Notice from the Center for Drug Evaluation of the National Medical Products Administration on the Release of “Clinical Technical Requirements for Drugs Already Marketed Overseas but Not Yet Marketed in China” (No. 29 of 2020)

　　Release date: 2020-10-16

　　The approval and launch of drugs already marketed overseas in China, or their generic versions, represents an important approach to addressing the urgent clinical needs of Chinese patients by improving the availability and accessibility of these medications. To accelerate the development and approval process for such drugs and strengthen scientific regulation, the Center for Drug Evaluation has, in accordance with the "Measures for Drug Registration Administration" (General Administration Order No. 27) and its supporting documents, formulated the "Clinical Technical Requirements for Drugs Already Marketed Overseas but Not Yet Marketed in China" (see attachment). In compliance with the requirements set forth in the "Notice of the Comprehensive Division of the National Medical Products Administration on Issuing Procedures for the Publication of Pharmaceutical Technical Guidelines" (NMPA Comprehensive Drug Administration [2020] No. 9), this document has been reviewed and approved by the National Medical Products Administration and is hereby released, taking effect from the date of its publication.

　　Hereby notified.

　　Center for Drug Evaluation, National Medical Products Administration

　　October 9, 2020

　　Attachment

　　Drugs already marketed overseas but not yet marketed domestically

　　Clinical Technical Requirements

　　Drug Review Center

　　October 2020

　　Table of Contents

　　I. Background 1

　　II. Scope of Application 1

　　III. Basic Considerations 1

　　IV. Basic Logic of Clinical Evaluation 1

　　(1) Clinical Needs Assessment 1

　　(2) Efficacy and Safety Evaluation 2

　　1. Clearly define the source of clinical data 2

　　2. Assessing the Quality of Overseas Clinical Trial Data 2

　　3. Understand the characteristics of biopharmaceutics and clinical pharmacology 3

　　4. Assess overall efficacy and safety 3

　　(3) Ethnic Sensitivity Analysis 3

　　(4) Decision-making based on benefit/risk assessment for Chinese patients 4

　　V. Clinical Trial Requirements 4

　　(1) Overseas originator drugs 5

　　1. Safe, effective, and non-racially sensitive 5

　　2. Safe and effective but lacking race-sensitive data or exhibiting race sensitivity 7

　　3. Insufficient safety and efficacy data 7

　　4. Clinical data indicate ineffectiveness or safety concerns 7

　　(2) Generic drugs manufactured both domestically and internationally 7

　　1. Considerations Based on Clinical Evaluation Results 8

　　2. Considerations Based on Formulation Factors 8

Clinical Technical Requirements for Drugs Already Marketed Overseas but Not Yet Marketed in China

I. Background

　　Bringing already-marketed drugs from overseas into the domestic market, or developing generic versions of such drugs, is an important approach to addressing the availability and accessibility of medicines in areas where Chinese patients have urgent clinical needs. To accelerate the development and approval process for originator drugs and generic drugs that are already marketed abroad but not yet available domestically, and in accordance with the "Drug Registration Management Measures" (General Administration Order No. 27) and its supporting documents, as well as the "Technical Guidance Principles for Accepting Overseas Clinical Trial Data" (Document No. 52 of 2018), we have formulated technical requirements for the clinical research and evaluation of these drugs, providing a technical reference for industry, academia, and regulatory authorities.

II. Scope of Application

　　These technical requirements apply to pharmaceutical products that are already marketed overseas but not yet marketed in China, and primarily cover two categories of situations: (1) originator chemical drugs and therapeutic biological products that are already marketed overseas; and (2) generic chemical drugs, both domestically and internationally.

III. Basic Considerations

　　The clinical technical requirements for drugs already marketed overseas but not yet marketed in China shall follow the fundamental logic of clinical evaluation. Based on a thorough assessment of Chinese patients’ clinical needs, the clinical safety and efficacy of the original overseas-developed drugs, and the impact of racial factors, these requirements—specifically the technical specifications for clinical trials needed to obtain market approval in China—shall be determined in light of the benefit-risk assessment for Chinese patients.

