There are nearly 200 stem cell filing projects and stem cell IND registration acceptance projects in China, and the number of stem cell clinical pipelines developed through new drug registration and application continues to increase. This article combines the clinical research of multiple stem cell drugs of Xingdetong to sort out the clinical development strategy of stem cell drugs.
General principles of clinical design of stem cell drugs
Guided by clinical valueFrom determining the direction of R&D to carrying out clinical trials, we should implement the concept of clinical demand-oriented and carry out patient-centered drug research and development, so as to realize the fundamental value of new drug research and development - solve clinical needs and maximize the benefits of patients.
Patient-centeredThe patient-centered drug clinical trial design needs to pay attention to and collect patients' experiences and needs for diseases and diseases, and take reliable, meaningful and representative patient experience data as the scientific basis for scientific consideration of key elements in clinical trial design, so as to fully reflect the clinical benefits and risks from the perspective of patients. At the same time, patients' feelings of participating in clinical trials should be fully considered in the design of clinical trials, so as to promote patients' active participation in clinical trials and efficiently obtain high-quality clinical trial data. Subject selection and inclusion and exclusion criteria
The selection of subjects in clinical trials of stem cell ** drugs usually does not include healthy subjects, and factors such as disease stage or severity and pediatric subjects also need to be considered (see above: How to select subjects in clinical trials of cell ** products).
The inclusion and exclusion criteria of subjects in stem cell ** drug clinical trials directly determine whether subjects can be enrolled, which is the most critical point in the drug clinical trial program, reflecting the rigor and scientificity of the clinical trial program. Xingdetong Cell Clinical Research Center counted the relevant contents of the inclusion and exclusion criteria in the ongoing clinical trial protocols of 16 stem cell ** products registered on the clinical trial registration platform of the Center for Drug Evaluation of the National Medical Products Administration, and published the relevant analysis results in the Chinese Journal of Clinical Pharmacology.
Fig丨16 clinical trial protocols of stem cell ** products were included, and the exclusion criteria were summarized and summarized.
According to the analysis of Xingdetong Cell Clinical Research Center, in these 16 clinical trials, the vast majority of the trial protocols included diagnosis, age, and voluntary signing of informed consent as the inclusion criteria as the basic conditions for being able to participate in the screening, and other special situations were basically placed in the exclusion criteria. After statistics, summary and analysis, it is found that the exclusion criteria in the clinical trial protocol of stem cell ** products in China still exist due to the use of animal-derived serum and antibiotics in the preparation of stem cell preparations.
In the clinical trial program of stem cell products, the inclusion and exclusion criteria of subjects are related to the indications studied, but it is far from enough to limit this, Xingdetong Cell Clinical Research Center recommends that we should fully understand the characteristics of stem cell products, and formulate scientific and reasonable inclusion and exclusion standards in combination with the mechanism of action, pharmacological effects, adverse drug reactions, etc. of stem cell products, so as to maximize the safety of subjects.
Early exploratory clinical trials
The primary purpose of early exploratory trials, especially first-in-human trials, is to explore safety and tolerability.
The clinical starting dose, if available in animal experiments or in vitro data, may be helpful in determining the risk level of the initial cellular dose. If there is prior clinical data for the same or related products, even with different routes of administration or different indications, it can also contribute to the clinical starting dose.
The impact of dose changes on the safety and efficacy of subjects in non-clinical studies and clinical data of similar products should be considered when selecting dose escalation for dose-escalation and cohort-size stem cell-related products in first-in-human trials. Larger cohort sizes may be required to provide greater safety assurance when conducting clinical trials in patients with chronic or non-fatal diseases than patients with severe, life-threatening conditions.
In the first human trial, a certain interval between subjects is generally used to administer the drug case by case to avoid multiple subjects being exposed at the same time and increasing the safety risk.
A single-dose regimen is recommended for stem cell-related products that are used for the first time in humans. Multiple dosing may be used in early trials when there is evidence suggesting a low safety risk and that multiple doses may increase activity.
The maximum tolerated dose of the acceptable severity of toxicity or adverse reactions of stem cell-related products should be judged based on the severity of the disease and the expected benefit and risk, and it is recommended that the applicant clearly explore the method in the clinical trial protocol. For stem cell-related products, its range of biological activity or optimal effective dose may also be determined through dose exploration, and if stable biological activity or clinical benefit can be observed at lower dose levels, it may not be necessary for the applicant to determine the maximum tolerated dose of MTD. In principle, the confirmatory clinical trial dose should not exceed the dose range of the exploratory study.
Exploratory trial control settingEarly exploratory clinical trials are mainly to observe safety, and the importance of control settings is not as important as confirmatory trials, if the combination of drugs affects the observation of adverse reactions of this product, or if the activity or efficacy of the product is initially observed in the early exploratory study, it may be necessary for the applicant to set up a control.
