Eight factors that need to be paid attention to in stem cell clinical trials:
2020-05-11
Stem cells are one of the most important fields in the frontiers of life sciences in various countries, and they are given priority support by the governments of various countries. In particular, governments at all levels in China have been supporting research in the field of stem cells. At present, stem cell products have been launched in the United States, Europe, Canada, South Korea and other countries. Although China has a similar number of clinical studies as the United States and maintains an absolute leading advantage globally, no stem cell products have yet been launched. While Japan, India, and Iran are rapidly emerging in the field of stem cell therapy, they may be ahead of China in clinical applications.
In order to maintain China's leading position in the field of stem cells, in addition to continuing to maintain the current development momentum in clinical research, we must increase efforts in product transformation.
1 Elements of concern in early clinical trials
Phase 1 clinical trials are a key step in the clinical transformation of stem cell products, and its main goal is to evaluate safety. Phase 1 clinical trials or First-in-human Clinical trial (FIH trial-the first human trial) can provide valuable data for clinical application, but the general principles of new drug development and stem cells must be fully considered when designing early clinical trials of stem cells The particularity of such as the characteristics of stem cells, the feasibility of the method of administration, the biological activity of stem cells, the initial effectiveness, etc.
Early clinical trials were mainly preliminary clinical pharmacology and human safety evaluation trials. Observe the human body's tolerance level and pharmacokinetics for new drugs, and provide the basis for formulating the administration plan, including the minimum effective dose, the dose-effect relationship, the feasibility of the administration route, etc. Therefore, the design of the clinical trial plan is very important and requires Overall consideration of various factors.
Starting dose
The starting dose of clinical trials is the key. However, the use of allometric scaling, as with small-molecule drugs, may be inaccurate for stem cells by inferring the dose administered in humans from the dose administered in small animals. It is recommended to refer to the previous clinical data of stem cell drugs as much as possible, even if the route of administration is different, it can also be used as a basis to indirectly prove the safety of the initial dose of the trial. For stem cells that are expected to be of low toxicity, the dose that produces the greatest biological effect and therapeutic potential should be explored.
2. Dose frequency
Most early trials of stem cell transplantation have chosen a single administration. The difference between cellular drugs and small-molecule drugs is that the elimination of small-molecule drugs in the body is regularly followed, but the situation of cellular drugs is relatively complicated. After transplantation of live cells into the body, they may also proliferate in the body, and it is difficult to predict the exact time of action, so the number and interval of administration must be strictly controlled.
3. Dose escalation
If you have no previous medication experience, it is recommended to use a staggered dosing approach. The staggered dose design can minimize the number of subjects at risk of unknown side effects of the drug. The treatment group can be completed in order from the lowest dose, and the data should be reviewed before increasing the dose. The staggered dose design is mainly to ensure that both acute and subacute adverse events can be monitored.
In addition, the duration of the product's biological activity should be considered when selecting the interval time for the staggered dose design.
4. Route of administration
To maximize the therapeutic effect of stem cells, the route of administration must be considered, and the method of administration should be selected according to different diseases. In addition to the commonly used intravenous administration, the reported administration methods include intraspinal canal (gradual freezing), carotid artery (stroke), muscle (lower limb ischemia), and coronary artery (myocardial infarction) administration.
5. Personalized stem cell product selection
Stem cell sources can be divided into autologous or allogenic sources. Self-derived stem cells are cells collected from the donor itself, and later only for their own use. Stem cells of allogenic origin are from normal healthy donors and can be mass produced for use by multiple people.
In contrast, autologous stem cells have more uncertainties-their proliferative capacity and cell function are affected by the donor itself. The function of stem cells derived from donors of different ages and physical conditions may vary greatly, which will Introduce uncertainties into the analysis of the results of subsequent clinical trials. Moreover, the production and preparation of autologous stem cells takes a long time, and it is difficult to ensure that the health status of the donor still meets the enrollment criteria for this clinical trial. Therefore, it is necessary to reserve a set of plans for this type of subject, or develop a set of independent standards to specify what type of patients can be given stem cell therapy.
6. Test population
The FIH trial has the potential risk of unintended side effects, so it is important to choose the right patient. The selection of subject groups for stem cell therapy clinical trials should focus on the balance between the potential risks and benefits of cell therapy and the accomplishment of research goals.
