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STEM CELL BATTLES
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I hope I am wrong, but… The Food and Drug Administration (FDA) may have just used its first hearings on human embryonic stem cell research for political purposes: laying the groundwork to block human trials for years.
There was a two-day hearing, April 10th and 11th, at Bethesda, Maryland, home of the FDA. The purpose of the first day was to hear testimony from invited experts in the field, primarily the three stem cell companies (Geron, Novacell, and Advanced Cell Therapies), closest to having a product which may help people. I provided written materials as did anyone else who wished to submit.
Transcripts of the meeting (only part of which was public) were not provided, and may not be available for “several months”.
The committee was there to listen, and comment, not to decide. We can only guess at their intentions at this time.
The primary resource for their thinking, therefore, is the briefing document they provided: “CTGTAC Meeting #45 Cellular Therapies Derived from Human Embryonic Stem Cells—Considerations for Pre-clinical Safety Testing and Patient Monitoring”.
My immediate reaction is that it appears to be written by an opponent of the research.
Example: It is standard practice that “phase one” clinical trials for the NIH are for the establishment of safety. “Phase two” is for efficacy. It is my understanding that a scientist can request that both be done at once, but this is not usual—nor is it customary for this to imposed as a requirement from above.
However, the rules appear to be changing.
As on Page 9 of the document:
“Given the potential risks of hESC-derived cellular products, data supporting a reasonable possibility of efficacy may need to be particularly strong, and design parameters may need to allow for detection of clinical benefit…Given all these considerations, …phase one trials of hESC-derived cellular products will have to be capable of measuring some indications of efficacy…” (emphasis added).
The committee’s leader essentially repeated that statement to a reporter:
“The FDA may require “particularly strong” evidence early in studies that stem cell treatments are effective, said Steven Bauer, chief of the FDA’s Cell and Tissue Therapy branch…”—Embryonic Stem Cells’ Safety Weighed by FDA Advisers, Elizabeth Lopatto, Bloomberg.com, 4/10/08
Example: the threat of cancer is raised in almost every paragraph. The word “tumorigenic” is repeated perhaps thirty times, like an advertising slogan. Anyone reading this unprepared would conclude stem cell research is riddled with cancer.
The facts are otherwise. Inserting undifferentiated hESCs into an animal model will of course make a teratoma—being able to make that non-cancerous lump of cells is one of the definitions of pluripotency—but not if the scientists differentiate the cells first.
To understand this, think of molten metal, which can be molded into any shape. If you were building a house, would you pour the white-hot liquid metal directly onto the wood? Probably not. The metal would be shaped into nails or screws or bolts, before being implanted them into the wooden structure of your home.
To its credit, the FDA did acknowledge that once the embryonic stem cells had differentiated, their teratoma days were over—but it then made the suggestion that even the tiniest fraction of undifferentiated hESCs could cause teratomas.
In other words, if you had a million embryonic stem cells, and you as a scientist had differentiated them into the kind of cells you wanted, and inserted them into the body, some few might still be embryonic, and might turn into teratomas.
However, at the hearings, Dr. Jane Lebowski of Geron presented data, citing a 12 month rodent study, (a very long one for rats which live only about 3 years) during which approximately 5% of the transplanted cells were undifferentiated—but none became teratomas.
The committee discussed many new conditions which might be imposed.
Example: Dr. Hans Keirstead’s experiment with remyelination (Geron) was initially complete in 2002. (This is the one done in the Reeve-Irvine Research Center, partially paid for by the Roman Reed Spinal Cord Injury Research Act.)
In the six years since, Dr. Keirstead has been in continual touch with the FDA, answering their requests for replication, etc., amassing a 25,000 page paper trail. (Think what 25,000 pages of paper trail means—if a typical book is 250 pages, he has written or helped write 100 books on the one experiment!) He has met every condition they have offered. And now?
