Status: PMA pending for new version; former versions approved, but not being manufactured/marketed

Organizations involved:

Forticell Bioscience, Inc. – Manuf.; R&D; Tech.

Ortec International – Former

Cambrex Bio Science Walkersville, Inc. – Manuf.; USA mark.

Lonza Biologics plc – Parent

Cambrex Bio Science, Inc. – Parent; Former

PDI Inc. – USA mark.; Former

Advanced Tissue Sciences Inc. – Patent dispute

Organogenesis, Inc. – Patent dispute

Cross ref: See also a similar product, Apligraf (Human Skin Equivalent) (#651), particularly the Biological section, for further information about skin. See also the entries for other cultured skin products.

Description: Bilayered Cellular Matrix or OrCel is a bi-layered cellular matrix in which normal human allogeneic skin cells (epidermal keratinocytes and dermal fibroblasts) are cultured in two separate layers within a Type I bovine collagen sponge. Donor neonatal foreskin dermal fibroblasts are cultured on and within the porous sponge side of the collagen matrix, while keratinocytes from the same donor are cultured on the coated non-porous side of the collagen matrix (forming the outer epidermis after application). This resulting structure resembles human skin with an outer non-porous epidermis-like layer of cultured human keratinocyte cells and an inner dermis-like layer of cultured human fibroblast cells. The pepsin-treated, non-porous collagen on the surface of the collagen matrix prevents invasion of the inner collagen layer by the outer cultured keratinocyte cells, and ensures the compartmentalization of the skin equivalent into epidermal and dermal layers.

OrCel is approximately 0.8 mm thick, and is stronger than epidermal grafts and more easily handled during grafting. OrCel is used to cover unhealed wounds and newly created autograft sites to enhance wound closure on these sites. Specifically, its is used for donor site wounds in burn patients, i.e., the wounds created where skin is taken from an uninjured part of the body to be engrafted to cover a burned area on another part of the body. OrCel is not a human skin replacement, and does not contain Langerhans cells, melanocytes, macrophages, lymphocytes, blood vessels, or hair follicles.

OrCel is provided as sheets measuring approximately 6 cm x 6 cm (minimally 36 cm2). Non-adherent inert mesh is placed on both aspects of the device to protect the cells, with blue mesh covering the fibroblast/dermal inner surface side and white mesh covering the keratinocyte/epidermal outer side. The device is packaged in a plastic tray with protein-free packaging medium containing Dulbecco’s Modified Eagles Medium (DMEM), water for irrigation, sodium bicarbonate, folic acid solution, HEPES buffer, L-glutamine, Minimum Essential Medium (MEM) non-essential amino acids, and sodium hy-drox-ide to maintain cell viability during storage and shipping. The plastic tray is sealed within a peelable inner pouch to provide a sterile barrier against moisture and gas. The inner pouch is, in turn, sealed inside a heavier-gauge outer pouch that protects the inner pouch sterility barrier and the product against damage during shipment. The product is packed with pre-chilled gel packs and shipped by overnight courier service to the destination in a padded and insulated shipping container that maintains a temperature of 11-19˚C (for up to 72 hr.).

A newer “cryopreserved” version of Orcel has been developed and is awaiting FDA approval.

Biological.: OrCel serves as a temporary living absorbable biocompatible matrix that provides a favorable environment for host cell migration. OrCel has been shown to contain the following cell-expressed cytokines and growth factors: FGF-1 (bFGF), NGF, GM-CSF, IL-1alpha , IL-1beta, IL-6, HGF, KGF-1 (FGF-7), M-CSF, PDGF-AB, TGF-alpha , TGF-beta1, TGF-beta2, and VEGF. In an in vitro assay, OrCel stimulated the release of cytokines into culture media. DNA analysis performed on two OrCel-treated donor site patient tissue samples showed no trace of allogeneic cell DNA after 2-3 weeks.

In vivo wound closure was studied in severe combined immunodeficient (SCID) male mice and female athymic nude mice. In male SCID mice, OrCel produced approximately 60% wound contracture and complete epithelialization in eight of 12 animals. In a range-finding study using OrCel with different cell densities, a trend toward greater wound closure was observed in nude mice treated with medium and high cell density OrCel than with acellular or low cell density OrCel.

The success (“take”) rate for OrCel is approximately 90%, which may be due to the presence of the dermal layer which promotes vascularization of the graft. The bovine collagen matrix is altered, gradually broken down, and replaced by endogenous collagen as fibroblasts interact with it physically and contribute to it biosynthetically. The breakdown of this laminate layer allows rapid normalization of the interface between the epidermis and dermis.

