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Clinical trials and safety considerations
- 1. Stem Cells inClinical Practice Zahraa A. Watad zahraawatad@gmail.com
- 2. Outline Introduction From Preclinical toClinical FDA Regulations Safety Consideration Efficacy Consideration Patient Criteria Follow-up & Monitoring
- 3. Introduction Stem cells area group of immature cells that have the potential to build and recover every tissue/organ in the body due to their unique proliferative, differentiation, and self- renewal abilities Regenerative medicine is considered a promising new source of treatment for un- treatable diseases in modern science Regenerative medicine is now regarded as an alternative to traditional drug-based treatments The ultimate target of which is returning normal function to defective cells and tissues
- 4. Introduction Biological mechanisms ofStem Cells The mechanisms of action through which stem cells can promote the regeneration of tissue are diverse, including 1. Inhibition of inflammation cascades 2. Reduction of apoptosis 3. Cell recruitment 4. Stimulation of angiogenesis 5. Differentiation
- 5. From Preclinical toClinical
- 6. -Before going tothe preclinical trial, the idea regarding the stem cells must be evaluated. The Evaluation Step, is important to select the target disease and make sure that the mechanism causing the disease is understood Preclinical studies aim: 1- Potential to treat the disease 2- Safety of the final product Preclinical studies types: 1-In vitro 2- In vivo Preclinical Studies
- 7. Preclinical Studies |Requirements for Clinical Trials Determination of whether to continue or discontinue development of the treatment Identification of the potential for special toxicity Identification and verification of the potential activity and toxicity Optimization of administration route and usage Establishment of a pharmacologically effective capacity The feasibility and establishment of the rationale
- 8. Preclinical Studies |Factors to be considered There are some factors need to be considered when conducting in-vitro and in vivo studies in stem cell research including; 1- Cell type determination The strengths and weaknesses of each type of stem cell should be identified in order to determine the maximum therapeutic effect of stem cells in various diseases. 2-Cell dose specification The effective range of administration (i.E., Dosage) of stem cells or stem-cell-derived products used in treatment should be determined 3-Route of administration Local vs. systemic transmission. 4- Safety & Efficiency These stem cell treatments can vary in risk
- 9. Clinical Studies Before atreatment is applied in humans, an application for a clinical trial should be submitted to the Food and Drug Administration (FDA), the European Medicine Agency (EMA) The FDA is responsible for certifying clinical trial studies for stem-cell-based products in the United States The EMA is an agency in the European Union (EU) which is responsible for evaluating any investigational medical products (IMPs) in order to make sure that the final product is safe and efficient for public use
- 10. Clinical Studies |Stages Before a treatment is applied in humans, an application for a clinical trial should be submitted to the Food and Drug Administration (FDA), the European Medicine Agency (EMA) Investigational New Drug (IND) Application includes: • Data from animal pharmacology • Toxicology studies • Clinical protocols • Investigator information **A lack of preclinical support (e.g., in vitro and in vivo studies) can lead to required modification or disapproval
- 11. Clinical Studies |Stages Before a treatment is applied in humans, an application for a clinical trial should be submitted to the Food and Drug Administration (FDA), the European Medicine Agency (EMA) Investigational Medical Products (IMPs) Application include • Chemical Preclinical Data • Pharmacological Preclinical Data • Biological Preclinical Data (e.g., from in vivo and in vitro studies )
- 12. Clinical Studies |Phases Clinical trials studies are conducted in different phases, each phase has different purpose, number of participants and different follow-up duration. Early Phase I emphasizes the effects of the drug on the human body and how the drug is processed in the body. Phase I of a clinical trial is carried out to ensure that a new treatment is safe and to determine how the new medicine works in humans. Number of participants: 20-80 In Phase II, the accurate dose is determined and initial data on the efficiency and possible side effects are collected. Number of participants: 100-300
- 13. Clinical Studies |Phases Clinical trials studies are conducted in different phases, each phase has different purpose, number of participants and different follow-up duration. Phase III evaluates the safety and effectiveness of products. The result of this phase is submitted to the FDA/EMA for new product approval, which allows manufacturing and marketing of the drug Number of participants: several hundred to thousands of volunteers Phase IV take place after the approval of new products and is carried out to determine the public safety of the new product The number of participants for clinical studies in rare diseases will be lower than when studying common diseases.