IV. Basic Logic of Clinical Evaluation

(1) Clinical Needs Assessment

　　The proposed indications for approval should be analyzed in light of the current epidemiological status of the disease in China, the severity and prognosis of the disease, as well as the existing treatment options and their limitations. It is essential to clearly identify the comparative advantages of this drug over currently available treatments in China, and thereby make an informed assessment of the extent of clinical needs among Chinese patients.

　　Regulatory authorities adopt an encouraging stance toward therapeutic drugs for critical illnesses and rare diseases that currently lack effective treatment options in clinical practice, conducting review and approval with the primary goal of ensuring public access to these medications.

(2) Efficacy and Safety Evaluation

　　First, the efficacy and safety of the drug should be scientifically evaluated based on the clinical study data of the originator drug, in accordance with China’s relevant technical requirements. The evaluation steps are as follows:

　　1. Clearly define the source of clinical data.

　　It mainly comprises two sets of data: first, clinical trial data used for registration, and second, post-marketing clinical data. At the same time, it is important to pay close attention to the dynamic assessments of originator drugs conducted by foreign regulatory agencies.

　　2. Assess the quality of clinical trial data from overseas studies

　　The prerequisite for scientifically evaluating clinical trial data is that the clinical trials must be conducted in accordance with internationally accepted GCP standards. Clinical trial data should be authentic, accurate, complete, and traceable. Applicants may submit to the drug review authority relevant documents or materials demonstrating the quality of the clinical trial data supporting their marketing applications. The inspection results and conclusions issued by regulatory authorities in countries with overseas regulatory frameworks can serve as references for assessing the quality of clinical trial data. China’s drug regulatory authority conducts necessary inspections of clinical trial data submitted to support registration and marketing within China, based on risk assessment.

　　3. Understand the characteristics of biopharmaceutics and clinical pharmacology.

　　In biopharmaceutics, attention should be paid to dosage-form bioavailability/bioequivalence (BA/BE), food effects, and in vitro dissolution profile data. In clinical pharmacology, focus should be placed on pharmacokinetics (PK), pharmacodynamics (PD), the PK/PD relationship, drug interactions, and other relevant factors, providing a scientific basis for the safe and effective clinical application of drugs. Reference should be made to guidelines such as ICH E5 and E17 to assess potential PK and/or PD racial differences between the Chinese patient population and overseas study populations.

　　4. Evaluate overall efficacy and safety

　　According to the current standards for evaluating efficacy and safety, a systematic review will be conducted on clinical trial data registered overseas and post-marketing data to determine the overall efficacy and safety of the investigational drug and to assess whether the benefits of using the drug in the general population outweigh the risks.

　　(3) Ethnic Sensitivity Analysis

　　The ethnicity sensitivity analysis should focus on the potential impacts—on safety and efficacy—arising from differences in pharmacokinetics (PK) and/or pharmacodynamics (PD) between the Chinese patient population and overseas populations. This analysis should, after first establishing that the overall benefits of the drug outweigh its risks for the target population, be conducted in accordance with the ICH E5 guidelines, leveraging existing clinical trial data from overseas studies to perform an ethnicity sensitivity analysis. The content of the ethnicity sensitivity analysis involves a comprehensive evaluation of relevant in vitro, in vivo PK, PD, efficacy, and safety data, to determine whether there are ethnicity-related differences in treatment response between the Chinese patient population and overseas populations. Additionally, the analysis should examine the regulatory measures taken by overseas regulatory agencies based on their review of clinical trial data. For drugs for which sufficient ethnicity sensitivity studies have already been conducted overseas, applicants should also consider China’s specific circumstances when submitting marketing authorization or generic drug applications. Since disease and medical practice are two key factors that may influence treatment response, these aspects should likewise be included in the analysis and assessment.

