiovascular (PAD, CLI, VLU, etc)  & wound 
    • 34% (6) for cartilage and bone repair

I encourage readers to comment below or email direct with any errors and/or omissions.

Friday, November 25, 2011

Sabrina Cohen Foundation Thanks Stem Cell Researchers


I'm proud to use every available resource at our disposal, including this blog, to highlight the efforts of the charity we support - especially during this holiday season.  

I would be so delighted to have you join me in supporting Sabrina Cohen and her efforts.  You can start by buying next year's calendar!

The Sabrina Cohen Foundation
The Sabrina Cohen Foundation for Stem Cell Research (SCF) is an internationally recognized nonprofit organization dedicated to building a global network of top scientists and clinicians in the field of Regenerative Medicine, while simultaneously funding cutting edge research and innovative therapies that will reverse spinal cord injury and effectively treat other impairments of the Central Nervous System.

The ‘CELLebrity’ Doctors Calendar
The 2012 CELLebrity Doctors calendar is now available for purchase from  All proceeds from calendar sales benefit the Sabrina Cohen Foundation for Stem Cell Research, a 501c3 non-profit organization directly funding stem cell clinical research.   



On the night of November 12, David Porosoff’s Artrageous Gallery hotspot was converted into something likely never imagined -- a hotbed of stem cell research.  Sabrina Cohen fused the vividly artistic backdrop and venue with gambling, cuban music, great food, and beautiful people all to further her mission of raising money and awareness for stem cell research.

Dr. Sally Temple with Sabrina Cohen
Dubbed the Havana Casino Night, the event had several highlights including the granting of the 2011 Sabrina Cohen Foundation award to stem cell researcher Dr. Sally Temple.  

Representing the 3rd recipient of the annual SCF award, Dr. Sally Temple is studying how neural progenitor cells may be employed to create cell-based therapies for neurodegenerative disorders.  Dr. Temple is the co-Founder and Scientific Director of the Neural Stem Cell Institute located in Rensselaer, NY.  NSCI is the first independent, non-profit stem cell research institute in the USA.

The night, sponsored in part by DMR, Evensky & Katz and Harke Clasby & Bushman, raised $10,000 which will be dedicated toward next year’s SCF Award for Stem Cell Research.  

The event also marked the lauch of the the Foundation’s 2012 CELLebrity Doctors Calendar, this year featuring women in the field of stem cell research.  The calendar features academics, industry executives, physicians, and advocates primarily from the United States but also representing Sweden, Australia and Canadian covergirl, Dr. Fiona Costello.

“In science you don't have to accept anything anyone tells you, you can come up with a hypothesis and test it yourself. And you can be the first one to do it,” says Dr. Costello, whose research focus is on multiple sclerolsis and other impairments of the central nervous system. 

“Stem cell science is often accused of being ‘hyped,” says Cohen, “but that doesn’t necessarily translate into monetary support for or society recognition of the enormous contributions made by stem cell resarchers.  They often toil in anonymity making significant discoveries at great personal sacrifice.  I consider it my job to find a way to financially support their work and bring profile to them as people.”  

The ‘CELLebrity’ Doctors Calendar
The 2012 CELLebrity Doctors calendar is now available for purchase from  All proceeds from calendar sales benefit the Sabrina Cohen Foundation for Stem Cell Research, a 501c3 non-profit organization directly funding stem cell clinical research.   

The Sabrina Cohen Foundation
The Sabrina Cohen Foundation for Stem Cell Research (SCF) is an internationally recognized nonprofit organization dedicated to building a global network of top scientists and clinicians in the field of Regenerative Medicine, while simultaneously funding cutting edge research and innovative therapies that will reverse spinal cord injury and effectively treat other impairments of the Central Nervous System.

Sabrina Cohen is the Executive Director and President of the foundation. She graduated from the University of Miami with a degree in Communications, double majoring in Advertising and Psychology, and holds a post-graduate degree in Copywriting from the Miami Ad School.  She is a C5 Quadriplegic, as the result of a spinal cord injury from a car accident in 1992. In 2006, she established SCF to raise funds for research because she believes the field of Regenerative Medicine will lead to the greatest advances of our time. Sabrina is a Motivational Speaker & Spokesperson continuously speaking in schools, universities and community centers. She has spoken at scientific conferences around the country, including the "World Stem Cell Summit" at the University of Wisconsin, Harvard University, Stanford University, Baylor College of Medicine at the University of Texas, and at the United Nations. Sabrina believes her wheelchair is a vehicle to promote change.  