- 14. Clinical Studies |Phases
- 15. Clinical Studies Type ofDisease : Stem-cell-based therapy is a new approach for the treatment of various diseases in different clinical trial studies
- 16. Clinical Studies Stem-cell-based Productsfor use in clinical trials studies are divided into 2 groups • Autologous Stem Cells The stem cells are collected from the patient’s own body • Allogenic Stem Cells The stem cells are collected from a healthy donor. * Requires more prerequisite tests, in order to check the donor’s health.
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- 18. FDA Regulations • AnyStem-cell–based Product that contains cells or tissues that “are highly processed, are used for other than their normal function, are combined with non-tissue components, or are used for metabolic purposes • Public Health Safety Act, Section 351, which regulates the licensing of biologic products and requires the submission of an investigational new drug application to the FDA before studies involving humans are initiated • The FDA has published guidelines for the submission of an IND in the Code of Federal Regulations (CFR). • These guidelines have been issued for the development of stem cell products with the highest standards of safety and potential effective translation to clinical trial studies.
- 19. FDA Regulations These regulationsare presented in • 21 CFR part 210, 211 (Current Good Manufacturing Practice (cGMP)) -To ensure the quality of the final products • 21 CFR part 312 (Investigational New Drug Application) -IND submission and conducting clinical trial studies, reviewed by the FDA • 21 CFR 610 (General Biological Product Standards) -Release requirements, testing requirements, labeling standards, • 21 CFR 1271 (Human Cells, Tissues, and Cellular and Tissue-Based Products) -Regulations for human cells, tissues, and cellular and tissue-based products (HCT/p’s) Current Good Tissue Practice (GTP) is part of 21 CFR 1271
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- 21. Safety Considerations Stem cell-basedtherapies bring with them new safety challenges that cannot be addressed using standard analytical procedures developed for other pharmaceutical products. A particular difficulty is the ability to monitor cell biodistribution. The ability to track the therapeutic cells is key to an objective assessment of risk with respect to inappropriate ectopic tissue formation or of tumorigencity. A Major Concern with stem cell therapy is that of tumorigenic potential. Another evident safety issue is that of immunogenicity
- 22. The Safety Issues Immunogenicityand Immunotoxicity Immunogenicity and immunotoxicity are potentially greater threats to recipients of cellular products than for conventional medicines, similar to transplantation therapies. 1- Immunotoxicity of the clinical product is difficult to assess. 2- Immunogenicity : a patient’s response to the administered product Immunogenicity may be influenced by multiple factors including • The site of administration • The maturation status of the cells • The number of doses • The immunological basis of the disease • An aging immune system.
- 23. The Safety Issues Tumorigenicity Teratomaformation is more common in induced pluripotent stem cells(iPSCs) 1. Contamination of differentiated cells with undifferentiated cells This risk will be ameliorated by developing appropriate purification protocols and the means for monitoring contamination 2. Mutations acquired during culture of the parent stem cell.
- 24. The Safety Issues •Infection A transplant using stem cells from a donor ( Allogenic Transplant) increases your risk for infections more than a transplant that uses stem cells from your own body ( Autologous Transplant) . Reasons: • If your stem cells come from another person, you will need to take anti-rejection medication. This medication weakens your immune system • Chemotherapy and radiation lower your white blood cell count. • Graft-versus-host disease (GVHD).
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- 26. Efficacy Consideration Efficacy isa safety consideration for one simple and totally obvious reason: suboptimal efficacy in a clinical trial can lead to many adverse patient “safety” outcome For example, prolonged hospitalization, increased cost, complications, etc Factors affecting efficacy: 1- Site-specific integration. 2- The longevity of the cells in the stem- cell–based product. 3- Biologic distribution.
