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Post by tradeup on Nov 21, 2014 22:04:57 GMT
What Master Line(s) will Ocata ultimately use to commercialize with? MA09-hRPE, to be used in Phase 2 trials, may not be a licensable product in the US. Speculation is that a xeno-free NED (No Embryo Destroyed) line will be introduced prior to Phase 3. Ocata's NED-7 Master Cell Bank is already in place. Another possibility is the creation of a NED line utilizing a new and improved "uncontroversial" IVF/PGD technique (see: UCSF method; ACT mentioned) via a cGMP IVF laboratory. Once the MA09-hRPE line proves itself in the clinic (safety and efficacy), switching to a NED line would be a manufacturing decision. To this date, it appears the company has kept confidential the methods used to create NED-7 (other than referencing the single-blastomere process). If we are waiting until 2018-2020 for an approved product, there is plenty of time to make the switch. Note: Ocata obtained an exclusive license from StemLifeLine (patent) to commercialize and sub-license single-blastomere lines. However, through the same agreement, Ocata is limited to non-exclusive rights to distribute hESC cell lines through stem cell banks like Roslin Cells which means they would share a portion of those revenue/royalties with StemLifeLine.The delay in introducing the NED line(s) may relate to any or all of the following: 1) donor eligibility/consent documentation issues, 2) creation of entirely new NED line(s), 3) regulatory uncertainty both in the US and Europe, and 4) completion of Phase 1 and 2 to ensure safety and demonstrate efficacy. Does Ocata intend to utilize MA09 for European-only use and introduce NED line(s) in P3 US studies? Potential issues regarding licensure of MA09 (US-focused): 1) Full donor eligibility and consent requirements; potential label restrictions 2) Non-GMP environment (IVF clinic); hESC-RPE derived and banked under cGMP conditions, but MA09 not sourced under cGMP 3) Involved the destruction of an embryo (less marketable, regulatory risk) --- 1) Full donor eligibility and consent requirements; potential label restrictions, and 2) Non-GMP environment (IVF clinic); hESC-RPE derived and banked under cGMP conditions, but MA09 not sourced under cGMP. When MA09 was created, GMP IVF laboratories did not exist and donor consent and eligibility requirements were non-existent or inadequate compared to today's standards. In the case of MA09, early development translated to xeno-contamination during the in vitro derivation and propagation of the cells. For reference, here is a 2007 Nature paper on the topic: Xeno-free derivation and culture of human embryonic stem cells: current status, problems and challenges << To develop a clinical-grade hESC line, it is a prerequisite to show that all steps in the derivation, passaging and culturing of hESC are completely free of animal products. >> The FDA accepted Ocata's MA09-hRPE biologic on the basis of extensive safety testing. According to Ocata's 2009 paper: Long-Term Safety and Function of RPE from hESCs, the RPE-derivation process was "augmented" to meet FDA compliance to be included in clinical trials: << Here we augmented previously published RPE-derivation protocols [9], implementing appropriate controls around the cell manufacturing and documentation process to achieve full compliance with the cGMPs/cGTPs. hESC-RPE cell lines were prepared for clinical application and tested for safety and efficacy in several different in vitro and animal models. >> My interpretation of the above is the cGMP/cGTP compliance pertains to the RPE-derivation protocols, but not the MA09 line itself. This remains a gray area in terms how the regulatory authorities views this, but comments on this topic at a 2014 annual International workshop (hosted by CIRM) seems to imply this could be a problem: << the guidance raises the question of suitability of material sourced from a non-GMP environment such as in vitro fertilization clinics. The donor testing and screening required by this guidance is not currently consistent with hESC-derivation procedures. Examples were provided of hESC-derived cell therapies that had apparently not met the full donor eligibility requirements but had, to date, been able to enter early phase clinical trials in the U.S. It is unclear whether these cell lines will be suitable for licensure. >> << Whiting and Carpenter also raised the issue of the timing for using good manufacturing practices throughout a product’s life cycle. Some early cell lines now in the development pipeline were not derived under cGMP conditions but were banked under cGMP conditions. >> In Bullard's recent SA article, there is an interesting quote from Dr. West of BioTime (competitor and former CSO of ACT) claiming: "the FDA allows clinical trials on products that cannot document prion status but to license the product you have to have documentation of prion status." And this extensive upfront donor testing and documentation did not exist when MA09 was created. According to the FDA, there are currently no FDA-licensed, approved, or cleared donor screening tests for prions. It appears the FDA guidelines allowed MA09 to be approved for clinical trials in part because of an exemption for lines created prior to May, 2005. MA09 appears to have been approved on the basis of 1997 guidelines when documentation of prion status, in particular, were not a requirement and neither was donor consent and extensive documentation. See current: FDA guidelines on Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based ProductsFDA guidance applies to cells and tissues procured on or after the effective date of the regulations contained in 21 CFR part 1271, subpart C (effective date May 25, 2005). This guidance replaces the guidance of the same title, dated February 27, 2007. This guidance does not replace the guidance concerning 21 CFR part 1270, entitled "Guidance for Industry: Screening and Testing of Donors of