Nomenclature: Skin, Cultured/Ortec [BIO]; Bilayered Cellular Matrix [FDA]; Interactive Wound and Burn Dressing [FDA]; OrCel [TR]; Composite Cultured Skin [TR former]; CCS [TR former]

Companies.: OrCel was being developed and is manufactured by Ortec International Inc., now Forticell Bioscience, Inc. Ortec originally used the contract marketing services and the sales force of PDI Inc. for U.S. distribution.

In Oct. 2003, Ortec concluded a 6-year agreement with Cambrex Bio Science Walkersville, Inc., a subsidiary of Cambrex Bio Science, Inc., for commercial manufacture of OrCel.

In Oct. 2004, Cambrex and Orcel modified their agreement, with Cambrex also assuming marketing, sales and distribution in the U.S. Cambrex now provides a dedicated sales force and manages the entire sales and distribution process in the U.S. In mid-2006, Cambrex’s contract manufacturing division and facilities were acquired and merged into Lonza Biologics plc. This likely did not include U.S. marketing of Orcel.

Manufacture: OrCel is manufactured under aseptic conditions by seeding the donor cells obtained from neonatal foreskin tissue from a single circumcised male infant onto collagen matrix. The donor’s mother is tested and found to be negative for syphilis and for human viruses, including cytomegalo-virus (CMV), herpes simplex virus type 1 and 2 (HSV 1 & 2), HTLV I & II, hepatitis B virus (HBV), hepatitis C virus (HCV), HIV-1 and HIV-2, Epstein-Barr virus (EBV), and human herpesvirus type 6 (HHV-6). The donor’s fibroblast and kerati-nocyte cells are tested and found to be negative for viruses and retro-viruses (including HTLV-I and -II, hepatitis B virus (HBV), HIV-1 and -2, EBV, and HHV-6), bacteria, fungi, yeast, mycoplasma, and tumorigenicity. The donor cells are tested and are found to be normal human cells using karyology, isoenzyme, growth, and morphological analyses. Prior to cell seeding, the collagen matrix is cross-linked and then coated on one side with a thin gel layer prepared from acid-soluble collagen. All animal derived reagents are tested for: viruses, bacteria, fungi, yeast, and mycoplasma before use, and all bovine material is obtained from countries free of Bovine Spongiform Encephalopathy (BSE).

OrCel is tested for morphology, cell density, cell viability, sterility, mycoplasma, and physical container integrity. OrCel is not terminally sterilized (to maintain cell viability). OrCel is shipped after a 48 hour incubation sterility test to confirm absence of microbial growth. Final (14 day incubation) sterility results are not available at the time OrCel is used.

FDA class: Medical device; PMA

Approvals: Date = 20010222; Humanitarian Device Exemption (HDE); Indication = use in patients with recessive dystrophic epidermolysis bullosa (RDEB) undergoing hand reconstruction, as well as to cover skin donor sites created during the surgery.

Date = 20010831; PMA (P010016), full approval; Indication = current burn treatment indication

Indications: [full text of the "Indications FOR USE” section of product insert/labeling]:

OrCel is indicated for the treatment of fresh, clean split thickness donor site wounds in burn patients

Status: Ortec originally received FDA approval in Feb. 2001 under a Humanitarian Device Exemption (HDE). HDE applications are exempt from the effectiveness requirements of a PMA. HDE approval allows full commercial marketing of a Humanitarian Use Device (HUD) intended to benefit patients in the treatment and diagnosis of diseases or conditions that affect or are manifested in fewer than 4,000 individuals in the U.S. per year (orphan indications:). There can be no comparable device already approved for a similar indication, and approval may be revoked when an equivalent device receives full approval. A HUD must be approved by the hospital’s Institutional Review Board (IRB) before it can be used in patients for its designated indication(s). However, the IRB does not need to review and approve individual uses. The FDA reviews the preclinical and clinical data and determines the benefits of using the product outweigh the associated risks (when no alternatives are available).

In Feb. 2001, the FDA granted Ortec an HDE for the non-cryopreserved version of OrCel for use in epidermolysis bullosa (EB) patients who suffer from Recessive Dystrophic Epidermolysis Bullosa (RDEB) undergoing hand reconstruction, a well as to cover donor sites (the area of burn patients from where skin was removed for culture or grafting from another part of the patient’s body) created during the surgery. This approval remains in effect.

Ortec filed a PMA for full medical device approval in early March 2001 for acceleration of healing of split thickness skin donor sites in burn patients. Approval was granted on Aug. 31, 2001; approval time of ~0.5 year). OrCel was launched in the first quarter 2002.

