According to the “Announcement of the National Medical Products Administration on Matters Relating to the Implementation of the ‘Measures for the Administration of Drug Registration’” (No. 46 of 2020), in order to advance the drafting and formulation of relevant supporting normative documents and technical guidance principles, under the deployment of the National Medical Products Administration, the Center for Drug Evaluation has developed the “Technical Guidance Principles for Conditional Approval of Drug Marketing (Trial)” (see attachment). In accordance with the requirements of the “Notice of the Comprehensive Department of the National Medical Products Administration on Issuing the Procedures for the Publication of Pharmaceutical Technical Guidance Principles” (NMPA Comprehensive Drug Administration [2020] No. 9), after review and approval by the National Medical Products Administration, this document is hereby released and shall take effect from the date of its publication.

　　Hereby notified.

　　Center for Drug Evaluation, National Medical Products Administration

　　November 19, 2020

　　Attachment

　　Technical Guidance Principles for Conditional Approval of Drug Marketing (Trial)

　　I. Overview

　　To encourage drug innovation oriented toward clinical value and accelerate the launch of clinically urgently needed drugs with outstanding clinical value, these Guiding Principles have been formulated based on the "Drug Administration Law of the People's Republic of China," the "Vaccine Administration Law of the People's Republic of China," the "Traditional Chinese Medicine Law of the People's Republic of China," and the "Measures for Drug Registration Management," drawing on international experience and taking into account China’s practical experience in drug review and approval.

　　The purpose of conditional approval for marketing is to shorten the development time of clinical trials for drugs, enabling their early use by patients with critical illnesses who cannot afford to wait any longer or by those in urgent need from a public health perspective. The quality of clinical trial data supporting conditional approval must meet the requirements and standards set forth by ICH as well as relevant domestic technical guidelines. Conditional approval for marketing does not cover cases where the clinical trial design or implementation contains defects that prevent the drug from meeting the requirements for marketing authorization.

　　Generally, the pharmaceutical, pharmacological, and toxicological requirements for drugs approved under conditional marketing authorization are the same as those for drugs approved through the standard marketing authorization process. For drugs that are urgently needed from a public health perspective or for drugs intended to respond to major public health emergencies, the evaluation may, depending on the specific circumstances, take into account the drug’s benefit-risk profile.

　　After receiving conditional approval for marketing, the marketing authorization holder must conduct new or ongoing clinical trials in accordance with the specific conditions attached to the drug registration certificate. These clinical trials are typically confirmatory clinical trials aimed at verifying the anticipated clinical benefits and providing sufficient evidence for routine market approval.

　　These guidelines apply to traditional Chinese medicines, chemical drugs, and biological products that have not yet been marketed in China.

　　II. Circumstances for Conditional Approval of Market Launch

　　(1) During clinical trials of a drug, a drug that meets any of the following conditions may apply for conditional approval:

　　1. For diseases that pose a serious threat to life and for which there are currently no effective treatments, as well as for drugs urgently needed in public health, where clinical trial data already demonstrate efficacy and can predict their clinical value;

　　2. Vaccines urgently needed to respond to major public health emergencies, or other vaccines designated as urgently needed by the National Health Commission, provided that their benefits have been assessed as outweighing the risks.

　　(2) Relevant Definitions

　　Conditional approval for marketing refers to drugs intended for diseases that pose a serious threat to life and for which no effective treatment is currently available, as well as pharmaceutical products urgently needed in public health. Although the existing clinical research data do not yet meet all the requirements for conventional marketing registration, clinical trial data already demonstrate efficacy and allow for the prediction of clinical value. Under the condition that the applicant must fulfill specific requirements, such drugs may be approved for marketing based on surrogate endpoints, intermediate clinical endpoints, or data from early-phase clinical trials. Vaccines urgently needed to respond to major public health emergencies, or other vaccines identified as urgently needed by the National Health Commission, may also receive conditional approval for marketing based on interim analysis data from Phase III clinical trials, provided that the benefits have been assessed as outweighing the risks.