Human Tissue Intended for Transplantation," (Ref. 2), which remains applicable to tissues recovered before May 25, 2005 and subject to 21 CFR part 1270. The 1997 FDA Guidelines, in place when MA09 was created, do not include requirements for donor documentation of prion status. If MA09 were to be approved as a licensable product, could the following product label requirement apply? According to the FDA Tissue Donor Guidance, a product from an incompletely tested donor (with exceptions to this rule) would have to be labeled, "NOT EVALUATED FOR INFECTIOUS SUBSTANCES." << For HCT/Ps excepted under § 1271.90(a)(1 through 4), if you do not test and screen a donor, then under § 1271.90(b)(2) you must label the HCT/Ps from that donor "NOT EVALUATED FOR INFECTIOUS SUBSTANCES" unless you have performed all otherwise applicable screening and testing under §§ 1271.75, 1271.80, and 1271.85. For instance, if you perform some but not all of the testing and screening that would otherwise be required in these sections, or if you do not use a registered, CLIA-certified laboratory, or FDA licensed, cleared, or approved donor screening tests, this label would apply. This label would not apply to reproductive cells and tissue labeled in accordance with § 1271.90(b)(6). >> ### CC comments for reference: (CC, Nov 8, 2012) Rabin: NED7 is our embryo-sparing and a xeno-free line. We now have the master cell bank in place for this line, and we plan to use it in future clinical trials, as well as for the commercial production of our RPE therapy. (2013 10K) The hESC line that we currently anticipate using for commercial manufacturing of our hESC-derived therapeutic cells doses is a line created in 2005 and termed "NED-7" (ASM 2013 Transcript, Re: NED lines) Lanza: << We have created the NED-7 Master Cell Bank. That's the line that was created from our single-blastomere technology, so no embryos were destroyed. There were no mouse feeders so it is no longer a xeno product and just to give you an idea of numbers here, our Master Cell Bank is 500 vials. We took just a few of those to create a working cell bank that has 260 vials and from that we just took two vials to create 800 bottles of RPE and that is enough for 800 patients and we could have easily made more from just those two vials. And so we are currently now waiting for manufacture and regulatory sign off on that. >> Rabin: << We've been working through trying to get all of the documentation associated with NED-7 so that it can be a licensable product, it's called licensure. And we're working through all those issues. It relates to consents from the original donors. It relates to the source of the cells, making sure they have been tested for a whole bunch of things that people didn't test for back in 2005 when those lines were developed. So it is our goal to get NED-7 to be a licensable product. But as we sit here today, I can't guarantee you that that will be the line we use. We are looking at the same time about the possibility of just developing another line using the single blastomere program where we've got clear consents, clear testing all the way through, because the last thing we would want to do would be to get all the way to Phase III and then have the FDA tell us we've got a licensure issue. So we are dotting all those i's and crossing all those t's right now. I think it's safe to say that five years ago this company didn't take record keeping and processing as seriously as we do now, and we want to make sure that we don't miss anything, because we don't want to spend hundreds of millions of dollars, be ready to approve, be ready to commercialize and then find out we have to change the cell lines and bridge to it >>
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horus
Junior Member
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Post by horus on Nov 21, 2014 23:38:42 GMT
"Do the requirements in the current good tissue practice rule apply to HCT/Ps recovered before the effective date? The requirements apply to HCT/Ps recovered on or after the effective date. We have amended part 1270 by modifying the definition of human tissue intended for transplantation [1270.3(j)] to limit its applicability to tissue collected before May 25, 2005." - www.fda.gov/BiologicsBloodVaccines/TissueTissueProducts/QuestionsaboutTissues/ucm102994.htm"Two comments opposed the retrospective application of any regulation or guidance to tissue recovered before its issuance, because tissue may have a shelf life of up to 5 years. The comments suggested that the final rule should apply to HCT/Ps recovered after the effective date, and that for tissues recovered before the effective date of the final rule, the regulations in part 1270 would continue to apply. (Response) We agree that the final rule will apply to HCT/Ps recovered on or after the rule's effective date. Cells and tissue recovered before that date are subject to the regulations in effect at the time of recovery. The regulations in part 1270 are being amended in this rulemaking so that those regulations will continue to apply only to human tissue for transplantation recovered before the effective date of this rule. See section IV.B of this document for further discussion." - www.gpo.gov/fdsys/pkg/FR-2004-11-24/html/04-25798.htm
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Post by HeyNow on Nov 21, 2014 23:40:35 GMT
As far as i can tell, you literally did not make or even attempt to make one arguement that MA09 cant be commercialized or isnt suitable for licensure. In fact, you pretty much laid out a roadmap for precisely how and why they could commercialize it.
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Post by HeyNow on Nov 21, 2014 23:45:07 GMT
And by the way... MA09 is cultured for three passages on MEFs everytime an RPE batch is made. Its a xenotransplant product whether they used MA09 or not. The RPE differentiation process you acknowledge to be cGMP compliant is in itself a source of xeno exposure.