A long list of new conditions may send him, Geron, Advanced Cell Technology, and Novocell, back to the drawing board, delaying the research for years, perhaps decades.
Both the briefing paper and comments from committee members speak of perhaps requiring:
· Multiple species of animal studies (and for long durations, “optimally, for the life span of the animal…”—a monkey can live twenty years!) even the possible development of porcine stem cell lines to try on pigs;
· New studies not only for resolved issues like teratoma formation, but also for the physiological effects of the location of the insertion of the cells, studies on stem cell interaction with other drugs (“concomitant medications”);
· New non-invasive assays to test for levels of undifferentiated hESCs in the human being (difficult to test that without human trials!) and much more.
As Neuralstem CEO Richard Garr said on CNN: “We hope… this isn’t just something that a stem cell unfriendly administration is trying to put into place before they leave.”—Aaron Smith, CNN-money.com, April 10, 2008.
Caution is one thing; endless study is another. There will never (ever!) be a time when medical research is risk-free. Even standard medical practice can go wrong, which is why you sign release forms at the hospital. If you have knee surgery, it is possible a blood clot may form in your artery and kill you—as happened to my aunt-in-law. Does this mean surgery should be outlawed, because it always contains an element of risk?
Ask the millions of suffering people: people like my son, who has been paralyzed for fourteen years: he will not personally benefit from the Keirstead research, which is designed to help only people with new injuries. But Roman knows the entire field must advance, for those with chronic injuries to have a chance at cure.
Now, I may be all wet on this. It is my nature to be politically suspicious, and I just do not trust the Bush White House. Most of his appointees seem ideologically opposed to the research. Then again, some in office now are definitely straight arrows: I have tremendous respect for people like Dr. Story Landis, chair of the National Institute of Health (NIH)’s stem cell effort, who has publicly spoken about the anti-embryonic stance of the Bush White House. (see for example, in Niche at Nature: “I don’t think that the NIH can do anything except talk about the fact that the science does not support the President’s policy and at the same time to implement the President’s policy. “—posted by Monya Baker, December 17, 2007. That takes courage.
But if the FDA committee does turn out to be guilty of political interference with science, that would unfortunately fit with a just-released report by the Union of Concerned Scientists, which states: “Scientific findings are being suppressed and distorted. Eight hundred and eighty-nine scientists personally experienced at least one type of political interference.”—Washington Post, Christopher Lee, April 24th, 2008. (emphasis added).
This matter should, I feel, be brought to the attention of Representative Henry Waxman, (D-Los Angeles) who is holding a hearing on the politicization of science next month.
P.S. To try and understand the complicated terminology and issues involved, I typed out the 11 page document, in laborious hunt and peck style. It is reproduced below. A few small sections are omitted; you can find the complete document on the FDA website. (http://www.fda.gov/default.htm) Type in the words human trials embryonic into the search box at the top of the page, and you will be taken to the original. (FDA HEARINGS) CTGTAC Meeting #45
Cellular Therapies Derived from Human Embryonic Stem Cells—Considerations for Pre-clinical Safety Testing and Patient Monitoring
April 10, 2008 Briefing Document
Introduction—1 Background-2 Properties of human ESC-2 Product Considerations-2 Preclinical considerations-3 Animal Models for Preclinical testing of hESC-derived cellular products-4 Immunological Tolerance to Cells of Human Origin-4 Selecting Site of Cell Administration—6 Impact of host microenvironment-7 Determining Study Duration-7 Safety Assessment-7 Clinical Considerations—8 Draft Advisory Committee Discussion Questions—10 Inappropriate Differentiation/Tumorigenicity—10 Characterization of hESC-derived Cellular Preparations—11 Patient Monitoring—11 References—11
INTRODUCTION:
This meeting is being convened to provide the FDA with insight and perspective regarding safety concerns confronting development of cellular therapies derived from human embryonic stem cells (hESCs). No specific products will be discussed for regulatory review purposes. Instead, invited experts and manufacturers who are developing cellular therapies derived from hESCs will present information on some of the issues concerning development of these types of products. Members of the committee (WHO IS ON COMMITTEE) will be requested to consider this information and provide a response to FDA questions. Discussion will be limited to characterization of hESC products, appropriate animal models for preclinical testing, and suitable monitoring for clinical studies.