　　A life-threatening illness refers to a disease or a stage of a disease—such as advanced malignant tumors—that, if left untreated promptly, could lead to the patient’s death within several months or even less time.

　　Medicines urgently needed in public health refer to those that have been identified by relevant authorities, such as the national health and health administration department, as being urgently required for market launch based on national public health needs.

　　Vaccines urgently needed for major public health emergencies refer to preventive vaccines required for diseases associated with major public health emergencies (Level II) or particularly major public health emergencies (Level I), as defined by the "Regulations on Emergency Response to Public Health Emergencies" and the "National Emergency Plan for Public Health Emergencies."

　　III. Technical Requirements for Conditional Approval of Market Launch

　　(1) Drugs approved for marketing under conditional approval shall provide effective treatment options and must meet at least one of the following conditions:

　　1. Compared with existing treatment methods, it significantly improves the prognosis of the disease.

　　2. It can achieve significant therapeutic effects in patients who are intolerant to or unresponsive to existing treatment methods.

　　3. It can be effectively combined with other key drugs or treatments that cannot be used in conjunction with existing therapies, and achieve significant therapeutic effects.

　　4. The efficacy is comparable to that of existing treatment methods, but it can significantly improve patient adherence by either avoiding the severe adverse reactions associated with current therapies or markedly reducing harmful drug interactions.

　　5. It can be used to address newly emerging or anticipated public health needs.

　　Existing treatment methods refer to drugs that have already been approved for use within the country to treat the same disease, or standard therapeutic approaches. Generally, these treatment methods should represent the current standard of care for the disease in question. Drugs approved under conditional marketing authorization shall not be considered as existing treatment methods until their clinical benefits have been confirmed.

　　(2) Key Considerations for Effectiveness Evaluation

　　The indicators typically used for evaluating drug efficacy should be clinical endpoints. A clinical endpoint refers to a characteristic or variable that directly reflects the therapeutic effect of a drug—that is, a direct assessment of how the drug impacts the patient’s symptoms (e.g., symptom relief), function (e.g., improvement in mobility, delay or prevention of functional decline), or survival.

　　For drugs that meet the criteria for conditional approval, marketing authorization may be granted conditionally based on surrogate endpoints, intermediate clinical endpoints, or data from early-phase clinical trials. Applicants shall thoroughly evaluate and justify the relevance and reasonableness of the selected surrogate endpoints, intermediate clinical endpoints, or early-phase clinical trial data in relation to the expected clinical benefits, and provide appropriate supporting evidence.

　　1. Likely surrogate endpoints for predicting clinical benefit

　　An surrogate endpoint is an endpoint measure used to indirectly reflect clinical benefit. For drugs that are urgently needed in clinical practice, it is desirable to use surrogate endpoints to rapidly evaluate efficacy.

　　Surrogate endpoints can include laboratory test results, radiological imaging findings, physical signs, or other indicators that do not, in themselves, measure clinical benefit but can serve as predictors of clinical benefit. For example, in certain types of cancer, radiological evidence of tumor shrinkage (response rate) may predict an improvement in overall survival. Depending on their predictive ability for clinical benefit, surrogate endpoints can either be well-established indicators that reasonably predict clinical benefit (and thus suitable for routine approval) or highly likely predictors of clinical benefit (and therefore eligible for conditional approval).

　　To assess whether a surrogate endpoint can predict clinical benefit and its predictive power, one must evaluate the biological plausibility of the relationship among the disease, the clinical endpoint, and the drug’s expected mechanism of action, as well as the evidence or experience supporting such a relationship. For example, this includes the relationship between the surrogate endpoint and the underlying disease etiology, the relationship between the surrogate endpoint and the clinical endpoint and its predictive value, the strength of the epidemiological association between the surrogate endpoint and disease prognosis, and the consistency between the extent to which the drug affects the surrogate endpoint and the extent to which it affects the clinical endpoint.