Sabrina Cohen was recognized by WebMD Magazine as a 2009 "American Health Hero”.  Sabrina is currently available for interviews highlighting the 2012 “CELLebrity” Doctors Calendar.

Tuesday, November 8, 2011

Commercializing Cell-based Regenerative Medicines


When introducing a regenerative medicine cell based product to a commercial setting, there are a number of things to take into consideration to ensure a commercially viable and safe product for patient use.

In this QandA interview by Pharma IQ, William Fodor, Director of Translational Sciences, Cell Therapy Group, gives a few insights into the commercial manufacturing scale‐up process of cell therapies.

Listen to the podcast here (registration required) or read the transcript below:

Pharma IQ: Can you give some advice on the best way for a company to develop standards for commercialization to improve safety?

W Fodor: As with any biological product, you have to do all the appropriate testing and there’s really no standards necessarily to be developed by the company because the regulatory process is pretty well outlined by the FDA and CBER. Cell therapy products are regulated by the office of Cell Tissue and Gene Therapy Division. So, it’s not that you need to develop standards for commercialization you just need to follow the regulations by demonstrating to the FDA that your product is safe, and maintains the identity, in other words, your product doesn’t change during your regular manufacturing process. Purity and potency are all assays that need to be developed within the manufacturing process for your particular cellular product.

Pharma IQ: And what are some approval processes and pitfalls to be aware of within the scale-up process?

W Fodor: As you are scaling up your process to meet clinical trial requirements and eventually commercialization, you absolutely need to maintain current good manufacturing practices, cGMP.  Typically, during a phase one, you can get away with certain reagents that may not be fully GMPs. Or in other words, if you use a growth factor or a certain media that doesn’t have or isn’t manufactured under full GMPs, as long as you test that particular reagent or media that you are using to ensure safety and sterility, you can typically get away with that in the phase one clinical trial process. But when you move to a phase two, you need to make sure that all your reagents and medias and any compounds that come in contact with your product are all manufactured under cGMP.

Pharma IQ: What are some technology transfer and patent protection concerns to be cognizant of?

W Fodor: With any cellular-based product, if there’s a technology that is out there that a company wishes to pursue, to improve yield, or the manufacturing process, you need to demonstrate that that technology fits within your manufacturing process. So typically, what is done is you’ll do validation runs to ensure that that new technology satisfies the regulatory process for your manufactured product.

With respect to patent protection, again, that company needs to maintain their IP portfolio and needs to make sure that they’re not infringing other intellectual property and that’s just standard for the industry.

Pharma IQ: And do you have any tips for ensuring quality and consistency no matter how little or how much one is producing?

W Fodor: Yes, when you manufacture a cell-based product, it’s not that much different than any other biologic product. And so, during your  manufacturing runs, whatever scale it is, you have to ensure safety, such as sterility tests for microplasma, or other adventitious agents; as well as bioburden and endotoxin.  These are all tests that  need to be performed.

You need to have an identity test to make sure that your cell product, at whatever scale you are manufacturing, that at the end of that manufacturing run, the product hasn’t changed. Again, no matter what scale you’re at, you need to make sure the identity of the product is consistent from batch to batch.

For identity, you can do a number of things for a cell-based product, if you want to look at cell surface antigens to ensure that the cell surface proteins on your cellular product don’t change over time or through your manufacturing process. And typically, what you like to do is keep it relatively simple. You don’t want to test for a hundred things because you’re just asking for the potential for something within those hundred tings to change. So typically, what you do is maybe three to four cell surface antigens to ensure your product identity is consistent. You can also run PCR tests to determine that an intracellular protein of interest doesn’t change during your manufacturing process.

You also need to ensure for purity, so you want to quantify the purity of your active cell type or your tissue type. And then potency; you need to demonstrate the product has a consistent potency and the biological activity of that final product doesn’t change during the manufacturing process.

And then typically, what you do is you archive. You archive samples from your manufacturing process. You cryopreserve those so you can always go back to ensure that that a particular batch was consistent with other batches that were manufactured.

To contact Bill for any follow-up or other questions related to cell therapies, see his contact information on the Cell Therapy Group website.

For a PDF copy of this interview, click here to download.

Friday, September 23, 2011

Cell Therapy & Regenerative Medicine Domains Available


Please pardon the crass commercial nature of this post.  I try to keep self-promotion to a minimum here but I'm looking to unload a number of domains I have the related to cell therapy and regenerative medicine and thought this might be the easiest way to get the word out.  Let me know if you are interested in any of the following:****

Funky ones:********** 

I have others - some of which are variations of ones listed above (such as with "the" in front) and would be available - some of which I'm still wanting to hold.

