Establishment of RWS guidance reflecting contributions of China to regulatory science.

China's accession to the ICH has accelerated the advancement of its regulatory science. To foster innovation and improve the efficiency of pharmaceutical research and development, the China National Medical Products Administration (NMPA) encourages the use of real-world evidence (RWE) to support drug regulatory decision-making and has constructed a series of real-world study (RWS) related guidance, reflecting the contribution of the NMPA to the field of RWS in drug clinical development. Based on the four guidelines on RWE, real-world data (RWD), RWS design and protocol development, and communication with regulatory authorities, the guidance has been extended to more specific clinical applications, such as oncology, rare diseases, pediatric drugs, and traditional Chinese medicine. This paper reviews the core content and features of the series of RWS guidelines, presents their role in promoting drug development, and discusses challenges of using RWE in support of drug regulatory decision-making in China.

Interpretation and reflection on the Measures for the Administration of Standards for Medicinal Products / 中国药房

In July 2023， the National Medical Products Administration issued the Measures for the Administration of Standards for Medicinal Products （hereinafter referred to as the Measures）. This article interprets the main content of the Measures， and analyzes its shortcomings as unclear definition of the drug standard code and the goals of drug standard information construction. It is recommended that the national drug regulatory department promptly apply to the standardization authority for the confirmation of the drug standard code “YB” letter， and the drug standard code and numbering rules would be included in the next round of amendments to the Measures. It is necessary to clarify the construction goals of the information system for drug standards at the same time， and build a national drug standard data-sharing platform based on the basic framework of user interface layer， computing processing layer， and data storage layer. Digital drug standards will be free， and access and download services for the public will be provided.

Progress and Challenges of the New Conditional Approval Process in China: A Pooled Analysis From 2018 to 2021.

PURPOSE: To speed the review and approval of drugs and address pressing medical needs, China began to advocate for the implementation of the conditional approval process in 2017. We aimed to assess the implementation of the conditional approval process in China and further analyze its potential problems and future challenges. METHODS: This study examined the new drug approval with conditions in China between 2018 and 2021, based on an analysis of drug technical review documents from the Center for Drug Evaluation (CDE). Using publicly available information, we further analyzed the characteristics and results of pivotal clinical trials of conditionally approved drugs, postmarketing study requirements and progress. FINDINGS: Between 2018 and 2021, China conditionally approved 50 drugs, with 80% (40/50) being antineoplastic agents. Premarketing pivotal trials predominantly used single-arm clinical trials (83.7%, 41/49), while postmarketing trials mainly employed randomized controlled clinical trials (81.0%, 34/42). In oncology drugs, conditionally approved drugs with progression-free survival (PFS) and overall survival (OS) as primary endpoints achieved significant clinical value in terms of efficacy. However, there were also pivotal clinical trials with response rate (RR) as the primary endpoint that demonstrated lower clinical benefits (8.9% of drugs with RR below 20%). Safety analysis revealed substantial variations in the proportions of grade ≥3 adverse events (AEs) and serious adverse events (SAEs) across pivotal trials (Grade ≥ 3 AEs: 9.0%-99.0%; SAEs: 8.0%-83.0%). For nononcology drugs, pivotal trials also demonstrated an acceptable risk-benefit ratio but exhibited methodological issues. Meanwhile, Most postmarketing studies lacked completion date restrictions (43.2%, 17/47), and no requirements were specified for the transition to full approval. Furthermore, surrogate endpoints were primarily utilized both pre- and postmarketing, but the rational selection of surrogate endpoints remains to be investigated. IMPLICATIONS: The conditional approval process expedites patient access to drugs for serious diseases. However, challenges pertaining to evidence assessment during approval and design flaws in postmarketing studies exist in China's conditional approval system, necessitating future improvements.

Balancing Intelectual Property Protection and Legal Risk Assessment in Registration of Covid-19 Vaccines in Malaysia.

The seriousness of the COVID-19 pandemic requires a look into the implementation of drug registration rules for COVID-19 vaccines. Amidst the surrounding exigencies, vaccines being a biological product, require comprehensive and continuing pre and post registration rules to ensure their safety and efficacy. The study focuses on Malaysia which has rules on drug registration that have been successfully applied to vaccines. The study shows that the rules have been tailor-made to emergency situations. At the moment, special rules have been introduced including to allow use of COVID-19 vaccines as unregistered product. Recognition of COVID-19 Vaccines Global Access (COVAX) facility and requirement for government sale only, are among the safety valves. The study shows that these however are temporary measures against the backdrops of possible entry of private players in the vaccination process. Therefore, regulatory responses to intellectual property (IP) related conditions underlying drug registration, and measures to ensure risk management involved in vaccine production, approval and administration are needed in the progressive rules pending further development of research in the area.

