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    Home > Medical News > Medical World News > CDE publicly solicited the opinion of the Technical Guidelines for Clinical Trials of Anti-Oncology Joint Therapeutics.

    CDE publicly solicited the opinion of the Technical Guidelines for Clinical Trials of Anti-Oncology Joint Therapeutics.

    • Last Update: 2020-08-03
    • Source: Internet
    • Author: User
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    On July 17th, CDE publicly solicited the opinion of the Technical Guidelines for Clinical Trials of Anti-Tumor Joint Treatment: Anti-tumor Drugs are one of the hot spots in the research and development of new drugs in the world.
    different mechanisms and different targets of drug combination therapy is still an important means to improve efficacy and overcome drug resistance.
    the current drug development of anti-tumor combination therapy is very active, and even from the early stage of clinical trials has entered the joint development of two or more innovative drugs.
    reasonable combination therapy can lead to better treatment options for tumor patients, but inappropriate joint development increases the risk of subjects, reduces clinical research and development efficiency, wastes time, financial resources and medical resources, and hinders the development of truly effective combination therapy drugs.
    for this reason, it is very important to establish a scientific and reasonable joint development path.
    in order to encourage innovation and guide the development of scientific and orderly clinical trials of anti-tumor drug joint therapy, the Drug Review Center has organized the "Technical Guidelines for Clinical Trials of Anti-Tumor Drug Joint Treatment" (Draft for Comments).
    the foreword and background of this guiding principle, and describes the background and purpose of writing.
    the basis of joint development, the rational basis should be presented before carrying out the exploratory clinical trial of joint administration. In the design part of clinical trial,
    expounds the experimental design principles and consideration of benefit evaluation for the joint development of anti-tumor drugs at different stages, as well as other problems in the trial design, including blinding, sequential testing, research endpoint, standard treatment adjustment and other special circumstances.
    attached: anti-tumor drugs joint treatment clinical trial technical guidelines (draft for comments) I, the foreword anti-tumor drugs is one of the current global research and development of new drugs, with the progress of new drug research and development, tumor treatment methods continue to increase, the overall efficacy gradually improved.
    because of the complexity of tumors, combination treatment of drugs with different mechanisms and targets is still an important means to improve efficacy and overcome drug resistance.
    the current drug development of anti-tumor combination therapy is very active, and even from the early stage of clinical trials has entered the joint development of two or more innovative drugs.
    reasonable combination therapy can lead to better treatment options for tumor patients, but inappropriate joint development increases the risk of subjects, reduces clinical research and development efficiency, wastes time, financial resources and medical resources, and hinders the development of truly effective combination therapy drugs.
    for this reason, it is very important to establish a scientific and reasonable development path for combination therapy.
    the U.S. Food and Drug Administration (FDA) issued a joint industry guide for the joint application of two or more new drugs in 2013, providing general guidance on clinical trial designs developed jointly against oncologists.
    With the increasing number of new anti-tumor drugs in China in recent years, the research and development environment is becoming more and more complex, it is urgent to formulate relevant technical guidelines suitable for China's current level of research and development and regulatory environment, and to clarify the clinical trial design and benefit consideration sandinalization for joint development of anti-tumor drugs.
    , the purpose of background combination therapy is usually to improve efficacy, reduce adverse reactions, or improve the convenience of treatment.
    the core purpose of combination therapy in the field of cancer therapy is to improve the efficacy.
    therefore, this guideline discusses the clinical trial design of anti-tumor combination therapy, which is the main goal of improving efficacy. Before carrying out the joint development of anti-tumor drugs,
    should first have a sufficient basis for the rationality of joint treatment as the theoretical basis for joint development, and then conduct joint therapeutic clinical trials based on scientific evidence based on the characteristics of clinical trial data of their respective single drugs.
    these guidelines will be based on different stages of joint treatment clinical trials, the experimental design principles and benefit evaluation of the joint development of anti-tumor drugs, with a view to providing reference for the joint development of anti-tumor drugs, scientific and orderly research and development.
    this guiding principle represents only the current views and perceptions of drug regulators.
    As scientific experiments progress, the relevant content sins in this Guideline will be continuously improved and updated.
    apply ingons to design and implement research, please refer to the Code of Quality Management for Drug Clinical Trials (good clinical practice, GCP), the International Association for the Coordination of Technology in Human Drug Registration (INTERNATIONAL international, ic) and other relevant guidelines that have been published in the country.