　　(4) Making decisions based on benefit/risk assessments for Chinese patients

　　On the basis that the clinical study data for the originator drug sufficiently demonstrate that its benefits outweigh the risks when used in the general population, the regulatory review decision should be made by analyzing data on the impact of racial factors on Chinese patients compared with those from overseas populations. If the analysis indicates that Chinese patients exhibit treatment responses consistent with the results observed in the general population, the drug can be approved for marketing. However, if differences are identified, it will be necessary to assess—on the basis of relevant research data—whether these differences affect the safety and efficacy of the drug for Chinese patients. If such effects are found, further evaluation is required to determine whether the applicant has conducted targeted studies and implemented necessary measures, including adjustments to dosage and administration based on racial factors, as well as the addition of contraindications or precautions specific to these factors, to support the drug’s use in Chinese patients. After conducting targeted studies and implementing the necessary measures, if the drug’s benefits continue to outweigh the risks for Chinese patients, it can then be approved for marketing.

V. Clinical Trial Requirements

　　For drugs that are already marketed overseas but not yet marketed in China, it is necessary to conduct a thorough evaluation of the clinical study data for the originator drug, based on the specific circumstances of each drug and guided by the fundamental logic of clinical evaluation. The clinical trial requirements should be determined according to the results of this evaluation. For drugs with different R&D backgrounds, the clinical trials that need to be conducted should be analyzed on a case-by-case basis.

(1) Original research drugs from overseas

　　We encourage foreign-origin innovative drugs to conduct clinical trials in China concurrently from the early stages of clinical development. For instance, under the framework of international multicenter clinical studies, and under identical clinical trial design and implementation conditions, systematic clinical trials—including pharmacokinetic (PK), pharmacodynamic (PD), PK/PD, efficacy, and safety studies—could be simultaneously conducted on both Chinese patient populations and overseas patient populations. These systematic clinical trials will help generate direct evidence that provides a complete chain of evidence regarding the impact of racial factors. Building upon the overall population’s safety and efficacy evaluations, they will further enable a comparative analysis of whether and to what extent there are differences between the Chinese patient population and the global general population in terms of dose-exposure-effect relationships, efficacy, and safety. When such differences are identified, these trials will facilitate a comprehensive assessment, allowing for a thorough balancing of the clinical benefits versus risks of the drug when used in Chinese patients, thereby supporting its marketing authorization application. The study designs should follow the recommendations of relevant ICH guidelines (such as ICH E5 and ICH E17).

　　Different overseas applicants adopt varying global clinical development strategies for originator drugs, resulting in differences in the content and level of support provided by their clinical trial data when submitting regulatory applications. Therefore, in accordance with the fundamental logic of clinical evaluation, the clinical trial requirements for overseas originator drugs should be determined based on Chinese patients’ clinical needs, the research data from completed clinical trials, and the results of analyses on the impact of ethnic factors.

　　The main requirements for clinical trials include the following three scenarios:

1. Safe, effective, and non-racially sensitive

　　After evaluation, this drug has been determined to be safe and effective and not racially sensitive; therefore, a waiver of domestic clinical trials may be considered.

　　For global data that already include pharmacokinetic (PK) and/or pharmacodynamic (PD), efficacy, and safety data on the Chinese population, if the analysis indicates that the benefits of using such data for Chinese patients outweigh the risks, the relevant clinical trial data—both domestic and international—can be directly used to support the marketing application.

　　For drugs for which global data do not include information on the Chinese population, but for which there are ample research and analytical data related to racial factors and no evident impact of racial factors has been observed, a case-by-case analysis should be conducted: (1) For drugs intended for serious or life-threatening diseases, rare diseases, or for which no effective treatment options currently exist— or for such diseases where the drug offers clear advantages over existing treatments in terms of improved efficacy or safety—approval for marketing may be considered under strict risk-control measures. Post-marketing clinical trials aimed at assessing the drug’s efficacy and safety throughout its entire lifecycle should also be conducted to support the benefit-risk evaluation of the drug. (2) For drugs that do not demonstrate clear clinical advantages over existing treatments, clinical trials should be conducted in accordance with the requirements outlined in “Section 5(1)2.”

