Chronic lymphocytic leukemia (CLL) is a mature B lymphocyte clonal proliferation tumor that mainly occurs in the middle-aged and elderly population. Its overall incidence rate is increasing due to the deepening of social aging. In the past 20 years, the treatment options for CLL have continued to increase, treatment concepts and clinical practices are changing rapidly, and the survival and progression-free survival of patients have continued to be extended. At the same time, due to the inert characteristics of CLL and its high incidence in the elderly, compared with other malignant tumors, clinical trials of new CLL drugs need to pay more attention to the treatment goals and needs of patients in the design and implementation, so as to achieve a balance between maintaining and improving the quality of life of patients and traditional anti-tumor treatment concepts. In order to further clarify the technical standards, enable new drug developers for CLL indications to more accurately grasp the characteristics of the disease, promote the concept of new drug development with patients as the core, and pay more attention to and understand the needs of patients in the design and implementation of clinical trials, our center organized the drafting of the "Technical Guidelines for Clinical Development of New Drugs for Chronic Lymphocytic Leukemia". After internal discussions in the center and soliciting opinions from some experts, a draft for soliciting opinions has now been formed.
We sincerely welcome all sectors of society to put forward valuable opinions and suggestions on the draft for comments, and give us feedback in a timely manner for subsequent improvement. The deadline for soliciting opinions is one month from the date of publication.
Please send your feedback to the following contact person’s email:
Contact: Du Yu, Zou Limin
Contact: duy@cde.org.cn, zoulm@cde.org.cn
Thank you for your participation and strong support.
Drug Review Center of the National Medical Products Administration
June 20, 2022
I. Overview
Chronic lymphocytic leukemia (CLL) is a mature B lymphocyte clonal proliferation tumor with specific immunophenotypic characteristics, characterized by lymphocyte aggregation in peripheral blood, bone marrow, spleen and lymph nodes, and is still an incurable disease. The disease mainly occurs in the middle-aged and elderly population, with a median age of onset of over 70 years old [1,2]. As the aging of society deepens, the incidence of chronic lymphocytic leukemia is on the rise. The median survival of CLL patients can reach 10 years, but the prognosis of different patients is highly heterogeneous. Its relatively hidden and indolent disease characteristics make the timing of treatment very important; at the same time, the high incidence of the disease in the elderly population further increases the complexity of treatment options [3]. In the past 20 years, the treatment options for CLL have continued to increase, from the initial chemotherapy alone to the era of immunochemotherapy. In recent years, with the emergence of various low-toxic small molecule oral targeted drugs, chemotherapy-free options have gradually become the preferred option. When choosing a CLL treatment plan, the patient's basic conditions, tolerance and treatment intention will have a great impact on the achievable treatment goals, and also bring challenges to the design and implementation of clinical trials in the process of new drug development. For CLL, which presents an indolent feature of disease progression and is prevalent in the elderly with relatively poor tolerance and more comorbidities, how to achieve a balance between improving the quality of life of patients and the traditional anti-tumor treatment concept in the process of disease management is an issue that must be paid attention to in the development of new drugs. This technical guideline will be based on current clinical practice, combined with the experience and challenges of new drug development in recent years, and put forward views on how to fully consider disease characteristics and patient needs in the design and implementation of clinical research on new CLL drugs.
Small lymphocytic leukemia (SLL) and CLL are different manifestations of the same disease, but the diagnosis must rely on pathological histology and immunohistochemistry. Except for local radiotherapy for Lugano stage I SLL, other treatment indications and treatment options are the same as CLL. Therefore, except for the clinical differences in diagnosis, efficacy evaluation criteria, etc., this technical guideline is also applicable to SLL.
The views and suggestions in this technical guideline only represent the current considerations of the drug review agency. Some of the contents may no longer be applicable as clinical practice changes. They are for reference by applicants and researchers in drug development and are not mandatory legally binding. When applying this technical guideline, please also refer to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and other relevant technical guidelines issued at home and abroad.