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- 28. Patient Criteria Stem celltherapy is being used to treat a variety of disease including; cancer, cardiac diseases, liver diseases, immunological diseases, and blood diseases. However, NOT every patient is eligible for stem cell treatment. Factors to consider before starting stem cell therapy: 1- The patient's disease. 2-Availability of a healthy donor ( HLA matching ) 3- General health and medical condition of the patients 4- Medical treatments 5- Immune system condition 6- Lifestyle 7- Psychological factos
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- 30. Follow-up & Monitoring. • The patient has to be followed-up ( 1 month – 3 months) after the transplant • The rest and recovery from the transplant requires ( 3 months – 1 years ) • Patient should be watched out for the following; 1. Infection 2. Organ damage 3. Caring for the central line 4. Immunization 5. Activity & Nutrition 6. Other side effects include; fatigue, diarrhea fever, hair loss,etc
- 31. References. • https://my.clevelandclinic.org/health/treatments/22790-allogeneic-stem-cell-transplantation • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159216/ •https://www.sciencedirect.com/science/article/pii/S1934590912000124 • https://static1.squarespace.com/static/611faaa8fee682525ee16489/t/62f2d083d0b7a55e403b3afc/1660 080259822/isscr-guidelines-for-stem-cell-research-and-clinical-translationd-2016.pdf • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9357075/pdf/41392_2022_Article_1134.pdf • https://www.isscr.org/ • https://my.clevelandclinic.org/health/treatments/22567-stem-cell-transplants • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3033847/ • https://slideplayer.com/slide/14971933/ • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4311340/ • Alberta Health Services
Editor's Notes
- #5 Relying on the natural abilities of stem cells, researchers have used their biological mechanisms for stem-cell-based therapy. The cause of a disease is a vital consideration in selecting the proper stem cell mechanism and in the regeneration of tissue/organs using stem cell Translation Research a relatively new field of research, has recently greatly developed, making use of basic research results to develop new treatments. 2- preventing the cell death.
- #7 Disease-related mechanisms refer to the cellular and molecular processes by which a particular disorder is caused stem-cell-based therapies are considered a treatment method intended to compensate for the disruption caused by such mechanisms in order to finally restore the defective tissue Aim: Efficacy and safety The strength of in vivo studies is that they can supplement the limitations of in vitro applications can be inferred in humans through the use of human-like biological environments. ( in vivo)
- #8 The general purpose of a preclinical study is to present scientific evidence supporting the performance of a clinical study, and the following are required for a decision to move forward to clinical study: 1- (e.G., Validation, separation of active ingredients in vitro, and determination of its mechanism in vivo), 2- (e.G., Secure initial dose verification), 3-(e.G., Safe administration method, repeated administration, and interval verification 4-(e.G., Toxicity analysis according to single and repetitive testing), 5-(e.G., Genetic, carcinogenic, immunological, and neurotoxic analyses)
- #9 1- this will enable us to build disease-targeted stem cells by applying the appropriate stem cells to the appropriate diseases. 2- and the minimum effective capacity must also be determined. And maximum effective capacity 3- studies have shown that IV is the most common route . the routes of administration should be different depending on the target organ. Clinical trials have reported that the number of cells and treatment efficacy under the same conditions, as in preclinical studies, are not significant, but also differ in significance depending on the route of administration 4- all medical treatments have benefits and risks. only safe stem cells that have been employed in regenerative medicine so far are omnipotent stem cells, such as HSCs (Hematopoietic Stem Cells (HSCs) and MSCs, which are isolated from their self-origin iPSCs and ESCs face many hurdles, as they present higher risk, including the possibility of rejection, teratoma formation, and genomic instability MSCs, which are generally considered immune-tolerant as an immunomodulator, transplantation of ESCs and HSCs requires close examination of the matching of histocompatibility antigen (HLA) between the donor and beneficiary
- #10 the researcher must check the safety possibilities at every step deciding whether preclinical studies are sufficient for translating to clinical trials raises several issues that must be assessed by competent authorities. FDA and EMA
- #12 Summaries of each
- #13 A new phase of clinical trials should be started until the results of the previous completed phase have been reviewed by competent authorities to ensure that the new drug is safe, efficient and effective for the treatment of the target disease. Early phase one; PK and PD
- #16 Blood and lymph are the most common diseases that have benefited from this new approach lymphatic disease, lymphoproliferative disease, thymoma, to treat immune system disease; neoplasm, heart, and blood disease; and gland- and hor- treat immune system disease; neoplasm, heart, and blood disease; and gland- and hormone- and so on. In addition, various clini Despite this huge number of clinical studies, this does not mean that all studies led to great results nor to producing a new treatment. Some clinical trials were done to increase the effiency of the treatment comparable to other different treatments , others were done to analyze some parameters after the administration of stem cells into the body
- #17 Allogenic stem cells have been used more than autologous in clinical trials studies ( 46.34% vs. 44.51%)
- #19 Any stem-cell-based product is subject to Public Health Safety Act.