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Post by Keybridge - Cult Member 003 on Nov 22, 2014 3:22:53 GMT
"In Bullard's recent SA article, there is an interesting quote from Dr. West of BioTime (competitor and former CSO of ACT) claiming: "the FDA allows clinical trials on products that cannot document prion status but to license the product you have to have documentation of prion status." And this extensive upfront donor testing and documentation did not exist when MA09 was created."
Granted, sometimes government regulations can be contradictory or work at cross purposes, but logic eventually has to prevail. If the FDA is concerned about the risk to public safety from prions per the licensure requirements, then why would they permit exposure to 100s or 1000s of trial patients to prions, and presumably to the diseases that results? Actually, the number of trial patients that could be potentially exposed to prions (given the presumed concern by FDA in your analysis) would be unlimited since all biologics in trials would be subject to the same rules.
It's also been pointed out that cell cultures can be tested for priors.
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Post by tradeup on Nov 22, 2014 16:31:44 GMT
And by the way... MA09 is cultured for three passages on MEFs everytime an RPE batch is made. Its a xenotransplant product whether they used MA09 or not. The RPE differentiation process you acknowledge to be cGMP compliant is in itself a source of xeno exposure. The FDA disagrees. It is only a xenotransplant product when animal feeder is used in the process, as was the case when MA09 was derived. In contrast, the NED-7 line is indeed "xeno-free," but perhaps without full donor documentation. FDA: << Xenotransplantation: For the purpose of this document, any procedure that involves the transplantation, implantation, or infusion into a human recipient of either (a) live cells, tissues, or organs from a nonhuman animal source, or (b) human body fluids, cells, tissues or organs that have had ex vivo contact with live nonhuman animal cells, tissues or organs. >> There is no question MA09-hRPE is in compliance with current good manufacturing practices, otherwise the clinical trial wouldn't have been approved, however in terms of licensure it's not so clear cut. Because MA09-hRPE qualifies as a 'more-than-minimally manipulated cell therapy product' there are additional requirements which must be met prior to commercialization, namely cGTP donor suitability (See: Table 2): - cGTP establishment registration, product listing - cGTP donor suitability criteria- cGTP manufacturing requirements - cGMP regulations (biologics, drugs) The point I was making above, and it is supported by some in the industry, is that regardless of MA09-hRPE being "augmented" at a later date to meet cGMP standards for clinical use, this doesn't change the fact when the line was derived it was create under non-GMP conditions. And it appears the FDA would have to make an exception to approve for licensing. That's a big risk. On the other hand, licensure also takes into consideration trial data accumulated that demonstrates product safety. FDA: Guidance for Industry: Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of Xenotransplantation Products in HumansMANUFACTURING AND PROCESS-RELATED GMP CONSIDERATIONS FOR HARVEST AND PROCESSING OF XENOTRANSPLANTATION PRODUCTS General Considerations You should use facilities for the harvest and/or processing of xenotransplantation products that have been designed to minimize the potential for contamination of the harvested and/or processed xenogeneic cells, tissue, or organs and cross-contamination between lots of these cells, tissues, or organs. For sponsors of investigational trials, you should phase in the validation activities described in this section during the investigational phase, as the clinical studies progress toward submission of an application for approval to market (e.g., BLA). The exception to this is sterility assurance validation, which you should complete before initiating clinical trials. Manufacturing process controls should be in adherence to cGMP regulations (21 CFR Parts 210 and 211). The IND regulations (21 CFR 312.23(a)(7)) allow that some controls may be introduced as appropriate for the phase of development. Process Validation Ultimately, before licensure or product approval, you should validate all critical processes used to manufacture the product. We have previously defined process validation (reference 11). We expect that process validation, when performed, will be prospective and at full scale, with the exception of studies performed to demonstrate viral clearance (removal/inactivation). Laboratory studies may also help to establish appropriate operating and process parameters and may be used in support of the formal study. We expect that information on the validation protocol(s) and summaries of data resulting from its execution will be included in the license application. www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Xenotransplantation/ucm074354.htm#f11Lot: Defined in 21 CFR 210.3(b)(10) as a batch, or a specific identified portion of a batch, having uniform character and quality within specified limits, and in 21 CFR 600.3(x) as that quantity of uniform material identified by the manufacturer as having been thoroughly mixed in a single vessel. Each lot of final product is subjected to appropriate tests to ascertain adherence to specifications prior to release of the product for clinical use. Licensed biological products may be subject to lot release as described in 21 CFR 610.2(a). Often in the case of xenotransplantation products, an entire lot is used for treating a single recipient. --- www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=610.2Title 21, Volume 7 Revised as of April 1, 2014 CITE: 21CFR610.2 TITLE 21--FOOD AND DRUGS CHAPTER I--FOOD AND DRUG ADMINISTRATION DEPARTMENT OF HEALTH AND HUMAN SERVICES SUBCHAPTER F--BIOLOGICS PART 610 -- GENERAL BIOLOGICAL PRODUCTS STANDARDS Subpart A--Release Requirements Sec. 610.2 Requests for samples and protocols; official release. (a) Licensed biological products regulated by CBER. Samples of any lot of any licensed product together with the protocols showing results of applicable tests, may at any time be required to be sent to the Director, Center for Biologics Evaluation and Research (see mailing addresses in 600.2 of this chapter). Upon notification by the Director, Center for Biologics Evaluation and Research, a manufacturer shall not distribute a lot of a product until the lot is released by the Director, Center for Biologics Evaluation and Research: Provided, That the Director, Center for Biologics Evaluation and Research, shall not issue such notification except when deemed necessary for the safety, purity, or potency of the product. ### It's probably also worth noting that Chris Mason* favorited this tweet from Alexey Bersenev (expert in clinical applications of stem cells): Alexey Bersenev @cells_nnm Nov 17 West of BioTime: The advantage of OpRegen over $OCAT or $STEM products is a donor material testing for prions*Chris Mason is an international expert on the translational and commercialization of reg med and was voted No. 3 in ‘Top 50 Most Influential People on Stem Cells Today’ - Terrapinn Poll, March 2013, one spot ahead of Lanza.