II. Special considerations for clinical research based on disease characteristics
(I) Determination of treatment indications
Most CLL patients only have abnormal laboratory tests but no clinical symptoms when diagnosed. The quality of life of patients is not directly affected by the disease, showing typical hidden and inert characteristics. The current clinical consensus is that "inactive" (such as asymptomatic or low-stage) CLL patients do not need to receive treatment immediately. The standard of care (SOC) is follow-up observation. Early intervention cannot improve the long-term survival of these patients [2]. In principle, clinical trials of new CLL drugs should focus on patients with treatment needs, that is, patients with treatment indications, and the "treatment indications" should be clearly defined in the protocol. The definition of "treatment indications" in clinical practice at home and abroad is basically the same, but the specific expressions are slightly different. Attention should be paid to coordination when conducting international multicenter clinical trials. Disease recurrence is not a sufficient condition for starting subsequent treatment. Clinical trials in the relapsed population should also determine whether the patient has a "treatment indication". If an innovative drug hopes to conduct a clinical trial of early intervention in CLL (that is, include patients without conventional "treatment indications"), it needs to be very cautious. According to the general rules of anti-tumor drug development, the concept verification should be completed in the patient population with "treatment indications" at least first, and then the research population should be expanded to patients without "treatment indications", and active communication should be conducted with the Drug Review Center. It should be pointed out that even if early intervention delays the time for patients without "treatment indications" to enter the next stage of treatment (for example, prolonging event-free survival), it does not mean that early intervention is beneficial to the management of the patient's entire CLL course.
(II) Selection of treatment goals
Generally speaking, during the treatment of tumors, reducing the intensity of treatment may directly affect the cure rate or remission rate of the disease, and affect the improvement of progression-free survival and/or overall survival. However, high-intensity treatment may also bring more treatment-related toxicity, causing early discontinuation of the drug in those who are intolerant, or irreversible damage to organ function, affecting the patient's long-term quality of life, and even increasing the risk of non-progressive death. A considerable number of CLL patients are elderly patients ≥75 years old, and their age is close to the average life expectancy of the whole population. Patients may obtain more meaningful clinical benefits from mild treatment regimens than younger patients, and treatment toxicity is more likely to cause irreparable damage to their quality of life and long-term survival. Therefore, when launching a clinical trial of a new drug in the CLL population, the target population should be predicted in combination with the drug's mechanism and potential toxicity. For example, cytotoxic drugs are selected for patients aged <65 years old or whose treatment goal is to delay disease progression through deep remission, while low-toxic targeted drugs or treatment regimens that can be maintained for a long time can be selected for elderly patients with poor physical condition or whose treatment goal is to improve the quality of life during the expected life span.
(III) Stratification of treatment population
After determining the treatment indications and treatment goals, stratified treatment should be carried out according to the patient's general condition, biological characteristics and treatment goals. Patients with certain biological characteristics (such as del 17p, TP53 mutation) usually have poor response to chemotherapy and have a greater clinical need for new treatment methods. Most CLL patients are elderly people over 70 years old. In clinical practice, there are many factors that affect treatment decisions. In order to improve the operability of clinical trial screening subjects, the patient's age and health status assessment results should be combined before enrollment to determine which treatment stratum the patient roughly belongs to. Although age is not the only factor that determines the patient's physical condition, as age increases, the individual's tolerance to treatment tends to decline, and it is associated with more comorbidities, impaired organ function, and cognitive impairment. The definition of "elderly" varies from country to country[4], but in the treatment of CLL, it is generally believed that those aged <65 years[3] have relatively good tolerance for high-intensity treatment and have a greater need for deep or lasting remission. Patients aged ≥65 years need to choose a treatment plan based on their physical condition. How to comprehensively judge the physical health status of patients still needs to be explored in hematological malignancies. Using appropriate health assessment tools for the elderly is a common means of judging the physical status of patients. The cumulative illness rating scale for geriatrics (CIRS-G) is a commonly used assessment tool in CLL clinical trials [1, 5]. However, these tools have been well correlated with important events such as death, disability or hospitalization in Western populations, but most of them lack scientific and rigorous validation studies in the Chinese population.