    . Before carrying out an exploratory clinical trial of joint administration, the basis for joint development should have a reasonable basis for joint development, which usually includes: (1) the rationality ;( of the joint development mechanism, the basis of the proposed joint scheme of single-drug clinical data.
    3.1 The basis of rationality is the rational basis of the joint development of anti-tumor drugs.
    Before joint development, applicants should conduct joint lying mechanism research on the basis of in-depth exploration and research on the mechanism of single drug action, and encourage active exploration of biomarkers for predicting the effective combination of treatment.
    principle, the rational basis of joint development of new drugs should come from the product's own non-clinical trial results, such as the existing clinical trial results of the same target product to support its joint effect mechanism, can also be used as a reference basis.
    routine requirements for non-clinical research data are subject to ICH S9 and its Q and A.
    3.2 Clinical data of single drug obtained relatively sufficient clinical data of their respective single drug, which will provide the basis for the design of scientific and reasonable combination drug dose selection, timing of administration, safety risk control and so on. Before entering the first combination treatment, the
    should obtain relatively sufficient data on the clinical pharmacology and safety effectiveness of a single drug to be combined with a new drug, including human pharmacokinicities parameters, safe dose range, dose-exposure-effect relationship, and the proposed phase II recommended dose (recommended dose II, RP2D) to assess the possible drug interactions (drug-drug, DDI), and other important toxicity risks between the proposed combination drugs.
    consider the dose-incremental design and risk control of combination therapy based on the data of single drug clinical trials.
    for each single drug has anti-tumor activity of the new drug, before joint development, recommended in the target indications to obtain the initial single drug effectiveness data, as a reference for the follow-up analysis of the cause design.
    the results of non-clinical studies do not have significant anti-tumor activity, but the combination with other anti-tumor drugs may improve efficacy of drugs, in accordance with ethical and related technical requirements, can be carried out in healthy subjects in a single drug clinical pharmacological research, further support in the tumor subjects in the joint treatment trial.
    . Clinical trial design is based on in-depth mechanism research data, explores the clinical advantages of joint development, and finally confirms that clinical value is the general principle of joint development of clinical trial design of anti-tumor drugs. There are different concerns in the research objective and design of the exploratory test and the confirmed test of
    combination drug use.
    4.1 Exploratory experimental anti-tumor drug joint development of the exploratory trial phase of the experimental trial, the goal is to explore the combination treatment dose (including the timing of drug use), potential beneficiary population and to explore the effectiveness of the combination therapy, whether it is effective, to provide a reasonable basis for determining the joint treatment plan to enter the definitive trial.
    exploratory research, the focus should be on joint climbing design, efficacy analysis and subject risk control.
    4.1.1 Climbing design should assess DDI risk according to the obtained single drug clinical pharmacology, combine the safety characteristics of single drug, and set the starting dose and dose increment design of combination therapy.
    in the case of the new drug A combined standard therapy (standard of care, SOC), you can usually choose a single dose of A drug RP2D (e.g. 1/2 RP2D) as the starting dose and SOC combined;
    In addition to the combined dose, it is suggested to pay attention to the mechanism of action, PK/PD and safety characteristics of the proposed combination drug, and to consider the rationality of the timing of administration.
    4.1.2 The core evaluation point of considering combination therapy is the rationality of combination drug use, therefore, the therapeutic cause is the core element of joint development and evaluation, and the idea of analysis of the reason should run through the joint development of anti-tumor.
    in early exploratory trials, special attention should be paid to the efficiencies of combination therapy , which can be compared in a variety of ways, such as forward-looking small sample randomized controls, historical data controls, or real-world data, to provide evidence of efficiencies in combination therapy.
    full therapeutic analysis research at the exploratory research stage will help simplify the program design of the definitive test.
    for example, target indications in A and B are not listed new drugs, the early available sufficient data show that A and B of single drug efficacy are significantly lower than SOC, but the efficacy of combination therapy may be better than SOC, according to the previous full efficacy analysis test results, in the confirmed test using the design of A-B vs SOC, not set A and/or B single drug treatment group.
    early research and development should also pay attention to another situation: if the plan to develop a joint treatment model of A-B, and A-target product single drug in the target indication has been approved, then single drug A should have the ability to independently become a drug, should focus on the experimental test A drug-based and joint B clinical value, to avoid A for therapeutic reasons can not be single-drug (target indications is less effective than the same target or similar multi-target varieties)
    whereever possible, attention should be paid to the effectiveness of combination therapy and the efficient determination of the joint model for entering a definitive trial.
