May 2019 – the Center for Drug Evaluation (China) has released a draft document for public review on “Key Considerations in Using Real-World Evidence to Support Drug Development”
Background and Purpose
Randomized Controlled Trials (RCTs) are considered the “gold standard” for evaluating drug efficacy and are widely used in clinical trials. With strictly controlled trial eligibility criteria and the utilization of randomization, RCTs minimize the impact of factors that potentially affect the causal inference, and hence result in more definitive conclusions and derive more reliable evidence. However, RCTs also have limitations: stringent entry criteria may reduce the representativeness of the trial population to the target population, the standard trial interventions used may not be completely consistent with real world clinical practice, the limited sample size and short follow-up time leads to insufficient evaluation of rare adverse events. These limitations bring challenges when extrapolating the RCT conclusions to real world clinical practice. In addition, for some rare and major life-threatening diseases that lack effective treatments, conventional RCTs may be difficult to implement, require substantial time costs, or raise ethical issues. Therefore, how to use real-world evidence (RWE) during drug R&D, especially as complementary evidence to RCTs in evaluating the efficacy and safety of drugs, has become a common and challenging question for global regulatory agencies, the pharmaceutical industry and academia.
First, we need to clarify the definition and scope of real-world evidence on a conceptual level.
Secondly, can and how will real-world data (RWD), as the fundamental basis of real-world evidence, provide sufficient support will face many questions that need to be discussed, including data sources, data standards, data quality, data sharing mechanism, data infrastructure and so on.
Third, the lack of regulatory guidance. At present, there are no mature and relevant regulations worldwide. Without sufficient experience, how to formulate guidelines that fit the reality of China’s pharmaceutical industry requires active exploration and innovation.
Fourth, the methodologies for evaluating real-world evidence needs to be streamlined. Real-world evidence stems from the correct and adequate analysis of real-world data. The analysis methods used are mainly for causal inference, which often requires more complex models and assumptions, screening of corresponding covariates, identification of confounding factors, definition of intermediate variables and instrumental variables, etc., All these will put forward higher requirements for statistical analysts as well as the urgent needs for regulatory guidelines.
Fifth, the scope of real-world evidence application remains to be determined. The main role of real-world evidence is to complement, instead of substitute, the evidence provided by conventional clinical trials, and to form a complete and rigorous chain of evidence to further improve the efficiency and scientific validity of drug development. Therefore, it is necessary to clearly define the scope of application of real-world evidence according to the stage of drug development, and in the meanwhile adopt appropriate adjustment as the actual conditions evolve over time.
In light of the above, this guideline aims to provide clarity on the definition of real-world research, outline the use and scope of real-world evidence in drug R&D, explore the basic principles for the evaluation of real-world evidence, and consequently provide scientific and practical guidance for the industry to consider when utilizing real-world evidence to support drug development