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Post by actcrazy on Nov 22, 2014 16:40:30 GMT
People have parts of animals sewn into them everyday.....how can that be? ie; heart valves, arteries and veins to name a few.
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horus
Junior Member
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Post by horus on Nov 22, 2014 17:17:19 GMT
"Whiting noted that there may be donor-eligibility issues in using therapies in the U.S. that were derived from non-U.S. cell lines. In particular, it was unclear whether the FDA guidance precluded the use of European-derived materials in the U.S. due to the perceived potential for transmissible spongiform encephalopathy (TSE) prion risk. Because there is no approved assay for TSE, the FDA may require different cell lines for material destined for use in the U.S., and this could be a major barrier to European companies performing clinical studies in the U.S. and, ultimately, commercializing the product."
So as I understand it there is no FDA approved screening assay for prions and thus it is not listed as one of the infectious diseases that need to be screened. In addition Ocata has said they are working very closely with the FDA and that the FDA has been very supportive. I would think that it's a complete non-issue especially considering that the safety trials have proven that there is no prion risk, or any other risks for that matter with the MA-09 cell line. The FDA I'm sure has scarcely seen safety data this good before for any drug.
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Post by HeyNow on Nov 22, 2014 18:18:48 GMT
And by the way... MA09 is cultured for three passages on MEFs everytime an RPE batch is made. Its a xenotransplant product whether they used MA09 or not. The RPE differentiation process you acknowledge to be cGMP compliant is in itself a source of xeno exposure. The FDA disagrees. It is only a xenotransplant product when animal feeder is used in the process, as was the case when MA09 was derived. In contrast, the NED-7 line is indeed "xeno-free," but perhaps without full donor documentation. FDA: << Xenotransplantation: For the purpose of this document, any procedure that involves the transplantation, implantation, or infusion into a human recipient of either (a) live cells, tissues, or organs from a nonhuman animal source, or (b) human body fluids, cells, tissues or organs that have had ex vivo contact with live nonhuman animal cells, tissues or organs. >> There is no question MA09-hRPE is in compliance with current good manufacturing practices, otherwise the clinical trial wouldn't have been approved, however in terms of licensure it's not so clear cut. Because MA09-hRPE qualifies as a 'more-than-minimally manipulated cell therapy product' there are additional requirements which must be met prior to commercialization, namely cGTP donor suitability (See: Table 2): - cGTP establishment registration, product listing - cGTP donor suitability criteria- cGTP manufacturing requirements - cGMP regulations (biologics, drugs) The point I was making above, and it is supported by some in the industry, is that regardless of MA09-hRPE being "augmented" at a later date to meet cGMP standards for clinical use, this doesn't change the fact when the line was derived it was create under non-GMP conditions. And it appears the FDA would have to make an exception to approve for licensing. That's a big risk. On the other hand, licensure also takes into consideration trial data accumulated that demonstrates product safety. FDA: Guidance for Industry: Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of Xenotransplantation Products in HumansMANUFACTURING AND PROCESS-RELATED GMP CONSIDERATIONS FOR HARVEST AND PROCESSING OF XENOTRANSPLANTATION PRODUCTS General Considerations You should use facilities for the harvest and/or processing of xenotransplantation products that have been designed to minimize the potential for contamination of the harvested and/or processed xenogeneic cells, tissue, or organs and cross-contamination between lots of these cells, tissues, or organs. For sponsors of investigational trials, you should phase in the validation activities described in this section during the investigational phase, as the clinical studies progress toward submission of an application for approval to market (e.g., BLA). The exception to this is sterility assurance validation, which you should complete before initiating clinical trials. Manufacturing process controls should be in adherence to cGMP regulations (21 CFR Parts 210 and 211). The IND regulations (21 CFR 312.23(a)(7)) allow that some controls may be introduced as appropriate for the phase of development. Process Validation Ultimately, before licensure or product approval, you should validate all critical processes used to manufacture the product. We have previously defined process validation (reference 11). We expect that process validation, when performed, will be prospective and at