Due to the clinical trials of stem cell therapy, there may be persistent or permanent side effects, including the risks caused by invasive routes of administration. Because of these risks, patients with severe conditions are more suitable for this trial than healthy volunteers. On the one hand, seriously ill patients are more willing to take risks to try clinical trials out of consideration of their own situation; on the other hand, this also reduces the exposure risk of healthy volunteers.
However, there are many uncontrollable factors in severely ill patients. For example, patients may have adverse events related to the progression of the disease, which will undoubtedly increase the difficulty of analyzing the efficacy and safety data of stem cell therapy. Therefore, the subjects of the FIH trial are preferably those with a predictable prognosis, no feasible treatment, and sufficient time to evaluate the efficacy before the disease worsens or dies. At the same time, it is best for these patients to have detailed medical records to facilitate their traceability and follow-up.
7. Safety monitoring and follow-up
The scope of monitoring in the FIH trial includes medication errors, reports of acute and chronic poisoning cases, and adverse interactions with other types of drugs and foods. Its purpose is to detect various types of adverse reactions as early as possible and study the induction of adverse events. Factors and causality to take the necessary preventive measures to avoid the recurrence of serious adverse events and ensure the safety of medication.
Stem cell therapy is still in the experimental stage, and there is still uncertainty about the frequency or severity of adverse events. Therefore, when performing safety checks, in addition to general physical examination, symptom observation, biochemical and hematological indicators, it may be Echocardiographic monitoring, immunological examination, etc. are also required. In addition, it is also necessary to retain relevant samples such as plasma or serum before and after treatment for subsequent analysis. After cell transplantation, it is recommended to evaluate the action time or biological activity of stem cells to determine the survival status and migration distribution of stem cells in the body. It is also best to provide data for stem cell in vivo tracking studies.
In order to fully guarantee the safety of the subjects, it is necessary to include the trial termination rule in the research protocol, especially when safety problems occur early in the trial. The stopping rules must clearly specify the number of adverse events (including accidental deaths) that must cause the test to stop, and the test should be suspended until the situation is fully evaluated.
After the visit during the trial period, the subjects should be followed up for a period of time to regularly understand the changes in the patient's condition, guide the patient's recovery, and know the frequency of adverse events to further reduce the risk of participants in the trial. In some cases, telephone follow-up may be sufficient to obtain the required information.
8. Efficacy evaluation
In addition to the evaluation of drug safety, the preliminary efficacy data of stem cells need to be evaluated. Although most FIH trials lack a sufficiently large sample size to evaluate the biological activity and efficacy of the product, the initial therapeutic effect is an important scientific basis for conducting a phase 2 clinical trial.
2 Summary and outlook
As mentioned above, in order to achieve satisfactory results in clinical trials, each of the above links must be carefully considered. In addition, in order to make the results of the experiment more stable and reliable, we must not be slack in cell culture and preparation. In addition, when applying for the stem cell FIH test, in addition to being familiar with the regulations and all the guidance documents, the researchers also need to contact the review agency in the early stage of development and maintain interaction to ensure that the clinical trial is conducted in a reasonable and compliant manner.
Stem cell therapy is a new theory and technology that is expected to achieve clinical transformation. In addition to the difficulty of researchers in this field, its clinical application prospects have also attracted the attention of a large number of drug development companies and venture capital companies. In recent years, regulatory agencies around the world have also paid more and more attention to the research progress in the field of stem cells, including the safety and effectiveness of stem cell therapy and how to conduct it in an orderly manner. At the same time, a number of drafts for consultation have been issued, such as the release in February 2019 "Regulations on the Clinical Application of New Biomedical Technologies (Consultation Draft)", "Administrative Measures for Clinical Research and Translational Application of Somatic Cell Therapy (Trial)" (Consultation Draft), etc. released in March Activities are carried out in a healthy and orderly manner, and standardize clinical research and translation applications of new biomedical technologies.
Stem cell therapy bears many expectations, and all circles are working hard to promote the clinical transformation of stem cells. I hope that all comrades working on the front line can get good clinical trial data, and hope that every step can make stem cell therapy more effective. Close to the clinic!