(IV) Other considerations
In view of the fact that elderly patients are prone to cognitive impairment, an informed consent form commensurate with their age characteristics should be provided, and if necessary, an informed consent form signed by the guardian should also be provided.
III. Dose exploration
Early studies of innovative anti-tumor drugs (especially the dose escalation stage) usually select relatively young patients or healthy volunteers with better physical condition scores for dose exploration. When CLL is the target indication, the dosage or regimen determined based on early studies may not be suitable for all patients (especially elderly patients or those with poor physical condition). The tolerance and treatment response of young patients may be different from those of elderly patients.
First, the overall direction and strategy of dose exploration should be selected according to the drug mechanism. For example, cytotoxic drugs can still adopt the traditional strategy of determining the maximum tolerated dose based on dose-limiting toxicity as an indicator for new anti-tumor drugs, because in theory, the efficacy of such drugs increases with increased exposure; for targeted drugs with biomarkers that have good correlation with efficacy, the dose before the pharmacodynamic index enters the plateau phase can be selected as the expansion dose or the recommended dose for phase II (RP2D) based on the results of the exposure-effect relationship analysis during the dose escalation process to reduce excessive exposure without efficacies.
Secondly, according to the specific method for determining the expansion dose or the dose of the later study, combined with the overall characteristics of the subjects included in the previous study, it is analyzed whether it is necessary to further conduct exploratory studies of relatively low-dose regimens in elderly patients, and whether it is necessary to adjust the dose according to the treatment goals of different populations. The tolerance characteristics and/or treatment goals of different populations should be fully considered during the dose exploration or expansion process, and a sufficient proportion of elderly patients (focusing on elderly patients aged ≥75 years) should be included in the clinical research stage to analyze and determine the impact of age/basic conditions on pharmacokinetics, tolerability and pharmacodynamics. Attention should be paid to the dose adjustment strategy for drug treatment toxicity. Whether it is more helpful to achieve long-term treatment benefits by suspending medication or reducing the dose.
The rationality of the duration of administration should also be one of the issues that need to be focused on in the exploration stage. Generally speaking, cytotoxic drugs often adopt a limited-cycle shock treatment strategy, while small molecule oral targeted drugs that have been successfully developed in recent years often adopt a long-term continuous treatment strategy. However, there is controversy over the benefits of maintaining the original dose and frequency of treatment after achieving remission (especially complete remission), especially for elderly patients with fragile organ function and more combined medications. The possibility and timing of drug discontinuation should be explored during clinical studies.
Elderly patients have a high proportion of combined liver and kidney damage, relatively weak bone marrow compensation ability, and a high possibility of having underlying diseases (such as hypertension, diabetes, cardiopulmonary disease) and needing to take other drugs for treatment. Therefore, studies on the effects of liver and kidney function on pharmacokinetics and drug interactions should be carried out as soon as possible, and more attention should be paid to the effects of drugs on cardiac electrophysiology. In early studies, if it is predicted that there will be no additional treatment risks, the restrictions on the subjects' liver and kidney function, bone marrow function, and cardiopulmonary function can be appropriately relaxed to make the enrolled patients more representative of the characteristics of CLL patients in the real world.
IV. Efficacy endpoints
The efficacy endpoints related to anti-tumor efficacy in clinical trials of CLL populations, including remission rate, time-related indicators and symptom endpoints, follow the general principles and definitions of anti-tumor drug clinical trial endpoints [6].
(I) Remission or progression
Clinically, the changes in tumor burden and the recovery of bone marrow hematopoietic function are used to determine whether the disease has remitted or progressed. Evaluation criteria that are widely used in clinical practice and supported by sufficient evidence should be used. The specific judgment criteria are not elaborated in this technical guideline. There are differences in the efficacy evaluation criteria commonly used at home and abroad. Attention should be paid to coordination when conducting international multicenter clinical trials [3, 7]. In the process of new target drug development, there may be situations where conventional efficacy evaluation criteria are not applicable. The clinical significance of these new phenomena should be closely observed from early clinical trials, and the possible impact of new treatment response types on progression-free survival or survival time should be analyzed. Remissions lasting less than 6 months are considered to be clinically insignificant [7].