 * ~$1,500 
** ~$5,000 
*** ~$10,000
**** ~$20,000

Friday, September 16, 2011

Commercial-stage Cell Therapy Companies and Products


Updated 2012-03-13 update

There are a number of products in the market which are made up entirely of cells or purport to have live cells in them and as such are included in our definition of cell therapy.

Some of these have received regulatory market approval.  However, a number of these products are being legally sold, even in highly regulated markets, without overt regulatory approval because they arguably meet the requirements set out for products which do not require such approval to be marketed.

Below is sample list of companies with cell therapy products* on the market in Europe, USA, or Japan.  In some instances there are reservations about whether or not these products still contain viable cells.  Our listing of these product is not an endorsement of their market claims nor of their strict regulatory compliance.

Company                                                    Product              
Advanced BioHealing (now part of Shire)    Dermagraft
AlloSource                                                 AlloStem
Altrika                                                        MySkin
Altrika                                                        CryoSkin
Alphatec Spine                                           PureGen
Amedica                                                     BioDfactor
Arthro Kinetics                                           CaReS
Avita Medical                                             ReCell® Spray-On Skin
Bio-Tissue                                                  Prokera
Bio-Tissue                                                  AmioGraft
BioTissue Technologies                               BioSeed-C
BioTissue Technologies                               chondrotissue
Cytori                                                         Celution System
Dendreon                                                   Provenge
euroderm                                                    Epidex
euroderm                                                    EpiGraft
Fidia Farmaceuitici                                      Hyalograft 3D
Fidia Farmaceuitici                                      Laserskin
Fidia Farmaceuitici                                      Hyalograft C
Fibrocell                                                      laViv
Genzyme (a Sanofi company)                      Epicel
Genzyme (a Sanofi company)                      Carticel
Genzyme (a Sanofi company)                      MACI Implant
Japan Tissue Engineering Co.                      J-TEC Epidermis
Japan Tissue Engineering Co.                      J-TEC Cartilage                                        
Japan Tissue Engineering Co.                      J-TEC Corneal Epithelium                        
Living Cell Technologies                              DIABECELL
NuTech                                                       NuCel
NuVasive                                                    Osteocel Plus
Organogenesis                                             Appligraf
Organogenesis                                             GINTUIT
Orthofix                                                      Trinity Evolution
TiGenix                                                       ChrondroCelect
Therakos                                                     Therakos Photopheresis

Most of these are only available in one or a few jurisdictions.  Sanofi's Genzyme products (Epicel & Carticel) are two of the few which are multi-nationally available.

South Korea is an interesting example of a country with a mature regulatory framework with more than its share of approval.  There have been 14 cell therapy products approved for sale in South Korea.  They are as follows:

Company                                                    Product    
Anterogen                                                  Adipocel
Anterogen                                                  Cupistem
Antrogen                                                    Queencell
Cellontech                                                  RMS ossron
Cellontech                                                  Chondron
Chabiotech                                                 Hyalgraft-3D+
Chabiotech                                                 Autostem
Creagene                                                    Creavax-RCC+
FCB-Pharmicell                                          Heartcellgram-AMI
Innocell                                                       Immuncell-LC+
Innomedisys                                                Innolak+
MCTT                                                        Keraheal+
Medipost                                                     Cartistem
NKBio                                                        NKM+
S-Bio Medics                                              Cureskin
Tegoscience                                                 Holoderm
Tegoscience                                                 Kaloderm

+ These products were brought to market in 2006-7 under a conditional approval unique to South Korea's regulation that allows commercial sale in certain instances while a pivotal trial is underway.

At present, the Korea-FDA is assessing a Biologics License Application (BLA) for CARTISTEM® being developed by Medipost. Once approved, CARTISTEM® will become available as the World's first hUCB-MSC derived adult stem cell drug for treating osteoarthritis and will be marketed in Korea in association with Dong-A pharmaceuticals

* This list does not purport to be exhaustive of all cell therapy products legally sold in these regions.  This list  does not include approved products in other highly-regulated jurisdictions, such as Australia, New Zealand, or Singapore, for example.  This list also excludes those cell-based treatments provided as a hospital or clinic-based service such as stem cell transplantation (hospital) or Regenexx (Regeneration Sciences, Inc.).

For the purposes of this list, “cell therapy” is defined loosely as any product which has in it live cells when administered to the patient including tissue transplants and devices.

Note that some of these products may be subject to emerging regulatory restrictions under the EMA ATMP regulations which may result in them having to be pulled from the market by the end 2012 at the latest.

