Medical network - May 23 on May 18, the CFDA repeating five guiding principles for the formal draft, respectively belong to two big announcement - "total bureau releases about adult medication data extrapolation to the pediatric population technical guidelines of circular no. 79 (2017)" and "total bureau releases about quality of generic drugs and curative effect evaluation and guiding principles for developing the inspection consistency" four guiding principles such as circular no. 77 (2017) ". 

 

Pediatric clinical opportunities: good for east Asian countries 

 

"Adult medication data extrapolation to the pediatric population technical guidelines" formal draft for pediatric patients in clinical trials in the face the difficulty of existence - unique ethical challenges (such as the use of placebo), practical difficulties, such as curative effect evaluation, need to provide special protection for children in the study), growth/development significant differences, etc., and clear the data extrapolation is for efficacy and safety of data. 

 

Typically, data extrapolation is mainly aimed at the validity data to obtain a clear dose. But in some cases, fully consider the drug to the different age stages of pediatric population security, especially related to the growth and development of forward security, must pay attention to safety data. 

 

In addition, the official has been clear about the scope of application is only applicable to existing products of China's adult data extrapolation to the pediatric population in China, there is no product of China adult data extrapolation is belong to the scope of application of the guidelines. 

 

The main principle of extrapolation is also adjusted. According to "draft", "pediatric population drug clinical trial data used by the main principle of extrapolation is for reasons of ethics and the efficiency, avoid unnecessary study the target population, thus reducing ethics concerns, and the allocation of resources to the areas most in need of research". Is in the "formal", "China will be known by scientific research methods of adult study information and conclusions, and extended to the unknown pediatric populations (target groups) to reduce in the unknown pediatric population in the study of unnecessary". This means that the principle of extrapolation is largely independent of ethics. 

 

In view of the higher the degree of similarity between predicted crowd, prediction accuracy is higher, the greater the chance of extrapolation, extra research data is lower, the necessity of "formal" for data source, improving evaluation methods such as the new: the known data sources, the formal draft added "diagnostic studies, pharmacokinetic (PK) and pharmacodynamics (PD) study"; "Similarity" estimates increase the assessment of drug exposure and drug effect relationships; When extrapolation is carried out, if the hypothesis is not verified, additional data may be added "if necessary, and the data may be used for segmentation." 

 

Methodology, "a formal draft" or "draft", according to the known data the extrapolation hypothesis in the known population and target groups of similar degree, the extrapolation model is divided into the following three types: fully extrapolation, part of the extrapolation and without extrapolation. 

 

The "completely extrapolated" model has a high degree of similarity between the target population and the known population, and is assumed to be highly accurate. The "partial extrapolation" model has certain similarities between the target population and the known population, and/or hypothesis (prediction) uncertainty. The "no extrapolation" model is not similar to the known population, and/or hypothesis is highly inaccurate. 

 

"Official" according to whether foreign pediatric population has approved indications, whether for pediatric population in the domestic and overseas references (or other supporting data), divided into "Chinese adult data indications and abroad has been approved by the pediatric population data using" "with Chinese adult and pediatric populations at home and abroad data references available data using" and "only China adult data extrapolation" three conditions to carry out the extrapolation. "Draft" is according to the data source is divided into "Chinese adult data extrapolation" "foreign pediatric population data extrapolation" and "existing literature or other supporting data extrapolation". 

 

"Formal version" of "Chinese adult data indications and abroad has been approved by the pediatric population data using" basic and draft of "foreign pediatric population data extrapolation" requirements, only increased the Chinese adult data. 

 

In the pediatric population data, overseas Chinese adult indications have been approved, different countries or areas of disease epidemiology, etiology, pathogenesis and prognosis of disease progression there is no difference; In adult patients with test data at home and abroad, there is no significant ethnic differences, including clinical pharmacology, pharmacokinetic and pharmacodynamic and therapeutics (medical practice effectiveness, safety data) aspects of difference, pediatric population can continue to use the foreign drug clinical trial data. 

 

Official version of "Chinese adult data and references available data to pediatric population at home and abroad to use" main corresponding draft "existing literature or other supporting data extrapolation" one. The formal draft is mainly about systematic evaluation. The system evaluation is divided into two categories: quantitative and qualitative. If there is heterogeneity between the studies that are included, it cannot be quantified, and it can be done in a qualitative way. A more comprehensive approach to the methodology of meta-analysis than to solicit submissions is more comprehensive. 

 

Indications for pediatric population data of China's adult has not been approved, but have a pediatric population evidence of clinical application at home and abroad, through the system evaluation method, the existing research evidence as revision, perfect the specification in the pediatric population medical information is the main basis, which can be avoided to clinical. 

 

Official version of "only China adult data extrapolation" corresponding to the draft of "Chinese adult data extrapolation", based on existing knowledge, adult clinical trial data extrapolation to pediatric population in most cases limited to efficacy data; And the availability of safety data for the paediatric population usually needs to be carried out in the pediatric population, and the pediatric population safety clinical trial is a must. 

 

Effectiveness of clinical trial process, the CFDA borrowed from the U.S. food and drug administration (FDA) of pediatric population study design and extrapolation decision-making flow chart (see figure 1), the same or similar mechanism according to different situations between drug in adult and pediatric population human pharmacokinetic PK and PD test results, the adult dose extrapolation for pediatric population dose. 

 

Figure 1 studies design and extrapolation of extrapolation decisions 

 

 

 

Positive direction 

 

To sum up, "adult medication data extrapolation to the pediatric population technical guidance principle" good domestic currently listed chemical drugs on the market in east Asian countries has increased pediatric indications of the products, the above products almost no research on race, can avoid direct clinical. 

 

Consistency evaluation "small change" : to promote enterprise execution 

 

In the four principles of the quality of generic drug and the consistency of efficacy, "the principle of research field inspection guiding principle" was changed to "the principle of the field verification guiding principle". However, the changes are not large, such as requiring mechanical validation of the drug solubility device and no performance verification test. 

 

"Guidelines" production site inspection, check the main points of new declaration data and bioequivalence research and clinical research zhongyuan excipients and the source of the inner packing materials and finished products prescription and production process, production batch consistency. Used in the bioequivalence, clinical study, in vitro evaluation of drug production process, should be the dynamic production process and production site inspection and declaration material content. The scope and focus of quality risk management has increased risk management activities within the company. The adjustment of the above content shows the idea of the whole life cycle management. 

 

"Production site inspection guidelines" to delete the production batch do not agree with to declare the batch, the production process with the declaration data for further study and validation, suggests that the technology and the information must be consistent with the requirements, when the inspection and validation studies don't belong to the category of consistency evaluation production site inspection. 

 

"Guidelines" clinical trial data verification reference for medical device innovation reform about encouraging drug clinical trial management related policy "(draft)" to undertake the project generics consistency evaluation of clinical trials of hospital administration of qualification for clear "was deleted. Combining "about further standardize quality of generic drugs and curative effect evaluation reference formulation selection consistency concerning all guidance (draft)" on the provision of reference preparations, such as "reference preparation of legal sources for the testing report, leaflet, etc" was deleted. 

 

There is no change in the "because of inspection guidelines". 

 

Positive direction 

 

To sum up, the consistency evaluation four guiding principles for the formal draft and changes between the draft is not large, the big four guiding principles are more in order to promote the process of evaluation of consistency. Domestic listed with the same production line production and drugs approed for sale in the European Union, the United States or Japan and property of the original drug, is expected to after the guidelines issued to speed up the consistency evaluation certification process.