Complete remission (CR): When lymph node, liver, spleen, peripheral blood test results and clinical symptoms indicate that the patient may have a CR, a bone marrow puncture or biopsy should be performed for confirmation. If the patient's other symptoms, signs and test results (including bone marrow puncture or biopsy) are consistent with CR except for bone marrow hematopoietic function, and it can be confirmed that anemia, thrombocytopenia or neutropenia are not related to CLL, the patient can be diagnosed with incomplete CR (CRi). In clinical trials, the outcomes of patients evaluated as CRi should be closely followed up rather than simply merging them with CR patients. In clinical trials, CT test results of lymph nodes, spleen and/or liver should be used as the basis for judging disease remission.
Partial remission (PR): The absolute value of peripheral blood lymphocytes and their changes relative to the baseline are usually one of the important indicators for judging whether CLL patients have remission or progression. However, some targeted therapeutic drugs cause a simple increase in lymphocytes in the early stage of treatment, and lymphocytes gradually return to normal after continued treatment. The efficacy evaluation criteria have been revised for this situation. Lymphocyte elevation alone is not used as the basis for disease progression. When other indicators meet the partial remission criteria, they are evaluated as partial remission with lymphocyte elevation (PR-L). In clinical trials, the outcomes of patients evaluated as PR-L should be closely followed up. These patients may not be evaluated as having disease progression before other evidence of progression appears, but they cannot be simply combined with PR patients. In particular, patients who are diagnosed as PR-L and whose only treatment indication is "progressive lymphocytosis" should be paid attention to.
Note. When comparing with historical data, PR-L should not be included in the ORR for comparison.
Progressive disease (PD): In the PD criteria, decreased platelets and hemoglobin should exclude non-CLL causes such as treatment toxicity and autoimmunity. When it is impossible to distinguish, a bone marrow puncture or biopsy should be performed for differential diagnosis.
Minimal residual disease (MRD): For patients who achieve CR, MRD testing should be considered to further evaluate the depth of remission. Applicants are encouraged to explore the value of MRD in prognosis and treatment optimization (such as discontinuation guidance) in clinical trials. Flow cytometry and polymerase chain reaction (PCR) are more mature MRD detection methods, and second-generation DNA sequencing technology (NGS) can also be used. The sensitivity of the detection method should be sufficient to detect 1 CLL cell in 10,000 white blood cells (MRD <10-4 or 0.01%). MRD testing can be done by sampling bone marrow and peripheral blood, but the test results of the two samples are different. Some studies have shown that undetectable MRD (uMRD) in bone marrow is a better prognostic indicator than uMRD in peripheral blood [8], but sampling peripheral blood is more convenient and less invasive. It is recommended to reasonably select the sample sampling and testing time points for MRD testing based on the specific trial drugs, the purpose of MRD testing, and the treatment goals of the patient population in the clinical trial, and predetermine them in the study protocol. When calculating the uMRD rate, all patients who received treatment should be used as the analysis set rather than those who achieved CR.
(II) Time-related indicators
Progression-free survival (PFS): defined as the time from the date of first treatment (the date of randomization in randomized controlled studies) to the date of the first symptom or sign of disease progression or the date of death from any cause (whichever occurs first).
Event-free survival (EFS): defined as the time from the first day of treatment (the date of randomization in randomized controlled studies) to the date of the first symptom or sign of disease progression, or the date of starting a new anti-tumor treatment, or the date of withdrawal from the trial due to drug toxicity, or the date of death (whichever event occurs first). When achieving remission is the treatment goal, the definition of "treatment failure" can be proposed in combination with the results of previous studies, that is, when the treatment goal has not been achieved after a certain period of treatment, the possibility of obtaining valuable clinical benefits from continued treatment is very small, and treatment should be stopped. In this case, "treatment failure" also constitutes an EFS event.