BACKGROUND
Properties of Human Embryonic Stem Cells
There is considerable interest in development of cellular therapy products derived from human embryonic stem cells primarily due to their ability to self-renew and proliferate while maintaining pluripotency and their capacity to differentiate in culture. These properties allow production of large numbers of undifferentiated hESCs that can then be induced to differentiate along specific cell lineages under carefully controlled manufacturing conditions. Due to the potential for hESCs to contribute to the repair or replacement of damaged or diseased cells and tissues, it is anticipated that differentiated cells derived from hESCs will be proposed as investigational cell therapy products for multiple clinical uses.
Human ESCs have an intrinsic capacity to generate teratomas (1, 2) which may contain differentiated cells originating from all three embryonic tissue types, endoderm, mesoderm and ectoderm. This characteristic provides evidence of pluripotence, but also raises a potential safety concern. When administered to animals in sufficient numbers hESCs give rise to teratomas comprised of either differentiated or undifferentiated cell types , depending on the microenvironment at the site of administration (3-7) It is conceivable that cell therapy products derived from hESCs will be heterogenous in their composition and consist of cells that have differentiated to variable degrees. Residual undifferentiated hESCs and partially differentiated cells will retain the capacity to proliferate and differentiate further. A related potential safety concern is the ability of cells to migrate from their target site of administration and possibly undergo differentiation that is inappropriate to a non target location.
The goal of the meeting is to obtain expert advice regarding product characterization, preclinical testing, and design of clinical studies sufficient to ensure patient safety in the first clinical trial of hESC-derived cell therapy products. FDA has considerable experience in the evaluation of investigational cell therapy products, and has published several relevant guidance documents to facilitate safe progress in this field. (8,9). However the use of cellular products derived from hESCs presents unique challenges worthy of further consideration.
PRODUCT CONSIDERATIONS
As with any investigational cell therapy product, detailed and comprehensive characterization of hESC source cultures and derivative cellular products is critical to ensuring the safety of a cellular therapy product derived from hESCs. An important approach to safe clinical use of this type of product will be to adopt manufacturing practices that minimize the number of undifferentiated hESCs present in the final formulated preparation. Reduction or elimination of undifferentiated hESCs from the final cellular product may be desirable or even necessary to reduce the potential for teratoma formation and diminish the possibility for inappropriate differentiation. Appropriate analytical methods will be needed to evaluate the products. The sensitivity, specificity, robustness, accuracy, an precision of assays used to characterize hESC-derived cellular products must be sufficient to provide a reasonable assurance of safety when administered to humans. Assays used as process controls and for lot release should include tests capable of detecting unacceptable levels of undifferentiated hESCs or other cellular impurities in hESC-derived cellular products that may form tumors, differentiate inappropriately, or present other safety concerns.
To achieve these goals, several parameters should be tested to optimize the ability of analytical test results to predict the behavior of the cellular product in vivo reliably. Current methods for characterization of source hESCs and derivative cellular products include detection of stage-specific markers by flow cytometry, analysis of gene expression by RT-PCR, and analysis of protein expression by Western blot; analytical technology is evolving rapidly that will complement or replace these method. The eventual choice of parameters that will be used to develop in-process and release tests will depend on the results of these characterization studies. Presently , there is no consensus in the field regarding the number, nature of optimal methods for analyzing markers best suited to predict safety and efficacy of hESC derived cellular products. Accordingly, it will be important to evaluate characteristics predictive not only of clinical effectiveness, but also of potential adverse outcomes. In the latter case, the question of analytical sensitivity is particularly important. The desired goal is to use the product characterization data in tandem with the animal data to determine a safe first-in human starting dose level accurately and to optimize both safety and potential benefit of early phase and subsequent trials.