full scale, with the exception of studies performed to demonstrate viral clearance (removal/inactivation). Laboratory studies may also help to establish appropriate operating and process parameters and may be used in support of the formal study. We expect that information on the validation protocol(s) and summaries of data resulting from its execution will be included in the license application. www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Xenotransplantation/ucm074354.htm#f11Lot: Defined in 21 CFR 210.3(b)(10) as a batch, or a specific identified portion of a batch, having uniform character and quality within specified limits, and in 21 CFR 600.3(x) as that quantity of uniform material identified by the manufacturer as having been thoroughly mixed in a single vessel. Each lot of final product is subjected to appropriate tests to ascertain adherence to specifications prior to release of the product for clinical use. Licensed biological products may be subject to lot release as described in 21 CFR 610.2(a). Often in the case of xenotransplantation products, an entire lot is used for treating a single recipient. --- www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=610.2Title 21, Volume 7 Revised as of April 1, 2014 CITE: 21CFR610.2 TITLE 21--FOOD AND DRUGS CHAPTER I--FOOD AND DRUG ADMINISTRATION DEPARTMENT OF HEALTH AND HUMAN SERVICES SUBCHAPTER F--BIOLOGICS PART 610 -- GENERAL BIOLOGICAL PRODUCTS STANDARDS Subpart A--Release Requirements Sec. 610.2 Requests for samples and protocols; official release. (a) Licensed biological products regulated by CBER. Samples of any lot of any licensed product together with the protocols showing results of applicable tests, may at any time be required to be sent to the Director, Center for Biologics Evaluation and Research (see mailing addresses in 600.2 of this chapter). Upon notification by the Director, Center for Biologics Evaluation and Research, a manufacturer shall not distribute a lot of a product until the lot is released by the Director, Center for Biologics Evaluation and Research: Provided, That the Director, Center for Biologics Evaluation and Research, shall not issue such notification except when deemed necessary for the safety, purity, or potency of the product. ### It's probably also worth noting that Chris Mason* favorited this tweet from Alexey Bersenev (expert in clinical applications of stem cells): Alexey Bersenev @cells_nnm Nov 17 West of BioTime: The advantage of OpRegen over $OCAT or $STEM products is a donor material testing for prions*Chris Mason is an international expert on the translational and commercialization of reg med and was voted No. 3 in ‘Top 50 Most Influential People on Stem Cells Today’ - Terrapinn Poll, March 2013, one spot ahead of Lanza. Ned-7 may be xeno-free but the process actc uses to go from hesc to hesc-rpe involves culturing on MEFs... you can read that in every paper they describe the protocol. Therefore the final RPE product isnt xeno-free, regardless of the starting hESC line, unless they change their RPE derivation method
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Post by HeyNow on Nov 22, 2014 18:34:01 GMT
As a more general point, you have only been able to show that OCAT needs extensive documentation and safety data for FDA approval and commercialization. How is this news at all? Also, OCAT says explicitely the cells they are using are fully cGMP AND cGTP comlpliant. Not sure why you are even trying to suggest they aren't by some mysterious interpretation of the word "augment"
Youve recently said MA09 can not be commercialized and also explicitely said they were not cGMP compliant (which thankfully youve walked back from after learning you were wrong). Such definitive statements without any convincing evidence is a little irresponsible. Are you at least willing to agree with this more conservative, revised statement: "Ocata can commercialize ma09-RPE so long as they satisfy the necessary paperwork, requirements, and safety criteria set forth by FDA"? If you think they cannot succeed in that so be it, but you admit your conclusion is based on your own interpretation of things like "augment" and influenced by quotes from michael west and others.
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Post by tradeup on Nov 22, 2014 19:06:33 GMT
Ned-7 may be xeno-free but the process actc uses to go from hesc to hesc-rpe involves culturing on MEFs... you can read that in every paper they describe the protocol. Therefore the final RPE product isnt xeno-free, regardless of the starting hESC line, unless they change their RPE derivation method Claim #32 of the RPE patent specifically allows for xeno-free differentiation of hES cells into RPE USPTO: 8,268,30332. The method of claim 28, wherein step (b) comprises culturing said EB in the absence of feeder cells.We don't know much about the protocol used to create NED-7, but perhaps when the line is introduced they will also culture the RPE without mouse feeders (per Claim 32).