Several of the products on this list did not receive overt regulatory approval but are being sold in regulated markets under exemption provisions which allow companies to bring cell therapy products to market which meet certain strict criterion.  At least a couple of the products listed are the subject of dispute between the company and the FDA or other regulatory agency as to whether or not they qualify under the 'exemptions'.

If you would like to suggest any revisions or additions to this list, please do so in the comment section below.

Cell Therapy Industry Video Channel

Cell Therapy Group and BioBusiness.TV are pleased to announce they are collaborating to build a "cell therapy" video channel focused on the cell therapy industry.  The initiative is part of BioBusiness.TVs "Best of the Web" initiative intended to bring together publicly available video content that complements their original content.

The Cell Therapy channel will focus on cell-based therapeutic products which are in clinical development by or are commercially available from companies around the world.   We will update this channel frequently.

To view other video content, see Cell Therapy Group’s YouTube channel.

To recommend video content, submit your comments below.

Thursday, September 15, 2011

Potential far-reaching implications of the ongoing fight over point-of-care autologous cell therapy

The FDA recently issued an untitled letter to Parcell Laboratories and its contract manufacturing organization, New England Cryogenic Center (NECC), pertaining to the product PureGen™ Osteoprogenitor Cell Allograft intended for the "repair, replacement, reconstruction of musculoskeletal defects". The letter stated:

"The PureGen™ Osteoprogenitor Cell Allograft is not the subject of an approved biologics license application (BLA) nor is there an IND in effect. Based on this information, we have determined that your actions have violated the Act and the PHS Act."

This would appear to be an indicator that the FDA does not intend to relax enforcement of its view of how autologous cell therapies are to be regulated despite its ongoing litigation on this very subject with RSI.

As followers of this blog know, since the battle's inception in 2008 I have followed the case of Regenerative Sciences, Inc and their war with the FDA over their right to provide certain autologous cell therapy treatments to patients in certain circumstances without FDA approval. My first blog entry on the topic was in September 2008 in which I pointed out that the FDA had written a letter to RSI that July taking issue with some of their practices.

My next blog on the subject was February 2009 in which I concluded "I think the FDA is building its case and a showdown is on its way to Denver-town."

At the advice of legal counsel, I pointed out in a March 2010 blog entry that my reference to FDA's July 2008 letter to RSI was not officially a "warning letter" as that is defined and as I had referred to it but rather an "untitled letter". I also commented that FDA's lack of enforcement action against RSI to-date was emboldening medical practitioners into thinking FDA was reconsidering their position on the legality of providing autologous, expanded cells to patients outside of an FDA-cleared IND or BLA.

I took some satisfaction in announcing on my blog in August 2010 that the FDA had finally taken action against RSI. My satisfaction was not rooted in a belief that the FDA is right (I've always been agnostic as to which side is right) but in the sense that things had occurred as I had predicted they would.

The action the FDA chose to take against RSI was to seek an injunction against RSI from continuing to provide the "offending" treatment - a version of the Regenexx™ procedure using mesenchymal stem cells (“MSCs”) grown outside the body after harvest for the later infusion back into the donor-patient for the treatment of various orthopedic conditions - which the FDA alleges is a "product" falling under its regulatory authority but for which RSI has never received any FDA clearance to provide to patients.

RSI counterclaimed against the United States, challenging the FDA’s authority to regulate the Regenexx™ Procedure in question and challenging certain FDA regulations. The United States moved to dismiss Defendants’counterclaims and for summary judgment.

I have continued to follow the case relatively closely through a number of source (see this sample media coverage in OthosSpineNews) as it continued to progress. Last month, for example, a blog I follow posted an eloquent case in support of RSI's position with the help of Mary Ann Chirba, J.D., D.Sc., M.P.H. of Boston College Law School.

So it was with much interest that I was recently notified of an order issued by the court which appears to have the potential to take the case in a very unexpected direction with enormous potential ramifications.

The context is that the judge was reviewing the FDA's motion for summary judgment, RSI's response, and FDA's reply when the judge issued this order to show cause.

At its essence the Judge has ordered the FDA to file a brief no later than 26 September showing the court why the term “chemical action” applies to stem cells. It is is a short Order the core of which reads as follows:

The Government finds its definition for a “drug” in the FDCA: “The term ‘drug’means . . . articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals” and “articles (other than food) intended to affect the structure or any function of the body of man or other animals.” 21 U.S.C. § 321(g)(1)(B)&(C).

This definition, at least as to subsection (C), would be broad enough to encompass a boot on a patient’s ankle to hold it secure after ankle surgery. The Court doubts that was Congress’s intent.