PRECLINICAL CONSIDERATIONS
According to Title 21 of the Code of Federal Regulations (CFR) Part 312.23 (a) (8), the sponsor of a clinical trial should provide “….adequate information about the pharmacological and toxicological studies…on the basis of which the sponsor has concluded that it is reasonably safe to conduct the proposed clinical investigations. The kind, duration, and scope of animal and other tests required vary with the duration and nature of the proposed clinical investigations.” The design and conduct of the preclinical studies are thus critical to the regulatory decisions made in allowing the administration of a cellular therapy into humans.
To evaluate the safety of a hESC-derived cellular product in vivo adequately, comprehensive preclinical studies to identify and understand potential toxicities need to be conducted before entering clinical trials. Based on the biological properties of these cells, both the potential for tumorigenicity and the potential for inappropriate differentiation at a non-target location are significant safety concerns. It is therefore important to consider carefully the biological relevance of the animal species and animal models used to assess the in vivo safety of the hESC –derived cellular product. Selection of the most appropriate animal species and models is a major unresolved issue that revolves around the issue of immune tolerance to hESC derived cellular products. Based on the biology of the hESC-derived cellular product, as well as the disease/injury of clinical focus, the route of administration , and other factors, more than one animal species may be needed to provide a comprehensive in vivo characterization and safety profile of these products.
In addition to the species used, the safety assessment of many cellular therapies has also made use of animal models of disease/injury that mimic some aspect of the pathophysiology of the proposed patient population. Such models help provide insight regarding dose /activity and dose/toxicity relationships. Thus the applicability of such models in the context of possible species restrictions due to the biology and immunologic tolerance of the animals to hESC-derived cellular products should be addressed. These factors will affect cell fate. Thus, cell survival, migration/trafficking, differentiation/mRNA or protein expression profile, integration (anatomical/functional) and proliferation also may need to be considered when selecting appropriate preclinical models prior to first administration into humans.
ANIMAL MODELS FOR PRECLINCAL TESTINGOF HESC DERIVED CELLULAR PRODUCTS
When conducting preclinical testing in an animal model, the impact of the immunosuppressive regimen or the immuno-deficient state of the animal model on the engraftment of the implanted hESC derived cellular product needs to be assessed. Each engraftment of the implanted hESC-derived cellular product needs to be assessed. Each hESC-derived cellular product may have unique patterns of proliferation and expression of antigens and will likely contain various ratios of differentiated and non-differentiated cells which can affect the biological actions of the administered product. These factors may affect what happens to the cells after administration and thus affect the safety and biological activity of the investigational hESC-derived cellular product in host animals. In order to allow for reasonable extrapolation of data generated in animals to humans,. It is important to assess the engraftment potential of the cells in animal models. Animal models should be sufficiently sensitive to predict whether unacceptable levels of undesirable cells could be present in the final preparation, especially with regard to tumorigenic potential.
IMMUNOLOGICAL TOLDERANCE TO CELLS OF HUMAN ORIGIN
The criteria for selection of the host animal (s) in order to support engraftment of the hESC-derived cellular product need to be considered carefully. Ideally the animal model should be immunologically tolerant to cells of human origin. The effects of humoral and cellular immunity on hESC implanted into mice are important considerations that have been investigated.. For example, Drukker et al (10) compared undifferentiated hESCs in immunocompetent...and immunodeficient…mice by implantation of 1 x 10tothe6th hescs in kidney capsules. Over the course of one month, all implanted immunocompetent mice failed to develop teratomas, while the imunodeficient mice differed in their ability to reject hESCs. Nk-deficient mice and…b-cell deficient mice failed to develop teratomas. In contrast, nod/scid mice (b and t-cell deficient) developed tumors. These results suggest that T cells play an important role in xenorejection of implanted hESCs. Tian et al compared teratoma formation following intramuscular implantation of hESCs in NOD/SCID (B and T cell-deficient) and SCID/Beige (SCID/Bg_ mice (B,T, and NK cell-deficient). All implanted mice developed teratomas, but the tumors formed at a faster rate in the SCID/Bg mice. This study suggests that NK cells may play a role in xenorejection of implanted hESCs.