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Post by tradeup on Nov 22, 2014 19:32:32 GMT
Youve recently said MA09 can not be commercialized and also explicitely said they were not cGMP compliant (which thankfully youve walked back from after learning you were wrong). Such definitive statements without any convincing evidence is a little irresponsible. I could have worded it better to avoid confusion, but I don't view the claim as irresponsible at all. I think you are being a bit fanatical about this. My point was MA09 apparently was not derived under full cGMP conditions, because the IVF clinic was not a cGMP IVF laboratory during the PGD screening (single-blastomere method). And the experts seem to agree ... << Examples were provided of hESC-derived cell therapies that had apparently not met the full donor eligibility requirements but had, to date, been able to enter early phase clinical trials in the U.S. It is unclear whether these cell lines will be suitable for licensure. >> << Whiting and Carpenter also raised the issue of the timing for using good manufacturing practices throughout a product’s life cycle. Some early cell lines now in the development pipeline were not derived under cGMP conditions but were banked under cGMP conditions. >>
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horus
Junior Member
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Post by horus on Nov 22, 2014 20:12:59 GMT
Youve recently said MA09 can not be commercialized and also explicitely said they were not cGMP compliant (which thankfully youve walked back from after learning you were wrong). Such definitive statements without any convincing evidence is a little irresponsible. I could have worded it better to avoid confusion, but I don't view the claim as irresponsible at all. I think you are being a bit fanatical about this. My point was MA09 apparently was not derived under full cGMP conditions, because the IVF clinic was not a cGMP IVF laboratory during the PGD screening (single-blastomere method). And the experts seem to agree ... << Examples were provided of hESC-derived cell therapies that had apparently not met the full donor eligibility requirements but had, to date, been able to enter early phase clinical trials in the U.S. It is unclear whether these cell lines will be suitable for licensure. >> << Whiting and Carpenter also raised the issue of the timing for using good manufacturing practices throughout a product’s life cycle. Some early cell lines now in the development pipeline were not derived under cGMP conditions but were banked under cGMP conditions. >> But once again it's irrelevant due to the amendment to regulation 1270 which limits cGMP applicability to tissue collected before May 25, 2005. In other words the FDA is not going to backtrack on the approval of a company's primary platform after approval had previously been granted and transmissible diseases are shown to not be an issue with the line via a stellar safety profile to date.
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Post by tradeup on Nov 22, 2014 20:35:21 GMT
But once again it's irrelevant due to the amendment to regulation 1270 which limits cGMP applicability to tissue collected before May 25, 2005. In other words the FDA is not going to backtrack on the approval of a company's primary platform after approval had previously been granted and transmissible diseases are shown to not be an issue with the line via a stellar safety profile to date. Who said they were going to backtrack approval? No license has been approved. Approval to conduct clinical trials vs licensure are two different things. This point has been made a number of times. West re: MA09: "the FDA allows clinical trials on products that cannot document prion status but to license the product you have to have documentation of prion status."Experts in the field seem to agree with the above. Do you think Chris Mason would have favorited the post if he disagreed? Professor Chris Mason is internationally recognised to be at the forefront of the emerging fields of cell therapy and regenerative medicine translation and commercialization. A background in basic science, clinical medicine, bioprocessing and business allows Chris a unique insight and understanding of the challenges facing the cell-based therapy sector as it grows into a competitive and sustainable global healthcare industry. Chris holds a Clinical Sciences degree from Imperial College London, a Medical degree from the United Medical and Dental Schools of Guy’s and St. Thomas’s Hospitals (now King’s College London) and a PhD under the supervision of Prof. Peter Dunnill in tissue-engineering bioprocessing from University College London. Chris is on a number of national and international committees, working groups and initiatives related to the academic, clinical and commercial advancement of cell-based therapies and tissue engineering including; Chair of the BIA Cell Therapy & Regenerative Medicine Industry Group and member of the ISSCR Industry Committee, the Alliance for Regenerative Medicine (ARM) Communication & Education Committee and ISCT Commercialization Committee. In May 2012, he became the first President of The Regenerative Medicine Coalition. He is a Senior Partner at Proteus Venture Partners, has a broad range of expertise in commercial consultancy and is on the Scientific Advisory Boards of a number of companies.
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horus
Junior Member
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Post by horus on Nov 22, 2014 20:58:25 GMT
Sorry I should have written: "In other words the FDA is not going to deny licensure of a company's primary platform after approval (of trials) had previously been granted and transmissible diseases are shown to not be an issue with the line via a stellar safety profile to date."
In my opinion it is implied that when trials (of any product) begin, that there is a reasonable assumption that the product is intended to be marketed. The FDA is concerned with safety and as long as that is demonstrated then commercialization can occur. I have no doubt that the amendment to regulation 1270 was done in large part for ACT/OCATA as a first mover. To allow trials to continue knowing that licensure would be impossible seems like a long shot and I believe the purpose of the amendment.