　　For domestically marketed drugs, if new dosage forms (with clinical advantages), new routes of administration, or new dosing regimens that have been approved overseas but not yet approved in China are added for indications already approved for the domestically marketed drug, or if all individual components of a new combination drug that has been approved overseas but not yet approved in China are already marketed in China, clinical trials may be considered for reduction or exemption based on the evaluation of overseas clinical trial data, provided that the following conditions are simultaneously met: ① Clinical trial data from the originally marketed reference drug demonstrate that the benefits of the drug for Chinese patients outweigh the risks, and no significant racial differences have been observed when compared with data from overseas populations; ② The overseas clinical trial data submitted for the drug’s new dosage form, new route of administration, new dosing regimen, or new combination drug can adequately support the evaluation of its safety and efficacy.

　　For situations in which an already-marketed drug in China is being approved for new indications overseas that have not yet been approved in China, in addition to following the basic clinical evaluation logic and clinical trial requirements outlined above, given the complex, multi-dimensional factors involved—such as disease conditions and drug characteristics—it is advisable to conduct a case-by-case analysis. We recommend communicating with the regulatory authority prior to submission.

2. Safe and effective but lacking race-sensitive data or with race sensitivity present.

　　Following assessment, if a drug is found to be safe and effective but lacks race-specific data or if existing data suggest the presence of race-related sensitivities, relevant bridging clinical trials should be conducted.

　　For global data lacking studies and data related to the impact of racial factors, necessary PK and/or PD studies, as well as efficacy and safety studies, should be conducted to support the drug’s marketing application.

　　Global data indicate that racial factors may influence the evaluation of safety and efficacy; therefore, it is necessary to conduct appropriate clinical trials (including dose-finding studies) to support the drug’s marketing application.

3. Insufficient safety and efficacy data

　　After evaluation, if the safety and efficacy data for this drug are found to be insufficient, the applicant should proceed with caution in its development. If the applicant intends to continue developing the drug, it should conduct the necessary exploratory and confirmatory clinical trials in accordance with the requirements for new drugs.

4. Clinical data indicate ineffectiveness or safety concerns.

　　If there is sufficient evidence demonstrating that the drug is ineffective or poses serious safety concerns, clinical trials in China are not recommended.

(2) Generic drugs manufactured both domestically and internationally

　　The clinical trial requirements for generic drugs of overseas-listed but domestically-unlisted pharmaceutical products must be determined after comprehensively considering both the clinical evaluation results of the originator drug and formulation-related factors.

1. Considerations Based on Clinical Evaluation Results

　　Based on the clinical evaluation results of the originator drug, the requirements for conducting necessary clinical trials in the Chinese patient population are consistent with those for the originator drug (see Section 5(1) for details). Given the difficulty in obtaining complete clinical trial data for the originator drug, which may hinder a thorough clinical evaluation of the originator drug itself, it is generally necessary to conduct the required clinical trials to support the safety and efficacy assessment of generic drugs for use in Chinese patients.

2. Considerations Based on Formulation Factors

　　For the evaluation of generic drug formulation, it is necessary to analyze each specific issue based on the characteristics of the drug. Details are as follows:

　　First, a reference listed drug should be identified. Typically, the reference listed drug should be an originator product with sufficient data on efficacy and safety, and preferably one that has been approved for marketing by the European Medicines Agency (EMA), the U.S. Food and Drug Administration (FDA), or the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) and designated as a reference listed drug. At the same time, the selected reference listed drug must be officially recognized in accordance with the requirements of the “Announcement on Issuing Procedures for the Selection and Identification of Reference Listed Drugs for Generic Chemical Pharmaceuticals (No. 25 of 2019).”

　　Second, based on the pharmaceutical and biopharmaceutical characteristics, studies should demonstrate that the generic drug is consistent with the originator product in terms of quality and efficacy. For example, in the case of oral solid dosage forms, in addition to conducting pharmaceutical comparative studies with the originator product, bioequivalence studies should also be carried out in accordance with the published technical requirements. As for complex dosage forms (such as liposomes, microemulsions, and topical formulations), it is further necessary—on the basis of pharmaceutical and non-clinical comparative studies and evaluations—to take into account the specific characteristics of the drug and its indications and, where appropriate, conduct clinical trials to support a comparable assessment of efficacy and safety between the generic and the originator products.