　　In pivotal registration clinical trials, if efficacy is evaluated using pre-specified surrogate endpoints that are highly likely to predict clinical benefit and yield positive results, conditional approval for marketing may be sought.

　　2. Intermediate clinical endpoints that can enable early assessment of clinical benefit.

　　An intermediate clinical endpoint generally refers to a clinical benefit assessment in the treatment of chronic or progressively worsening diseases, where short-term clinical benefits are typically considered highly predictive of long-term clinical outcomes. For example, when a drug for multiple sclerosis is seeking regular approval, it must provide a 2-year evaluation of its clinical efficacy. However, in the case of conditional approval, an intermediate clinical endpoint could be a 1-year evaluation of the drug’s efficacy.

　　In pivotal registration clinical trials, if the results of studies using intermediate clinical endpoints can reasonably predict that the drug is likely to be effective and provide clinical benefits, conditional approval for marketing may be sought.

　　3. Early clinical trial data

　　Early clinical trial data typically refer to clinical data obtained before the initiation of confirmatory clinical trials. If, based on early clinical trial data, a reasonable prediction or assessment of clinical benefit can be made, conditional approval for marketing may be applied for prior to completion of the confirmatory clinical trials.

　　For urgently needed new traditional Chinese medicines (TCMs) targeting major public health emergencies, high-quality real-world evidence from human use or well-designed clinical study summaries can be regarded as early clinical trial data.

　　In addition, for urgently needed innovative vaccines targeting major public health emergencies and other critical situations, it is permissible to consider using interim analysis data from Phase III clinical trials to support conditional approval for market launch. For example, during a vaccine’s Phase III clinical trial, 1–2 interim analyses can be conducted according to the study protocol. These interim data will be reviewed by an independent Data Monitoring Committee (IDMC). If the interim analysis results indicate that the investigational vaccine demonstrates superior protective efficacy compared to the placebo control group and meets pre-specified criteria—suggesting that the benefits outweigh the risks—then a request for conditional approval of the vaccine for market launch can be submitted.

　　(3) Key Points for Communication and Exchange Regarding Conditional Approval for Market Launch

　　Communication and exchange with regulatory authorities are crucial throughout the new drug development process. During clinical trials, communication primarily involves updates to the clinical trial protocol and discussions of relevant issues arising during the trial.

　　For drugs that meet the criteria for conditional approval, applicants may submit a request for conditional approval during the clinical trial phase. Applicants should communicate and exchange information with the Center for Drug Evaluation of the National Medical Products Administration (hereinafter referred to as the CDE) regarding the clinical trial design supporting conditional approval as well as the results of the clinical trials.

　　1. Before conducting clinical trials to support conditional approval for market launch

　　Applicants are encouraged to communicate with the Center for Drug Evaluation prior to initiating clinical trials intended to support conditional approval, based on the actual circumstances of drug development, in order to clarify the following issues:

　　(1) The rationale for the surrogate endpoints, intermediate clinical endpoints, or early clinical trial data selected in clinical trials, as well as the criteria by which these can reasonably predict clinical benefit;

　　(2) Design and implementation plan for post-marketing clinical trials.

　　(3) Other preconditions for conditional approval include pharmaceutical studies, pharmacological and toxicological studies, and so forth.

　　2. Before submitting the listing application

　　Before applying for conditional approval for marketing, the applicant shall communicate and exchange information with the Center for Drug Evaluation regarding the clinical trial data already obtained, pharmaceutical and pharmacological-toxicological data, the applicant’s intention to seek conditional approval for marketing, as well as the design and implementation plan for post-marketing clinical trials and the post-marketing risk management plan. Prior to such communication and exchange, the applicant shall submit to the Center for Drug Evaluation all completed clinical trial results, the rationale and basis for seeking conditional approval, the protocol for post-marketing clinical trials and their completion deadlines, and the post-marketing risk management plan. If, following the communication and exchange, the applicant is deemed to meet the requirements for conditional approval, it may then submit a New Drug Application (NDA). For applications that do not meet the conditions and requirements for conditional approval, the applicant shall, based on the clinical trial results, decide whether to continue product development and, if so, determine the appropriate design for ongoing clinical trials.