Tian et al (11) also studied the relationship between the immune status of the animal, engraftment potential of the hescs and teratoma formation. The hESCs were allowed to differentiate on mouse bone marrow (BM) stromal cells for 7-24 days. The pre-differentiated hESC cells were given 2 or 4x10-6th cells/mouse by intravenous of intramedullary infusion in NOD-SCID mice (b and t-cell deficient) or NOD-SCID mice that were pre-treated with anti-ASGM to also delete NK cells. Mice were followed for 3 to 6 months. Although no teratomas were observed in any animal, NOD-SCID mice treated with anti-ASGM showed 3-10fold better cell engraftment at 3 months post BM implantation than mice that were injected intravenously. These results suggest that NK cells play a role inn xenorejection of hesc-derived cells and that anti-body-mediated suppression of NK cells may enhance engraftment in vivo.
Erdo et al (12) performed direct comparisons of allogeneic (mice) and xenogeneic (rats) administration of mouse embryomnic embryonic stem cells (mESCs) . The mESCs were implanted intracerebrally in mice, or rats immunosuppressed with Cyclosporine A. A tumor incidence of 75-100% was observed in mice receiving 500 or more MESCS. In contrast, no tumors were detected in rats receiving 8x10to the5th mESCs.
To address tumorigenic assay sensitivity, Lawrenz et al (13) developed a spiking assay in an immunodeficient mouse model that could detect low numbers of mESCs present within a large dose of human fibroblasts. The mESCs were implanted into balb/c nude mice using two different approaches. A new method used subcutaneous injection of mixtures of cells embedded in matrigel containing 2x20tothe6th human fibroblasts spiked with different numbers of mESCs. The second method used kidney capsule implantation of mixtures containing 10tothe6th human fibroblasts and different numbers of mESCs. Both methods could detect teratoma formation in cell mixtures containing as few as two mESCs. No tumors were observed in immunocompetent mice.
These studies show increased sensitivity for detection of tumorigenic cels following administration of allogeneic compared to xenogenic ESCs. In the allogeneic situation, immunosuppression is important for sensitive detection of tumorigenic cells. Thus the immune status of the host anima, whether due to administration of exogenous immunosuppressive agents, or the use of genetically immune deficient animals, may be a major determinant of long-term in vivo outcome. Each model provides distinct advantages and limitations. Therefore the criteria for the selection of host animals that support engraftment of the hESC-derived cellular product need to be adequate and justified with regard to proposed clinical trials.
SELECTING CELL DOSE LEVELS AND STARTING CELL POPULATIONS
Cell does is an important consideration when designing preclinical animal studies, especially for cellular products that may consist of partially differentiated cells, fully differentiated cells, and residual undifferentiated hESCs. General recommendations for preclinical study designs for cellular therapy products include several dose levels that bracket and exceed the anticipated clinical dose range, based on a predefined parameter, such as bodyweight or organ weight/size/volume. However, for hESC-derived cellular products, the potential contribution of the heterogenous population of cells in the final clinical product to adverse findings, such as tumor formation and /or inappropriate differentiation, is an important issue that may affect selection of the cell doses used in animals.