If a control is required, the selection of the control should take into account multiple factors such as the purpose of the study, the degree and severity of disease progression, and the selection, for example, a placebo control in a phase I clinical trial A blank control may be useful to evaluate the safety of the investigational product and to preliminarily evaluate its effectiveness.
Other considerations: Applicants may consider the design of an early exploratory study based on the overall clinical study plan, incorporating design elements that will be useful for future product development in the early stage study, e.g., setting efficacy or in vivo pharmacodynamic observations in phase I clinical trials to gather preliminary evidence of efficacy. The applicant may consider designing the early study as a Phase I and Phase II trial conducted in combination, after the dose escalation and recommended dose are clarified, enter the expansion phase to continue to enroll additional patients at the recommended dose level to further observe the efficacy of the stem cell-related product. If this type of design is used, the principles and methods for moving from the dose escalation phase to the expansion phase should be specified in the protocol. Confirmatory clinical trials
The purpose of a confirmatory study (or pivotal study) of a stem cell-related product is to confirm the safety and efficacy of the preliminary findings in the exploratory study and to provide critical evidence of benefit risk assessment for drug registration.
Comparison (RCT) and blindingFor some indications, where there may be a lack of a suitable comparator, or where placebo is ethically inappropriate, a comparator may be considered with the best supportive level**.
Confirmatory trials of stem cell-related products are often recommended to remain blinded.
The evaluation criteria for efficacy and safety efficacy indicators should be consistent with the diagnosis and treatment guidelines or clinical consensus related to the indication.
Any unvalidated endpoint or surrogate endpoint should first be confirmed in an exploratory study for relevance to the patient's clinical benefit before being used in a confirmatory clinical trial. The clinical endpoint of a confirmatory trial should also focus on the duration of efficacy, and it is recommended that applicants set up sufficient observation periods to evaluate the long-term benefits of subjects according to the disease characteristics of the target population and the clinical benefit evaluation criteria.
Safety risks: Safety risks should continue to be monitored during the confirmatory clinical study phase. The safety analysis set should be large enough to adequately evaluate the safety of stem cell-related products to ensure safe use after marketing.
If there are significant pharmaceutical changes in the clinical trial process, these changes should be implemented prior to the start of the confirmatory trial and the impact of the process change on the efficacy and safety of the product should be evaluated from a clinical perspective.
Long-term follow-upDue to the uncertainty of the long-term survival and long-lasting effect of stem cell-related products, the applicant should conduct appropriate long-term follow-up of all subjects who received ** during the clinical trial. Monitoring long-term safety and duration of action in pediatric subjects may be more difficult than **, and applicants should consider this appropriately when planning long-term follow-up.
Post-marketing studies or surveillance
After obtaining marketing authorization for a product, it may be necessary for the applicant to collect real-world information on efficacy and safety through post-marketing observational studies or focused monitoring, and communicate with regulatory authorities through regular drug safety update reports (PSUR) or drug re-registration.
The field of cell ** is the key layout and characteristic layout of Xingdetong. As a "specialized, special and new" CRO, Xingdetong has laid out cell-related research very early, and the company has taken the lead in establishing a cell clinical research center, accumulating rich experience in cell research, and establishing a leading position and influence in the industry. In the process of continuously undertaking and completing cell clinical research projects, Xingdetong discovers and summarizes the common problems in the process of cell research, proposes solutions to common problems, and is committed to opening up the last mile of cell R&D and clinical application.
Xingdetong has undertaken nearly 30 cell** research projects, including stem cells, immune cells and other cell **IND clinical trials and IIT clinical research projects, and has successfully helped two cell drugs to be approved for IND. Xingdetong has now formed a complete cell product development consulting and service business, and has formulated a cell product adverse event monitoring plan, risk control plan, quality control plan, etc., to protect the rights and interests of subjects. The technical team of Xingdetong Cell Clinical Research Center is familiar with cell product research and development, clinical development, approval procedures and national regulatory laws and regulations, and can provide customers with one-stop services for cell drug development, from early project approval to R&D process to final registration. Xingdetong Cell Clinical Research Center can also help sponsors solve the pain points and difficulties faced by cell drug development (GMP plant planning, cell preparation process, SOP formulation, etc.), help enterprises avoid detours, promote the transformation of achievements, and accelerate the launch of cell products.
At present, there is a scarcity of systematically trained cell clinical researchers in the industry, and Xingdetong and the Clinical Research Committee of the China Medical Education Association have cultivated many batches of outstanding talents for the industry, which can help enterprises or institutions carry out stem cell clinical research related training. Xingdetong can provide the whole industry chain service covering the development of cell ** products:
References for this article:
1.Zhang ailing. Analysis of the inclusion and exclusion criteria of subjects in the clinical trial protocol of stem cell ** products[J].Chinese Journal of Clinical Pharmacology, 2023, 39(14).
2.Technical Guidelines for Clinical Trials of Human Derived Stem Cells and Their Derived Cells** Products (Trial) 2023
3.Technical Guidelines for the Research and Evaluation of Cell Products (Trial), 2017