　　The minutes of the communication and exchange meeting will serve as an important basis for the acceptance, filing review, and evaluation of the conditional approval application for market launch. During the review of the marketing application, the applicant may continue to communicate and exchange further information with the Drug Review Center on the above-mentioned matters and reach a consensus.

　　IV. Conditions Attached to the Conditional Approval for Market Launch

　　(1) Clearly state that this drug has been “conditionally approved.”

　　For drugs approved for marketing under conditional approval, the package insert shall indicate under the sections “Indications”/“Main Functions and Indications” and “Clinical Trials” that this product has been conditionally approved based on surrogate endpoints (or intermediate clinical endpoints or early clinical trial data). Clinical endpoint data have not yet been obtained, and the efficacy and safety of the product remain to be further confirmed after marketing. The section “Approval Number” shall clearly state “Conditionally Approved for Marketing.” The relevant information on the drug label must be consistent with that in the package insert.

　　(2) Post-Market Requirements

　　Given that drugs approved under conditional marketing authorization have not yet met all the requirements for standard marketing registration, applicants should jointly discuss and reach consensus with the Center for Drug Evaluation on matters such as the studies to be completed after marketing authorization. Such discussions should include at least the following: a post-marketing clinical study plan, the target completion date for these studies, the deadline for submitting the final clinical study report, and a post-marketing risk management plan. Applicants shall commit to completing all clinical trials on schedule.

　　1. Post-Marketing Clinical Study Plan

　　The post-marketing clinical study plan shall include the overall clinical trial plan as well as all clinical trial protocols committed to by the applicant and approved after review by the Drug Review Center. For example, if a product has been conditionally approved for marketing based on surrogate endpoints and early clinical trial data, a confirmatory clinical trial with clinical endpoints as the primary efficacy indicators should be designed and completed. If a product has been conditionally approved for marketing based on intermediate clinical endpoints, the confirmatory clinical trial should continue to be completed.

　　2. Research Completion Date

　　The applicant should comprehensively consider the actual circumstances of the clinical study and clearly specify and commit to the completion date for post-marketing studies.

　　3. Clinical Study Report Submission Date

　　The applicant should comprehensively consider practical factors such as statistical analysis following the completion of the clinical study and the preparation of the clinical study report, and clearly specify and commit to the anticipated submission date for the clinical study report.

　　4. Post-Market Risk Management Plan

　　The marketing authorization holder of a pharmaceutical product shall, in accordance with the established post-marketing risk management plan, implement appropriate risk management measures for existing or identified risks as well as potential risks, thereby ensuring patient medication safety.

　　After conditional approval for marketing, any new or ongoing clinical trials must still comply with the relevant requirements of ICH E6 and the “Good Clinical Practice for Drug Clinical Trials,” and a periodic Drug Safety Update Report (DSUR) must be submitted throughout the drug development period until the drug is routinely marketed.

　　The marketing authorization holder of a drug shall, in accordance with the specific conditions attached to the drug registration certificate, complete any new or ongoing clinical trials within the prescribed time limit and submit a supplementary application to the Drug Review Center for routine approval and market launch.

　　7. References

　　[1] U.S. FOOD AND DRUG ADMINISTRATION (FDA). Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics.

　　[2] Beaver JA, Howie LJ, Pelosof L, et al. A 25-Year Experience of US Food and Drug Administration Accelerated Approval of Malignant Hematology and Oncology Drugs and Biologics: A Review. JAMA Oncol, 2018, 4(6):849-856.

　　[3] European Medicines Agency (EMA). Guideline on the scientific application and the practical arrangements necessary to implement Commission Regulation (EC) No 507/2006 on the conditional marketing authorisation for medicinal products for human use falling within the scope of Regulation (EC) No 726/2004.