The importance of reducing the numbers of undifferentiated hESCs in the final cellular product has been investigated in a rat model. Brederlau et al (3) investigated the effect of pre-differentiation of hESCs on teratoma formation. The hESCs were differentiated in culture for various times, followed by administration of 10tothe 5th hESCs into 6-ohda lesioned strata of female hemi-parkinsonians sprague-dawley rats. The animals were immunosuppressed transiently with cyclosporine A, beginning at one day prior to cell administration and continuing for two weeks. The rats were followed for 13 weeks. The incidence of teratoma formation correlated inversely with the pre-differentiation culture time. The incidence of teratoma formation was 100, 25, and 0 percent for hESC pre-differentiated for 16, 20, and 23 days respectively. Notably, 82% of the mice implanted with 16-day pre-differentiated hESC were lost due to teratoma formation between 6 to 11 weeks post implantation mice, while only 25% mice implanted with 20 day pre-differentiated hESCs were lost due to teratoma formation between 12 to 13 weeks post implantation. Implanted cells that underwent longer in vitro pre-differentiation had increased numbers of B-iii-tubulin (marker of progenitor cells) and tyrosine hydroxylase (marker of dopamine neurons) positive (marker of dopaminergic neurons) positive cells, with a corresponding decreast in OCT 4 (marker of undifferentiated cells) positive cells in the brains of rats examined at 2 weeks post implantation. Overall the data suggest that prolonged in vitro predifferentiation of hESCs can reduce the incidence of teratomas in vivo. Thus the relative composition of the cellular product in the host animals is likely a major contributing factor to the formation of tumors. Therefore the criteria for the selection and adequate characterization of cell dose needs to be examined.
SELECTING SITE OF CELL ADMINISTRATION
The anatomic location of the implantation site in animals is another important consideration. The local environmental niche of the host animal will affect cell survival and subsequent differentiation, and thus could 1. diminish or enhance the desired biological response, or 2. result in misleading conclusions regarding the safety and effectiveness of a cellular product if cell fate is compromised. Cell fate could be also be influenced differently by implantation into a normal microenvironment vs. a site of disease or injury. In addition, undesirable proliferation or differentiation that occurs in some anatomical sites may be more deleterious than others; for example spinal cord or brain vs. peritoneal cavity.
IMPACT OF THE HOST MICROENVIRONMENT
The physiological environment and the anatomical location where cellular products are administered may exert a significant influence on safety. Shih et al. (14) investigated whether engraftment of human fetal tissues in severe combined immunodeficient (SCID) mice could provide a physiologically relevant microenvironment for hESCs to differentiate. Human fetal tissues from thymus, pancreas, and lung were engrafted under the kidney capsules of SCID mice. Three months later, 5 x 10 to 3rd hESCs (two different lines) were implanted into the engrafted fetal tissues. The fetal tissues were harvested 2-3 months post cell implantation. Tumors were observe in all human thymus and lung grafts implanted with hESCs derived from the two different lines. Depending on the cell line administered, from 42-50% of the human pancreatic grafts had tumors. These tumors displayed an aggressive growth pattern, with histological characteristics of primitive, undifferentiated teratocarcinomas rather than non-malignant, differentiated teratomas. Tumor formation was dose dependent in the spleen and lung grafts at 8-12 weeks post cell implantation, with 0%, 25-35%, or 100% teratoma formation at doses of 50, 500 or 5000 cells respectively. In contrast, approximately one million hESCs given in various anatomical sites in NOD-SCID mice were necessary for tumor development. These results suggest that the physiological environment and the anatomical location may exert a significant influence on tumor formation. Therefore the site of cell implantation in the animal host (s) that will be biologically relevant to the clinical situation needs to be considered with regard to the proposed clinical trial.
DETERMINING STUDY DURATION
The duration of preclinical studies should be adequate to assess the potential for tumorigenicity and other long-term consequences associated with administration of hESC-derived cellular products in humans. Optimally, animal studies should be extended for the lifespan of the animal, which will vary with the species, strain, disease/injury condition, and/or immune status. Based on these parameters, however, study durations can potentially vary to a great extent, thus the question of extrapolation from resulting animal safety data to the clinical circumstances remains. Given the considerations presented in this document and the questions regarding relevant animal species/models that still remain, discussion regarding 1. the limitation of study duration intervals in animal studies and 2. the translation of animal study results to the safety profile of the hESC-derived cellular product in humans is warranted.