    4.1.3 Risk Control Combination Therapy increases the risk of subjects, with special attention to subject risk control, and recommends the development of risk control plans for clinical trials for joint therapy.
    the potential safety risks of combination therapy are comprehensively assessed on the basis of the pharmacodynamic mechanism of the proposed combination drug, the target toxicity/adverse reaction mechanism, the risk of drug interaction, etc.
    consider the details of the entry criteria of the program design, the prevention, identification, monitoring and intervention of important combination drug risks, clarify risk management measures, and continuously improve the risk control plan based on the safety data obtained in the previous clinical trial.
    4.2 Confirmed experimental anti-tumor drugs joint development of the definitive test phase, the goal is to confirm that the risk of combined therapy for the target patient population is significantly greater than single drug treatment or standard treatment.
    therefore, the rationality of combination therapy should be confirmed through reasonable research and design.
    applicants should first assess the adequacy of pre-clinical trial data before conducting a key study of combined drug use to support registration.
    4.2.1 Support data considerations Should have relatively sufficient exploratory clinical trial data to support dose selection, timing and safety of combination therapy before conducting a definitive trial.
    wherever possible, the evidence that a combination of synergies should be obtained from target indications, such as that A-SOC is superior to SOC, or that A-B is better than A-B and that it is better than B.
    , when it is unlikely to obtain a combination drug efficiencies in early small-sample exploratory trials, the combined drug tests of the population of patients with the same tumor late stage can be designed and carried out, drawing on the evidence of the benefits of the same tumor patient.
    for example, the use of joint efficiencies in patients with advanced non-small cell lung cancer supports joint development in assisted/new assistive therapy for non-small cell lung cancer that can be surgically removed.
    4.2.2 Trial Design and Benefit Consideration After evaluation, pre-exploratory clinical trial data to support the joint treatment into the confirmed trial, will be based on the results of the pre-efficacy analysis of the experimental results, the clinical practice of target indications and the development and registration of the same target drug, comprehensive consideration of the test design, the current a.
    in this case, clinical endpoints (e.g. OS) or widely used alternative research endpoints (e.g. PFS) should be used to demonstrate clinical benefits by comparing SOC-place.
    (2) A-B model adopts the A-B model (When A, B are not SOC), according to the pre-efficacy analysis results of the target indications, the efficacy of single drug and clinical trial data of the same target products, comprehensive consideration of the test design.
    there are usually three clinical development models: 1) three-arm design test if A in the early test showed significantly better efficacy than B, and a drug's same target products in the target indications have been approved, must consider the three-arm design: A -B vs A vs SOC.
    generally have to prove that A-B is superior to A," and that A-plus is superior to That-E, equivalent or non-inferior to SOC, to confirm the clinical value and prescription rationality of A-B.
    A and SOC seisdegrade, equivalent or non-poor design depends on the results of a registered trial of A's same-target drugs (Figure 1).
    If A has a single drug-ready potential in previous tests, but target indications do not have A's same-target product approved, the same must be considered for the three-arm design: A-B vs A vs SOC.
    at this point it is confirmed that a better A-B than A-B and SOC usually support the rationality of joint therapy in A-B, at which point a descriptive statistical comparison of A and SOC can be made, without a rigorous statistical design (Figure 1).
    Figure 1, A-B model confirmation test three-arm design and benefit consideration 2) the same period RCT test if A in the preliminary test shows that there is a single drug-based potential, whether or not there is a A of the same target product approved, can consider the same period RCT design.
    such as a D vs SOC and A-B vs A (when A may be better at SOC), or A vs SOC and A-B vs SOC (when A may be equivalent or inferior to SOC).
    in this case, it is generally necessary to prove that A-B is superior to A or SOC, that A-superior, equivalent, or non-inferior effect is in soC in order to confirm the clinical value of A-B and the reasonableness of prescription (Figure 2).
    Figure 2, A-B model contemporaneous / sequential RCT design and benefit consideration 3) two-arm RCT test case 1, in front.
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