Duration of remission (DOR): defined as the time from the date of confirmation of remission (the time of completing bone marrow confirmation for complete remission) to the date of the first symptom or sign of disease progression, or the date of starting a new anti-tumor treatment, or the date of death (whichever event occurs first). When calculating DOR, if the patient initially evaluated as CRi or PR-L subsequently converts to CR or PR, the time of evaluation as CRi or PR-L can be used to calculate DOR; otherwise, CRR or ORR can only be included in the sensitivity analysis and DOCR or DOR can be calculated.
Overall survival (OS): defined as the time from the date of first treatment (the date of randomization in randomized controlled studies) to the date of death. In CLL studies, it is recommended to distinguish the cause of death as CLL-related or non-CLL-related. Non-CLL-related deaths during trial drug treatment should be further analyzed to see if they are related to treatment toxicity. For elderly patients, the impact of life expectancy on OS needs to be considered.
Innovative mechanism-target drugs should actively analyze the correlation between symptom improvement, remission rate, PFS and OS after treatment in early exploratory studies as the basis for selecting alternative endpoints in key registration studies. The subjects included in the early exploratory studies should be followed up for a long time and with high quality. The follow-up data can serve as a supplement and support for key registration studies.
(III) Quality of life evaluation and patient-reported outcomes
As mentioned above, considering that a considerable number of CLL patients are elderly patients, it is necessary to strike a balance between pursuing deep remission and reducing treatment toxicity. Maintaining or improving their quality of life (QOL) during treatment may be as important as prolonging their survival time. Studies have shown that QOL is valuable for the prognosis of CLL patients [1]. Therefore, when conducting clinical trials of new drugs in CLL patients, QOL assessments should be routinely performed or patient-reported outcome scales should be used to obtain patient experience, insights, or demand data, and even the effects of different doses on QOL should be considered when determining the dose. QOL can be evaluated using mature and validated scales, such as the EORTC QLQ-C30 and its supplement QLQ-ELD14 for elderly patients, which are commonly used QOL scales in clinical trials; PRO measurement scales suitable for specific drugs or populations can also be developed in accordance with relevant guidelines [9]. It is encouraged to analyze comprehensive quality and survival indicators such as quality-adjusted time without symptoms of disease or toxicity (Q-TWIST) in clinical trials as a supportive basis for the evaluation of benefits and risks after treatment.
V. Pivotal registration studies
This chapter is mainly aimed at pivotal registration studies. Exploratory studies should have good continuity with pivotal registration studies, and their research results should support each other. Therefore, the definitions and requirements proposed in this chapter can also be referred to when designing exploratory studies.
(I) Baseline assessment
For patients with initial diagnosis, some key diagnostic indicators (such as peripheral blood flow cytometry to determine immunophenotyping) should be reviewed and confirmed by the central laboratory before entering the clinical trial; other patient populations involving key examination indicators in the inclusion and exclusion criteria should also be screened based on the test results of the central laboratory. Perform a comprehensive physical examination, especially palpation of superficial lymph nodes, liver and spleen. Evaluate physical status, organ function, comorbidities, etc. to assess physical status. Conduct comprehensive routine chromosome karyotype analysis, and use peripheral blood for fluorescence in situ hybridization (FISH) to detect cytogenetic abnormalities such as del (13p), +12, del (11q), and del (17p), and clarify whether there are gene mutations such as TP53, IGHV, NOTCH1, SF3B1, or BIRC3. Research and development units are encouraged to predict the biological characteristics of benefited patients based on the targets or mechanisms of action of new drugs and selectively screen subjects, or focus on observing the effects of these biological characteristics on treatment response in trials. If necessary, new biomarkers should be explored and analyzed for their value in determining the therapeutic advantages of new drugs.
Complete and record clinical staging, including Binet staging and Rai staging, and use the chronic lymphocytic leukemia international prognostic index (CLL-IPI) for risk stratification. Complete treatment indication assessment.
(II) Population definition
Newly diagnosed patients who have not received systemic treatment in the past: In clinical practice, the treatment plan is determined based on the patient's age, presence of del (17p)/TP53 gene mutation and physical condition. Therefore, the specific requirements for the above situations need to be clearly stated in the definition of the target population. If there is no del (17p)/TP53 gene mutation, they are divided into three categories: young patients aged <65 years, patients aged ≥65 years but in good physical condition, and patients aged ≥65 years and in poor physical condition. Patients with del (17p)/TP53 gene mutation have a poor response to chemotherapy. In addition, corresponding requirements can be made for other prognostic factors such as IGHV gene mutation status and CLL-IPI risk stratification based on the advantage population identified in previous studies.