Neither party references the definition for “device,” found in the statute at 21 U.S.C. § 321(h). A “device,” is a certain kind of “article” used in diagnosis, cure, mitigation, treatment or prevention of disease, 21 U.S.C. § 321(h)(2), but which, presumably unlike a drug, “does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes.” 21 U.S.C. § 321(h).

These contrasting definitions immediately raise the question of why the Court should not interpret the meaning of the word “drug” to include not only an article for use in diagnosis, etc., and intended to affect the structure or function of a patient, but also an article that “achieve[s] its primary intended purposes through chemical action” and which is “dependent upon being metabolized for the achievement of its primary intended purposes.” Id.

The United States is ORDERED TO SHOW CAUSE why the Court should not read the definition of “device” at 21 U.S.C. § 321(h) as informing and restricting the definition of “drug” at 21 U.S.C. § 321(g)(1)(B)&(C).

It will be most curious to see how the FDA argues out of the corner that many believe the Judge has painted the agency. The FDA recently defined “chemical action” in its draft "Guidance for Industry and FDA Staff: Interpretation of the Term “Chemical Action” in the Definition of Device under Section 201(h)of the Federal Food, Drug, and Cosmetic Act". What is curiously absent from the document is any mention of cells or HCT/P’s despite CBER’s approval stamp on the document.

Another line of argument centers around whether cells - notably 'stem' cells - are “metabolized" as that term is defind.

If one extrapolates the ramifications of where the court appears to be currently leaning, the implications of this judgment may have far-reaching implications for biologics in general well beyond cell therapy and certainly well beyond autologous cell therapy.

As some quite logically argue, one potential scenario is that this judge rules all biologics fail to fall within the legislative "drug" definition. The argument goes like this. The drug regulations live under title 21, which has narrow definitions for what constitutes a drug. The FDA’s authority over biologics comes from title 42, which is merely to control communicable disease transmission in transplants, with no authority to take the drug provisions from title 21 and apply them to title 42. So the agency is risking a loss of control over all biologics.

What’s curious here - and perhaps somewhat ironic for RSI at this stage - is that they only ever set out to challenge their ability to regulate autologous cells used by a physician as part of his or her medical practice yet now the FDA's authority to govern all biologics is currently under question.

The fact that I cannot fathom the courts striking FDA's jurisdiction over all biologics when the dust settles on this case does not make the arguments any less compelling and it does leave open the possibility that a lower court Judge such as the one presiding over this case may be inclined to make a ruling which essentially ensures the issues are punted to the appellate courts for a more considered ruling. In such circumstances, even if the FDA were to prevail at the end of the day (perhaps a decade down road) the uncertainty such a ruling would rain down on the sector would be commercially stifling - even if if were just limited to autologous cell therapy let alone if were any broader.

My dated and unpolished law degree can only take this analysis so far and anyone interested in some further but delightfully light and practical reading on the potential ramifications of the case could do no better than read a paper published recently by the relevant practice groups at the law firm K&L Gates entitled "Cultured Stem Cells for Autologous Use:Practice of Medicine or FDA Regulated Drug and Biological Product in which they review the case and its potential implications - the latter of which the authors are not guilty of underestimating in the following concluding sentence of their analysis:

The court’s decision will, to a large degree, dictate the types of legal strategies and business models that will be necessary to successfully perform stem cell procedures in the future.


post-script: The potential stink of commercial uncertainty wafting from this case is even more egregious when combined with the uncertainty around what to expect from the FDA in its much-anticipated and typically overdue guidance on adipose-derived cell therapies.

Rumor has it that the FDA is leaning toward considering most (if not all) means of deriving cell populations from adipose tissue (typically lipoaspirate) to be governed as what we colloquially refer to as a '351' thus taking it out of the purview of the practicing physician and into the hands of companies prepared to follow the traditional "drug development' model for new medicines. The rationale here is that the mechanical and/or enzymatic digestion required to separate the desired cell populations from the stroma take the process beyond "minimal manipulation'.

Watch for this guidance from CBER OCTGT in the weeks to come and/or any relevant rulings by the Tissue Reference Group. This would be a serious blow to those building business models around point-of-care, autologous adipose-derived cell therapy treatments.

What makes this even more interesting is the pace of which US-based medical practitioners (and/or companies supporting them) are adopting and selling autologous cell-based products, services and/or treatments for sundry indications in ways which many would argue are apparently in obvious and flagrant disregard for the FDA's regulatory authority over such treatments. Included for consideration on such a list would be the following:

IntelliCell Biosceinces


Arizona Stem Cell Center