Endpoint index of clinical trial of tumor drugs

There are three end points in clinical trials of cancer drugs: the first is based on the end point of death events: overall survival (OS), and the second is based on the end point of tumor measurement: mainly including progression-free survival (PFS) and Disease-Free Survival. DFS), time of progression, TTP, time of treatment failure, objective remission rate, ORR and clinical benefit rate (CBR). The third category is the endpoint based on symptom assessment: patient reported results (PRO) and QOL.

Overall survival (OS) refers to the time from random grouping to death from any cause. (For the subjects who have been lost to follow-up before death, the last follow-up time is usually used as the time of death), which is the most reliable evaluation index of anti-tumor drugs at present and is often used as the preferred end point.

Advantages: The overall survival time can reflect the exact clinical benefit, and the endpoint evaluation will not be biased (because the research process can be fully evaluated and accurately measured, and the death certificate can be provided). At the same time, the significant extension of OS with clinical significance and statistical significance can usually support the approval of new drugs.

Disadvantages: large sample is needed, and the follow-up time is long. Follow-up treatment will interfere with the judgment of drug efficacy and the influence of non-tumor death on the results.

Progression-free survival (PFS) refers to the time from randomization to tumor progression or death, which is currently considered as a surrogate index to predict the clinical benefits of OS.

Advantages: Compared with the overall survival time, the progression-free survival time does not have to wait for the death event, the required sample size is small, and the follow-up time is shortened. Compared with the total survival, the effect of progression-free survival will be greater (because the two groups have the same treatment, the difference of progression-free survival between the two groups is often greater than the difference of total survival between the two groups, which means that fewer events are needed to test the difference, which means that the number of cases is greatly reduced. At the same time, PFS is less affected by non-research drug treatment. (Because patients often start to consider dressing change after drug treatment is ineffective, that is, the disease progresses, the measurement of PFS is often before the patient changes dressing, which makes PFS less susceptible to non-research drug treatment such as overall survival. )

Disadvantages: PFS may have different definitions in different studies, and its measurement is not as accurate as OS. (Because the measurement of PFS mainly depends on some radiological examinations, the patient made progress during the radiological examination, and the date of progress was the day of the radiological examination. In fact, it is very likely that the patient has made progress before this radiological examination, but he has not been diagnosed by radiological examination, especially when the interval between radiological examinations is long. At the same time, there is inevitably subjective bias, and the influence of frequent radiological examinations on tumor and non-tumor deaths may not necessarily be transformed into survival benefits.

Disease-free survival (DFS) refers to the time from random grouping to tumor recurrence or death for any reason, and is often used as the main therapeutic index after radical surgery or radiotherapy. It is often used as the main end point of phase III clinical trials of anti-tumor drugs.

Advantages: Like PFS, DFS needs fewer samples and shortens the follow-up time.

Disadvantages: its endpoint is difficult to record, and non-tumor death may interfere with the judgment of DFS, so it is easy to be influenced and lead to bias, especially in open research. Different studies may have different definitions of DFS.

Time to progress) refers to the time from the beginning of random grouping to the objective progress of tumor, and is the main observation and evaluation index of anti-tumor phase II clinical trial. (Because of the short time of the second phase clinical trial of tumor, the follow-up data is sometimes insufficient to summarize and evaluate the overall survival time. )

Advantages: the sample size required for disease progression time is small, and the follow-up time is shortened. When there are more non-tumor causes of death than tumor causes, it can be a suitable indicator.

Disadvantages: Affected by factors such as lack of data, biased evaluation and different definitions of different studies.

Time to treatment failure (TTF) is defined as the time from randomization to treatment failure or withdrawal from the trial. The reasons for withdrawing from the trial can be patient requirements, disease progression, etc. Compared with PFS, TTF includes all-cause treatment failure, comprehensive drug effectiveness and safety characteristics, although it includes death, but the judgment of drug withdrawal may be subjectively influenced. The analysis of these two endpoints is usually considered as sensitivity analysis, which can not be used as the main evidence of conclusive research conclusions, but can be used to support the results of the main endpoints.

The objective remission rate (ORR) refers to the proportion of patients whose tumor volume has shrunk to a predetermined value and can maintain the minimum time limit (mainly for solid tumors). According to the degree of tumor shrinkage, it can be divided into complete remission (CR) and partial remission (PR), which is the main evaluation index of curative effect in phase II clinical trials.

Advantages: the objective remission rate can be used to evaluate early and small sample studies, and provide preliminary evidence for the biological activity of drugs and credible evidence for further phase III experiments. ORR is usually based on objective and quantitative evaluation, which is more suitable for rich population trials, attributing the curative effect to drugs and excluding the natural process of diseases.

Disadvantages: it is impossible to directly evaluate the clinical benefit and comprehensively evaluate the drug activity, and it is also affected by frequent imaging or other evaluations.

Patient Report Results (PRO): This is a report directly from patients about their symptoms, health-related quality of life, treatment compliance and treatment satisfaction.

Advantages: It can reflect the direct feeling of patients' clinical benefit.

Disadvantages: the reliability, validity and responsiveness of the scale are different, and the evaluation bias and the lack of data in PRO measurement affect it. Therefore, it is not the main end point of clinical trial approval of commonly used anticancer drugs in the guidelines of FDA and CDE, but can be used as an auxiliary index to support the main results. Because symptoms and quality of life are subjective, it is suggested to set blindness to reduce bias.

In addition, new endpoints such as minimal residual disease (MRD) support the accelerated approval of acute lymphoblastic leukemia, while non-metastatic survival (MFS) supports the traditional approval of non-metastatic castration-resistant prostate cancer (nmCRPC). Biomarkers can also be used as one of the composite endpoints.