Ortec discontinued manufacture of the “fresh” form or Orcel for commercial sale and halted sales of OrCel in early 2003 to concentrate its limited resources on the completion of an ongoing pivotal Phase III trial with OrCel for the treatment of venous stasis (leg) ulcers, an indication with a much larger potential market than the currently approved indications:, using a new “cryopreserved” form of OrCel. Marketing and sales will restart and Cambrex will assume commercial manufacture of OrCel upon approval of OrCel for this new indication (originally expected 2004).

In Dec. 2003, Ortec began filing a PMA for approval of “cryopreserved” Orcel for treatment of venous leg ulcers, with submission of the manufacturing and controls section. The PMA filing was completed in Jan. 2004, and accepted on March 31, 2004.

In March 2005, Ortec provided an update concerning the Premarket Approval (PMA) for “cryopreserved” OrCel. The company asserted it has addressed all the issues raised by the FDA and clarified all the issues which were brought to its attention, some of which had been raised for the first time at a meeting just a few weeks earlier. This included providing “the result of a probability test demonstrating that there is only a 1.4 chance in 100 that the results achieved in our statistical analysis are not accurate and an analysis of the overall safety profile which demonstrates there are no statistically or clinically significant safety concerns attributed to OrCel.” The company asserts that the “PMA meets the objective criteria for approvability.”

In July 2006 Ortec submitted an HDE Supplement application requesting FDA approval to market cryopreserved OrCel for use in epidermolysis bullosa (EB) patients who suffer from Recessive Dystrophic Epidermolysis Bullosa (RDEB) undergoing hand reconstruction, a well as to cover donor sites (the area from where skin was removed for culture or grafting from another part of the patient’s body) created during the surgery.

In Sept. 2006, Ortec received an approvable letter from FDA noting that its HDE Supplement is approvable subject to an inspection by the FDA of its commercial manufacturing facility.

In Feb. 2007, Ortec filed a PMA supplement application to market cryopreserved OrCel for the treatment of venous leg ulcers, submitting to the FDA the Manufacturing and Controls (CMC) section, the first of two modules of the application. The final section of the application, which will include a summary of safety and effectiveness in the clinical studies and device labeling, was expected to be filed with the FDA in the second quarter 2007. These filings are amendments to the PMA application accepted by FDA in March 2004.

In mid-2007, the “cryopreserved” PMA and HDE are still pending, and Ortec is conducting a confirmatory trial that had been requested by FDA (see the Trials section below). A pivotal clinical trial evaluating a cryopreserved version of OrCel in the treatment of venous leg ulcers has been completed and a Pre Market Approval (PMA) application has been filed. Ortec has completed a confirmatory trial requested by the FDA, and the data from this trial are being integrated with the results of the pivotal clinical trial and submitted as a clinical supplement to the PMA.

FDA has granted Ortec approval to initiate a pivotal (Phase III) trial evaluating cryopreserved OrCel for the treatment of diabetic foot ulcers.

In July 2012, Forticell Bioscience, Inc. was still reporting the PMA filing (from 20070 as being active.

Tech. transfer: U.S. 6,039,760, Eisenberg, M., “Composite living skin equivalent,” March 21, 2000, a continuation of U.S. 5,282,859, assigned to Ortec International, describes skin equivalents and processes for preparing them. U.S. 6,638,709, assigned to Ortec, covers the freezing process for OrCel, and provided protection into 2020.

In 1996, Ortec prevailed in a U.S. patent reexamination challenge filed by Organogenesis, Inc. See the Apli-graf entry (#651) for patents held/licensed by Or-ga-no-genesis. In March 2002, Ortec successfully defended its European patent EP0526550 covering OrCel in an opposition filed with the European Patent Office by Advanced Tissue Sciences, Inc. (ATS) in Nov. 1998. See the Dermagraft entry (#652) for patents held/licensed by ATS.

In Jan. 2006, Ortec reported that Advanced Tissue Sciences (became Advanced BioHealing, Inc.) had withdrawn its appeal against the grant of Ortec’s European patent covering OrCel. Ortec was originally granted its European patent in Dec. 1997 and received notification in Nov. 1998 that it was being challenged by Advanced Tissue Sciences. In March 2002, Ortec reported it had successfully defended Advanced Tissue Sciences’ opposition filed with the European Patent office and, subsequently, Advanced Tissue Sciences again appealed the patent offices’ decision, and the appeal was later withdrawn. Withdrawal of the appeal concludes this litigation and Ortec’s European patent remains as originally issued.

Medical: The OrCel sheet is laid over the wound bed, positioned so that there is a slight overlap (~ 0.5 cm) onto intact skin. More than one sheet may be used to cover a wound surface. OrCel is then covered with a non-adherent dressing and an outer gauze wrap.