Relapsed or refractory patients: Relapse: patients achieve CR or PR, and the disease progresses after remission lasts ≥6 months; Refractory: treatment failure (no PR), disease progression during treatment or remission lasts <6 months [3]. For patients with relapsed or refractory disease, the next-line treatment plan will be determined based on the previous treatment plan, duration of remission, presence of del (17p)/TP53 gene mutation, and physical condition, so it should be clarified when defining the target population. For refractory patients, if the previous treatment plan is a small molecule targeted drug that requires continuous administration, the shortest treatment duration should be clarified for those who fail the treatment (the requirement can be made based on the median time to remission after drug treatment). Determination of the number of treatment lines: Each treatment plan should have enough cycles to achieve the treatment goal; there should be clear records of previous treatment failure, disease recurrence or progression before starting the next-line treatment; if a certain treatment plan is continuously remitted for ≥2 years and the treatment plan is repeated after progression, the same dosing plan should be counted as 1 line.
Stratification factors: The patient's clinical stage, CLL-IPI risk stratification, del (17p)/TP53 gene mutation, IGHV gene mutation status, previous treatment lines, whether it is refractory to a certain class of drugs, etc. may affect the patient's treatment response to other drugs/plans. It is recommended to select reasonable stratification factors based on specific drugs and other research design elements.
(III) Comparison Selection
In principle, the best available treatment for the target population should be selected as the comparison therapy for the pivotal registration study. As described in “5.2 Population Definition”, there are many factors to consider in the treatment decision-making of CLL patients, and the selection of the comparison regimen should match the population definition. Generally speaking, patients with del (17p)/TP53 gene mutations have a poor response to chemotherapy. At this stage, BTK inhibitors ± CD20 monoclonal antibodies can be selected as comparison therapy; patients without del (17p)/TP53 gene mutations, young people or those in good physical condition can choose high-intensity immunochemotherapy regimens, while patients in poor physical condition can choose reduced-intensity immunochemotherapy regimens or chemotherapy-free targeted therapy regimens as comparison therapy. The comparison therapy can be a single standard regimen or recommended regimen, or it can be multiple regimens that researchers can choose. If a new drug is added (add-on) or a new drug is used to replace an existing drug on the basis of an existing standard regimen or recommended regimen, it is recommended to use the basic regimen before the addition or replacement as the comparison therapy. In recent years, new CLL treatment options have emerged, evidence-based evidence has been updated very quickly, and treatment concepts in clinical practice are also evolving. Therefore, it is recommended to communicate with the Center for Drug Evaluation on the selection of control treatments before conducting key registration studies.
There are differences in the availability of drugs for CLL indications at home and abroad, and standard treatment options and recommended treatment options are not exactly the same. When conducting international multicenter clinical trials, attention should be paid to coordination and active communication with the Center for Drug Evaluation should be conducted.
(IV) Study endpoints
The main treatment goals of CLL include symptom improvement, durable disease remission, and prolonged survival [2]. When determining the primary endpoint of a clinical trial, the characteristics of the target population, the mechanism of action of the drug, and the safety characteristics should be combined to select indicators that both meet the treatment goals and reflect the advantages of drug treatment as the primary study endpoint. Regardless of the direct treatment goal, it should not be at the expense of the patient's survival time, and the patient's quality of life should be maintained or improved while prolonging survival time.