SAFETY ASSESSMENT
As with any investigational cell therapy product, it is important to understand the conditions under which undesirable events can occur, and to determine how these safety concerns can best be evaluated in vitro and in vivo preclinical studies before clinical use. As expressed throughout this document, the tumorigenic potential of hESC-derived cellular products is a significant safety concern. In addition to the tumorigenicity question, the potential for other adverse events exists. Thus it is important to have the tools to assess endpoints of toxicity, such as ectopic tissues expression, inappropriate differentiation, an undesired phenotype expression.
CLINICAL CONSIDERATIONS
The decision to initiate clinical trials of hESC-derived cellular products requires consideration of factors that are common to trials of cell therapy products in general: the characteristics of the cellular product; the results of comprehensive pharmacological/toxicology studies in relevant animal models; the nature and severity of the targeted illness; the age, gender, and other demographic characteristics of the intended patient population; and the proposed anatomical site(s) of concomitant medications and treatments on both the patient and cellular product. The possibilities of immune rejection or other unanticipated immunological responses must be addressed as well. Early clinical trials of novel cell therapies should be designed to take all these factors into account, with enrollment criteria permitting maximum possible benefit to patients, given the possible risks.
In addition to these general principles that are applicable to all cellular therapies, there are special safety concerns for hESC-derived cellular products that need to be considered carefully in designing clinical trials.
It is expected that the administered hESC products may consist of cell populations comprised of fully differentiated cells; partially differentiated progenitor cells; and possibly, low levels of undifferentiated hESC. Subsets of this heterogenous cell population may have the potential for functional integration, as well as de-differentiation, migration, further differentiation, proliferation, and tumor formation. Clinical trials must be capable of monitoring and detecting those events which may pose safety concerns. It is important to recognize that many of these potential adverse events may occur over protracted periods of time. Early manifestations of potential adverse events, including formation of teratomas or other tumors, may not be detectable with current non-invasive technology, which will include imaging as well as possible use of blood-born markers.. These considerations will be important in determining key design parameters for clinical trials of hESC-derived cellular products: duration of patient follow-up; selection of procedures for safety monitoring (e.g., conventional x-ray, ultrasound, CT and MRI scanning, PET scanning, testing of immune responses to the cellular product, and other clinical and laboratory modalities.
Early-phase clinical trials of all cell therapies expose subjects to potential risks that differ substantially from those associated with phase 1 drug trials, Accordingly, there ar generally significant differences between the two product classes in early trial design. Cellular products cannot be subjected to terminal sterilization, and their pharmacological disposition is unpredictable; for some products, unchecked proliferation , as opposed to exponential decay for conventional drug, is a real possibility. Many indications under consideration are serious and/or life-threatening, but the life expectancy of the study population may be measurable in years or decades. The anatomical sites of administration (e.g. intracranial, intraspinal, intracardiac) proposed for many cellular products, including hESC-derived products, may pose additional risks arising from the surgical procedures, the vulnerabilities of the sites themselves, and subsequent accessibility of the sites in the event of medical necessity, including removal of the product.
For cellular products, a reasonable balance between risk and benefits will be likely only in patients with the targeted disease. Given the additional safety concerns for hESCs, the risk-to-benefit evaluation is brought into even sharper focus.
Early-phase clinical trials of hESC-derived cellular products will have to be designed carefully in order to insure the safety of enrolled subjects, who will undoubtedly be patients with the targeted disease. Given the potential risks of hESC-derived cellular products, data supporting a reasonable possibility of efficacy may need to be particularly strong, and design parameters may need to allow for detection of clinical benefit. As for all cell therapies, such expectations of potential therapeutic action are generally based on pre-clinical demonstrations of proof-of-concept, and specific requirements for such data will vary among products and clinical indications.