OrCel is also used off-label (unapproved uses) for treatment of skin lesions associated with epidermolysis bullosa (EB), Stevens-Johnson syndrome (SJS), toxic epidermal necro-lysis (TEN), and erythema multi-forme (EM).

Trials: The mean time to 100% wound closure in an 82-patient multicenter Phase III clinical trial evaluating skin graft donor sites was significantly shorter for OrCel-treated donor sites than for the control-treated sites. The median healing time for the donor site wounds treated with OrCel was on the average one-third shorter than control treated wounds. Treatment with OrCel resulted in statistically significant improvements in scar outcomes compared to the control therapy at weeks 12 and 24 following treatment.

Results from the pivotal Phase III trial in 136 patients supporting the pending PMA for venous leg ulcers were reported in early 2004. The median time to healing for patients given OrCel plus standard of care (the Profore bandage system) was 57 days vs. >90 days for the standard of care, (p = 0.034). Overall, 59% of Orcel patients had 100% healing at 12 weeks vs. 36% of patients receiving the standard of care (p = 0.067); and 85% of OrCel patients had no recurrence of wounds within 3 months, compared to 70% of control patients.

In July 2005, Ortec began a confirmatory trial for treatment of venous ulcers in 60 patients. The company had submitted a final version of the trial protocol to FDA. In May, FDA requested a confirmatory trial to show safety and effectiveness only in patients with venous leg ulcers. Ortec had earlier submitted data showing significance in both the intent to treat population as well as patients with ulcers. FDA believed the analysis of the patients for which OrCel was to be indicated was not prospectively defined.

In Sept. 2006, Ortec reported that a preliminary review of unaudited data of all the patients treated in its 12-week confirmatory venous leg ulcers trial indicated OrCel healed more wounds and achieved 100% wound closure of those wounds sooner in comparison to the control group, and that statistical significance was achieved for the primary clinical endpoints of incidence of patients achieving 100% wound closure as well as acceleration of wound closure. These statistically significant differentials in favor of the OrCel-treated patients were evident as early as the third week and were maintained from week five through week eleven using the statistical approach required and approved by FDA.

Ortec has completed a pivotal Phase III trial with OrCel for diabetic skin ulcers.

Disease: A slow healing skin graft donor site complicates the care of burn patients, and OrCel therapy has been shown to accelerate the healing of these wounds. Split thickness skin grafting is a frequently used technique in the management of serious burns. Once it has been determined that a burn patient will require split thickness autografting, a donor site is selected. These are areas of healthy, non-injured skin, which are harvested for autograft use, thereby leaving an open wound requiring coverage. There are many dressing options for donor sites in the postoperative period, including OrCel. The type selected depends on the size of the donor site created, the anatomic location on the body surface, and the proximity to other wounds. Common dressings include dry fine-meshed gauze, or impregnated fine-meshed gauze (e.g., with scarlet red), hydrocolloid dressings, and biologic and synthetic wound dressings.

Epidermolysis bullosa (EB) is a severe devastating congenital skin disorder characterized by painful ulcerations and widespread permanent scarring resulting in deformity of the hands and feet. Many of these patients require surgeries to allow greater use of their extremities, resulting in a need for replacement skin. Recessive Dystrophic Epidermolysis Bullosa (RDEB), the most severe form of EB, is a devastating congenital skin disorder characterized by painful ulcerations and widespread, permanent scarring resulting in deformity of the hands and feet which require repeated surgeries and result in a need for replacement skin, such as OrCel.

Market: From Dec. 2001 through Dec. 2002, gross revenues from sales of OrCel were $265,665. Marketing was halted in early 2003 [to concentrate on trials and approval of “cryopreserved” Orcel for venous stasis (leg) ulcers]. As of mid-2007, cryopreserved Orcel had not yet been approved or formally (re)launched by Cambrex.

The 2007 Average Wholesale Price (AWP) is $1,250.00/sheet, with a Direct Price (Manufacturer’s discount prince) of $1,250.00/sheet (Red Book, 2007; unchanged from 2004).

The Center for Medicare Services (CMS; Medicare) reimbursement rate during 2006 was ~$1,100 per unit.

Over 1.25 million people are treated annually for burns at U.S. medical facilities. Ortec reports donor site wounds represent a potential market over $100 million/year.

R&D: Ortec has completed a pivotal Phase III trial with OrCel for diabetic skin ulcers. Along with its prior approved burn-related and pending venous leg ulcer indications:, OrCel has been estimated by the company to have a potential market in excess of $1 billion/year. However, such cellular therapies have had difficulty gaining acceptance and, as shown by other products in this section, sales of most such products remain small by pharmaceutical standards.