CLL is an indolent disease. According to the risk stratification of CLL-IPI, even the 5-year survival rate of high-risk patients reaches 63.6% [3]. When OS is not feasible as the primary efficacy endpoint, it is acceptable to use the alternative endpoint PFS as the primary efficacy endpoint to support routine approval [10]. When the primary analysis results of the primary efficacy endpoint of PFS are used as the key data for marketing authorization application, the OS data of the same period should show a good correlation between PFS benefit and OS improvement. After the completion of the primary analysis of the primary efficacy endpoint, long-term follow-up of time-related indicators such as PFS and OS should be continued as the basis for overall benefit-risk evaluation. When analyzing OS data, the impact of causes of death, especially non-CLL-related deaths, on the results should be considered, and deaths caused by treatment toxicity and deaths caused by patient aging should be distinguished. If necessary, indicators such as age-adjusted life expectancy can be used to perform sensitivity analysis on death data. ORR and PFS results evaluated by an independent efficacy evaluation committee under blinded conditions should be provided to support the evaluation results of the investigators.
The key registration study must evaluate the patient's QOL as part of the benefit-risk assessment in accordance with the requirements of "4.3 Quality of Life Evaluation and Patient-Reported Outcomes" of this technical guideline. Life extension without quality or low quality is of no clinical value.
In recent years, new drugs and new regimens have emerged continuously, and the PFS of CLL patients has been significantly improved. Even the clinical research and development cycle with PFS as the primary efficacy endpoint has been significantly extended, which has brought considerable challenges to the development of new drugs. R&D institutions are encouraged to strengthen exploration in the following directions: 1. Exploration of superior populations. Explore whether innovative drugs have outstanding advantages in those who respond poorly to existing treatments. For example, IGHV non-mutation and CLL-IPI risk stratification as extremely high risk are independent prognostic factors, which means shorter PFS and OS; explore biomarkers that can be enriched in the population, break the conventional diagnostic limitations, expand the target indication population and shorten the research and development cycle. 2. Correlation study of surrogate endpoints and clinical endpoints. In the exploratory research stage, actively discover effectiveness indicators that can represent the advantages of drug treatment, and study and verify the feasibility of the effectiveness indicator as a surrogate endpoint with good correlation with the clinical endpoint. 3. Breakthrough of traditional treatment strategies. Conduct in-depth analysis of clinical needs that cannot be met by current conventional treatment strategies, propose solutions, and explore and verify them in new drug clinical studies as the basis for the design of key registration studies.
VI. Safety evaluation
Since most CLL patients have blood cell decreases due to the primary disease, if peripheral blood cell decreases occur during treatment, it is necessary to analyze whether the cause is treatment-related blood toxicity or disease recurrence/progression. If necessary, bone marrow puncture or biopsy should be performed. In clinical trials, a bone marrow puncture/biopsy before the patient starts treatment can help identify unexplained peripheral blood cell decreases during treatment.
Since most CLL patients have a certain degree of peripheral blood cell count decrease at the baseline of clinical trials, the use of the same blood system toxicity evaluation criteria as other tumor types may result in patients already having grade 2-4 blood system toxicity when starting treatment. Therefore, based on the characteristics of CLL, the modified blood system toxicity rating criteria shown in Table 1 can be considered [1].
Table 1 Rating criteria for hematologic toxicity in CLL clinical studies
The rating of non-hematologic toxicity is based on the same criteria as other tumor types, and the latest version of NCI-CTCAE is usually used in clinical trials.
VII. Post-marketing requirements
The post-marketing requirements for innovative CLL drugs should be considered from at least the following three aspects:
1. Continue to enrich the safety and efficacy data of long-term medication: Continue to follow up pre-marketing registration studies, conduct real-world studies after marketing, widely collect safety and efficacy data of long-term medication for patients, and in a more diverse large sample Observe the safety of medication in the population.
2. Optimization of dosing regimen: Many issues related to dosing regimens may not be resolved through pre-marketing registration studies, such as the rationality of long-term uninterrupted medication and the timing of discontinuation, and should be studied and optimized after listing. Considering the impact of individual risk and prognostic factors on the selection of CLL treatment options, applicants are encouraged to continue to explore whether patients with different characteristics need differentiated treatment after the drug is listed.
3. Clinical risk management plan: Develop reasonable patient care plans or educational materials based on the characteristics of elderly patients to reduce the risk of medication errors in elderly patients, or reduce the risks caused by long-term combined use with other drugs.
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