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Post by Keybridge - Cult Member 003 on Nov 22, 2014 21:08:42 GMT
But once again it's irrelevant due to the amendment to regulation 1270 which limits cGMP applicability to tissue collected before May 25, 2005. In other words the FDA is not going to backtrack on the approval of a company's primary platform after approval had previously been granted and transmissible diseases are shown to not be an issue with the line via a stellar safety profile to date. Who said they were going to backtrack approval? No license has been approved. Approval to conduct clinical trials vs licensure are two different things. This point has been made a number of times. West re: MA09: "the FDA allows clinical trials on products that cannot document prion status but to license the product you have to have documentation of prion status."Experts in the field seem to agree with the above. Do you think Chris Mason would have favorited the post if he disagreed? Professor Chris Mason is internationally recognised to be at the forefront of the emerging fields of cell therapy and regenerative medicine translation and commercialization. A background in basic science, clinical medicine, bioprocessing and business allows Chris a unique insight and understanding of the challenges facing the cell-based therapy sector as it grows into a competitive and sustainable global healthcare industry. Chris holds a Clinical Sciences degree from Imperial College London, a Medical degree from the United Medical and Dental Schools of Guy’s and St. Thomas’s Hospitals (now King’s College London) and a PhD under the supervision of Prof. Peter Dunnill in tissue-engineering bioprocessing from University College London. Chris is on a number of national and international committees, working groups and initiatives related to the academic, clinical and commercial advancement of cell-based therapies and tissue engineering including; Chair of the BIA Cell Therapy & Regenerative Medicine Industry Group and member of the ISSCR Industry Committee, the Alliance for Regenerative Medicine (ARM) Communication & Education Committee and ISCT Commercialization Committee. In May 2012, he became the first President of The Regenerative Medicine Coalition. He is a Senior Partner at Proteus Venture Partners, has a broad range of expertise in commercial consultancy and is on the Scientific Advisory Boards of a number of companies. "West is considered to be a pioneer in the field of human embryonic stem cell. He founded Menlo Park-based Geron and also worked with Alameda-based Advanced Cell Technology. "Mike is a great visionary in this field who has always been way ahead of the curve in his thinking," said Chris Mason, a professor at University College London in England, who collaborated with West on the project. "And of all that he's done, this might be one of the most important." Just a wild guess, but Mason has a close relationship with West, and may be just showing support to West. Not sure I would read anything into Mason's retweet, other than a pat on the back.
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Post by tradeup on Nov 22, 2014 21:11:15 GMT
Sorry I should have written: "In other words the FDA is not going to deny licensure of a company's primary platform after approval (of trials) had previously been granted and transmissible diseases are shown to not be an issue with the line via a stellar safety profile to date."In my opinion it is implied that when trials (of any product) begin, that there is a reasonable assumption that the product is intended to be marketed. The FDA is concerned with safety and as long as that is demonstrated then commercialization can occur. I have no doubt that the amendment to regulation 1270 was done in large part for ACT/OCATA as a first mover. To allow trials to continue knowing that licensure would be impossible seems like a long shot and I believe the purpose of the amendment. I understand and agree it probably should be that way, but you do realize this contradicts what both experts in the field are saying and what Rabin stated last year. Rabin (2013): << We've been working through trying to get all of the documentation associated with NED-7 so that it can be a licensable product, it's called licensure. And we're working through all those issues. It relates to consents from the original donors. It relates to the source of the cells, making sure they have been tested for a whole bunch of things that people didn't test for back in 2005 when those lines were developed. So it is our goal to get NED-7 to be a licensable product. But as we sit here today, I can't guarantee you that that will be the line we use. We are looking at the same time about the possibility of just developing another line using the single blastomere program where we've got clear consents, clear testing all the way through, because the last thing we would want to do would be to get all the way to Phase III and then have the FDA tell us we've got a licensure issue. So we are dotting all those i's and crossing all those t's right now. I think it's safe to say that five years ago this company didn't take record keeping and processing as seriously as we do now, and we want to make sure that we don't miss anything, because we don't want to spend hundreds of millions of dollars, be ready to approve, be ready to commercialize and then find out we have to change the cell lines >>
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Post by actcrazy on Nov 22, 2014 21:27:53 GMT
University College London , isn't that where Prof. P. Coffey is working out of? hmm? Now, this well connected in the Reg. Med. field Chris Mason who is also a senior partner at Proteus Venture, might have an agenda? Disclosure; I'm not a fan of Dr. West. All fishy smelly..imo. Go OCAT
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Post by HeyNow on Nov 22, 2014 21:32:19 GMT
Ned-7 may be xeno-free but the process actc uses to go from hesc to hesc-rpe involves culturing on MEFs... you can read that in every paper they describe the protocol. Therefore the final RPE product isnt xeno-free, regardless of the starting hESC line, unless they change their RPE derivation method Claim #32 of the RPE patent specifically allows for xeno-free differentiation of hES cells into RPE USPTO: 8,268,30332. The method of claim 28, wherein step (b) comprises culturing said EB in the absence of feeder cells.We don't know much about the protocol used to create NED-7, but perhaps when the line is introduced they will also culture the RPE without mouse feeders (per Claim 32). Yeah perhaps... of course that is a patent claim, which says literally nothing about how the RPE are or have been or will continue to be derived. For that youd have to read the materials/methods in their papers. The RPE are derived using mouse feeders.
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horus
Junior Member
Posts: 96
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Post by horus on Nov 22, 2014 21:33:04 GMT
I guess what I am really questioning is this issue of prions that keeps coming up. The FDA recommends screening (ie Questionnaire) of donors for TSE's but as there is no FDA approved assay to actually test for TSE's then it is simply a series of questions for the donor: Persons who have been diagnosed with vCJD or any other form of CJD (Refs. 3 and 75).