Given all of these considerations, many phase 1 trials of hESC-derived cellular products will have to be capable of measuring some indications of efficacy, or at least desirable therapeutic activity. These considerations of both safety and potential benefit will affect the selection of cell dose, as well as other characteristics of early-phase clinical trials.
DRAFT ADVISORY COMMITTEE DISCUSSION QUESTIONS
The availability and biological properties of human embryonic stem cells (hESCs) have spurred significant interest and effort towards development of new cell therapy products derived from them. Due to the abilities of hESCs to proliferate differentiate, and form teratomas, the use of cellular therapies derived form hESCs raises several critical issues elated to preclinical and product safety testing and patient monitoring. Preclinical evaluation of cellular therapies derived from hESCs should inform the rational, safe design of clinical trials, including identification of potential toxicities as well as the initial doses and dose escalation scheduled to be used in a proposed clinical trial. Product characterization should include assessments of potentially tumorigenic cells in the manufactured product. Patient monitoring should take into account the potential adverse events associated with use of hESCs. The following questions address critical issues related to the clinical use of hESC derived cell therapy products.
INNAPROPRIATE DIFFERENTIATION/TUMORIGENICITY
Characteristics of undifferentiated hESCs include their proliferative potential, their ability to differentiate, and their capacity to form teratomas. Please discuss optimal study designs for preclinical assessment of inappropriate differentiation, including tumorigenic potential, of an investigational cellular product derived from undifferentiated hESCs. Please consider the following in your discussion:
Criteria for selection of clinically relevant animal species/models that support engraftment of the administered hESC cells, for example, optimal strategies for evaluating potential host (xeno) rejection of administered hESC-derived products?
Optimal site of cell implantation in the animals in order to obtain meaningful test results.
Appropriate study duration
Most appropriate dosing method, i.e. absolute undifferentiated hESC number vs. percentage of undifferentiated hESCs present in the product, to extrapolate cell doses tested in animals to planned clinical dose.
CHARACTERIZATION OF HESC DERIVED CELLULAR PREPARATIONS
Cellular products derived from hESCs may consist of heterogenous cell populations, some that are required for the intended effect, some that may be deleterious, and some that are inert. Thus, detailed characterization of hESC-derived cellular products with respect to identity and purity is important. The goal of product characterization is to establish the relationship between analytical test results used in product characterization and the outcomes for preclinical/clinical studies. Identification of the putative therapeutic as well as undesired cell subtypes present in a cellular preparation is essential in order to extrapolate doses in animals to humans accurately. Please consider the following:
Please discuss which product characteristics might be predictive of adverse events such as ectopic or inappropriate differentiation, including tumorigenesis or other undesired outcomes. Please include in your discussion the specificity and sensitivity of specific assays used to distinguish undifferentiated, appropriately differentiated, and inappropriately differentiated derivatives within a heterogenous cell preparation.
PATIENT MONITORING
Safety monitoring of subjects during clinical trials of hesc-derived cellular products may be complicated by several characteristics of the product that may cause various clinical outcomes that could emerge over a protracted period. First-generation hESC-derived cellular products may consist of heterogenous cell populations comprised of fully differentiated cell types, partially differentiated progenitor cells, and possibly, low levels of undifferentiated hESCs. Accordingly, cell products derived form hESCs may exhibit a variety of properties that reflect the specific cell mixture, including the capacity for proliferation, further differentiation, migration, and functional physiologic integration. Early-phase clinical studies are focused mainly on patient safety but, as described above, it may often be desirable or even necessary to provide for the possibility of some degree of beneficial therapeutic activity as well. Please consider the following:
Taking into account the capabilities of existing analytical tools and non-invasive monitoring technologies, please discuss features of early phase clinical trial design that will facilitate monitoring of patient safety following administration of hESC-derived cellular products. Please comment on other trial design features, such as cell dosing, that can help to increase the probability of obtaining a measurable therapeutic benefit while ensuring maximum safety.
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