- #20 The 21 CFR part 210 contains the minimum current good manufacturing practice (cGMP) considered at the stages of manufacturing, processing, packing, or holding of a drug the 21 CFR part 211 contains the cGMP for producing final products. The 21 CFR 211 includes FDA guidelines for personnel, buildings and facilities, equipment, and control of components, process, packaging, labeling, holding, and so on, all of which are critical for pharmaceutical production The section, 21 CFR part 312, provides different information, including the requirements for an IND, its content and format, protocols, general principles of IND submission, the FDA describes the administrative actions of IND submission, the responsibilities of sponsors and investigators, and so on, in this section The 21 CFR part 610 contains general biological product standards for final product characterization . 21 CFR 1271 : in order to ensure adequate control for preventing the transmission of communicable disease from cell/tissue products. purpose of GTP is to present regulations for the establishment and maintenance of quality control for prevention of introduction, transmission, or spread of communicable diseaes
- #22 once administered, the cells may be essentially indistinguishable from host cells the ability to track the therapeutic cells is key to an objective assessment of risk with respect to inappropriate ectopic tissue formation or of tumorigencity. is especially important where the cells are administered intravenously The ability to determine the bio- distribution of administered cells raises technical issues, as monitoring the fate of exogenous cells will require the development of novel technologies. Furthermore, the detection of misplaced cells may necessitate a mechanism for their removal, The delivery of a cell with unlimited potential for renewal and the capacity to differentiate into any human cell type carries a burden of safety concern not associated with any other class of treatment.
- #23 as studies are typically run in immune-compromised or -suppressed animals. An alternative is to generate a species-specific homolog that may provide supportive data on the risk of immunotoxicity. potential that a human patient may generate an immune response to an administered product Immunogenicity may be influenced by multiple factors including the site of administration (potential sites of immune privilege e.g., the eye), the maturation status of the cells, the number of doses, the immunlogical basis of the disease, and an aging immune system. Sites with immune privilege are anatomical regions that are naturally less subject to immune responses ( CNS, Eye, brain )
- #24 Teratoma formation is due to having undifferentiated cells/ contamination the risk posed by these cells is the potential for their contamination of the preparation of differentiated cells for transplantation Risk of tumorigenicity come from the contamination of the iPSCs with undifferentiated cells and mutations of the adult stem cells while they were in the culture that adult stem cells or stem cell-derived differentiated cells themselves may be tumori- genic, perhaps due to mutations acquired during culture of the parent stem cell
- #25 through the employment of validated markers and new technologies such as imaging.
- #26 Chemotherapy if it is bone marrow transplant, chemo is given to remove the old stem cells. If you receive stem cells from a donor, the transplanted stem cells may attack your body ( GVHD)
- #28 For some therapies, such as restoring insulin levels in blood, the site-specific integration of the stem-cell–based product is not required for efficacy. However, for others, such as repairing the dopaminergic neurons damaged in Parkinson’s disease, site-specific integration of cells is essential for a therapeutic effect. in either case, integrating the cells into a nontarget location could raise questions about safety. 2- to determine the likely duration of the therapeutic effect. 3- safety and efficacy, we need to monitor the journey of cells after transplantation. To see where the effect is being exerted
- #30 1-Not all types of diseases respond to stem cell therapy. In case of allogenic stem cell transplant , a donor whose human leukocyte antigens (HLA) closely match the patient’s -people who have stem cell transplantation go through intensive chemotherapy before treatment. Medical conditions , End organ damage (cardiac, renal, hepatic, pulmonary) ( contraindications) may affect transplantation. Drug drug interactions with immunosuppressants meds and other meds that patient will take after transplantation Systemic or uncontrolled infection, if the patient has active infection then stem cell therapy is C/I transplant patients that smoke have a 30% increased risk of graft failure. Obesity (BMI > 30) reduced graft survival 7- Psychological factors affecting the ability to adhere to treatment and follow-up
- #32 The organ damage. Is very rare but some people get very sick after transplant because of complications affecting their major organs Central line to prevent infection Immunization: since the patient underwent chemo or radiation so the patient has lost the immunity to vaccine- preventable diseases. Patients can get re-immunized 6 months after the transplant. 5 to help the patient gain his energy back 6- and give the proper meds