Note: Numbers 19 to 26 in this section are designed to screen for TSEs, including CJD and vCJD. If the living donor or the individual knowledgeable about the donor’s medical and travel history is not familiar with the term “Creutzfeldt-Jakob Disease” or “variant Creutzfeldt-Jakob Disease,” you may try to describe those in layman’s terms. If the person being interviewed is still not familiar with those terms, you may consider the lack of familiarity with those terms as a negative response to questions using those terms.
Persons who have been diagnosed with dementia or any degenerative or demyelinating disease of the central nervous system or other neurological disease of unknown etiology (Refs. 3 and 75). Potential donors who have a diagnosis of delirium (e.g., delirium caused by toxic/metabolic diseases or recent head trauma) would not necessarily be considered to have a diagnosis of dementia and should be evaluated by the Medical Director. (HCT/Ps from donors with dementia confirmed by gross and microscopic examination of the brain to be caused by cerebrovascular accident or brain tumor and who are confirmed not to have evidence of TSE on microscopic examination of the brain may be acceptable based on an evaluation by the Medical Director). Persons who are at increased risk for CJD (Refs. 3 and 75). Donors are considered to have an increased risk for CJD if they have received a non-synthetic dura mater transplant, human pituitary-derived growth hormone, or have one or more blood relatives diagnosed with CJD (see criterion 22 of this section). Persons who have a history of CJD in a blood relative (Refs. 3 and 75) unless:
The diagnosis of CJD was subsequently found to be an incorrect diagnosis; The CJD was iatrogenic; or Laboratory testing (gene sequencing) shows that the donor does not have a mutation associated with familial CJD.
Persons who spent three months or more cumulatively in the United Kingdom (U.K.) (see Appendix 5) from the beginning of 1980 through the end of 1996 (Refs. 3 and 75). Persons who are current or former U.S. military members, civilian military employees, or dependents of a military member or civilian employee who resided at U.S. military bases in Northern Europe (Germany, Belgium, and the Netherlands) for 6 months or more cumulatively from 1980 through 1990, or elsewhere in Europe (Greece, Turkey, Spain, Portugal, and Italy) for 6 months or more cumulatively from 1980 through 1996 (Refs. 3 and 75). Persons who spent 5 years or more cumulatively in Europe (see Appendix 5) from 1980 until the present (note this criterion includes time spent in the U.K. from 1980 through 1996) (Refs. 3 and 75). Persons who received any transfusion of blood or blood components in the U.K. or France between 1980 and the present (Refs. 3 and 75).
The actual tests required are listed here and do not include TSE's:
DONOR TESTING: SPECIFIC REQUIREMENTS (§ 1271.85)
For what diseases must I test all donors of HCT/Ps, and what tests should I use?
You must test all donors of HCT/Ps, unless subject to an exemption in § 1271.90(a), for the diseases listed in section VI.A.1. through 5., as required in § 1271.85(a). You must use an FDA-licensed, approved, or cleared screening test, as described in section V. (§ 1271.80(c)). Current FDA-licensed donor screening tests for HIV, Hepatitis B, Hepatitis C, and HTLV are listed at the website: www.fda.gov/cber/products/testkits.htm. You may also check this website: www.fda.gov/cber/tissue/prod.htm for links to HCT/P-related, FDA-licensed, approved or cleared donor screening tests. The tests listed in this section adequately and appropriately reduce the risk of transmission of relevant communicable disease. Our recommendations on specific tests may change in the future due to technological advances or evolving scientific knowledge:
HIV, type 1 (FDA-licensed screening test either for anti-HIV-1 or combination test for anti-HIV-1 and anti-HIV-2 (Refs. 79 and 90); and FDA-licensed screening NAT test for HIV-1, or combination NAT); (establishments not utilizing an FDA-licensed screening test that tests for group O antibodies must evaluate donors for risk associated with HIV group O infection as described in section IV.E.27. and 28. (Refs. 66 and 76)) HIV, type 2 (FDA-licensed screening test either for anti-HIV-2 or combination test for anti-HIV-1 and anti-HIV-2) (Refs. 79 and 90); HBV (FDA-licensed screening test for Hepatitis B surface antigen (HBsAg) (Ref. 72) and for total antibody to Hepatitis B core antigen (anti-HBc)(IgG and IgM) (Refs. 91 through 98); HCV (FDA-licensed screening test for anti-HCV5 ; and FDA-licensed screening NAT test for HCV, or combination NAT) (Refs. 2, 69, 90, 91, and 99); and Treponema pallidum (FDA-cleared screening test for syphilis or FDA-cleared diagnostic serologic test for syphilis6) (Refs. 80 and 100).
I am simply unwilling to give any weight to a quote from West or a tweet that was "liked" regarding testing for prions for which there is no FDA approved test or requirement that I can find.
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