Drug Development in Autosomal Dominant Polycystic Kidney Disease: Opportunities and Challenges.

Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disorder characterized by relentless growth of innumerable renal cysts bilaterally, associated with decline in glomerular filtration rate over the course of decades. The burden of ADPKD and its treatment is associated with a significant economic and societal cost. Despite several clinical studies conducted over the past decade, only one treatment has been approved by regulatory agencies to slow disease progression in ADPKD. Elucidating feasible endpoints and clear regulatory pathway may stimulate interest in developing and translating novel therapeutics. This review summarizes the recent progress, challenges, and opportunities in drug development for ADPKD. We discuss the traditional and accelerated regulatory approval pathways, the various clinical trials endpoints, and biomarkers in ADPKD. Furthermore, we propose strategies that could optimize the clinical trial design in ADPKD. Finally, we owe it to our ADPKD patient community to strive for international collaborative studies geared toward discovery and validation of surrogate endpoints and to rally for funded infrastructure that would allow phase 3 master protocols in ADPKD. These advances will serve to derisk and potentially accelerate the development of therapies and eventually bring hope to patients and families who endure through this devastating disease.

Analysis of the incentive effect of the patent linkage system on the application of generic drugs in China and suggestions for countermeasures / 中国药房

OBJECTIVE To optimize the system of patent linkage system and provide a reference for encouraging generic drugs to apply for listing. METHODS On the basis of literature research， combined with the author’s work experience， the situation of generic drug application and patent challenge were analyzed comparatively after the implementation of the patent linkage system in China. Based on the patent linkage system， the reasons for the insufficient incentive for the challenge of generic drug patents in China were analyzed； corresponding countermeasures and suggestions were proposed. RESULTS & CONCLUSIONS The patent linkage system in China was implemented in 2021， but due to the implementation of the system being still in its initial stage， the relevant documents for practical guidance are not yet complete， and the supporting incentive mechanism is not yet sound， resulting in a weak willingness of generic pharmaceutical enterprises to initiate patent challenges. It is suggested that China can further improve the patent linkage system by improving the patent information registration platform of generic drugs， developing professional drug patent agencies， and establishing the patent common challenges platform of the first generic drug， in order to incentivize Chinese generic drug enterprises to increase innovation motivation， challenge original research drug patents， and apply for listing， achieving the effect of suppressing drug prices and benefiting the people through full competition.

[Reflections on supervision strategies of new Tibetan drug registration].

Tibetan medicine is an essential part of Chinese medicine and has unique theoretical experience and therapeutic advantages. According to the development principle of inheriting the essence, sticking to the truth, and keeping innovative, the supervision department should give clear and reasonable guidance considering the characteristics of Tibetan medicine, establish a standard system for quality control, clinical verification and evaluation, and accelerate the research and commercialization of new drugs. In view of the needs of drug supply-side reform and the current situation of Tibetan medicine and new pharmaceutical research, we ponder and provide suggestions on the confusion faced by the current supervision of Tibetan drug registration, hoping to contribute to the supervision strategy of Tibetan drug registration and the high-quality development of Tibetan medicine industry.

A judicialização da fosfoetanolamina sintética no Brasil / The judicialization of synthetic phosphoethanolamine in Brazil

Este artigo analisou a judicialização da fosfoetanolamina sintética no Brasil, a partir de estudo exploratório das decisões judiciais da vara de fazenda pública da comarca de São Carlos, em São Paulo, após a interrupção do fornecimento da substância pela Universidade de São Paulo. O estudo catalogou os argumentos constantes da Ação Direta de Inconstitucionalidade 5.501/DF, que julgou inconstitucional a Lei n. 13.269/2016, que autorizou a produção e a prescrição da fosfoetanolamina sintética para quaisquer tipos de câncer (neoplasia maligna) enquanto os estudos clínicos não fossem concluídos. As sentenças de primeira instância concederam a fosfoetanolamina com base no testemunho dos pacientes sobre impactos positivos do uso da substância em sua saúde e pela ausência de registro de efeitos colaterais. Juízes que concederam acesso à fosfoetanolamina tinham ciência da carência de evidências científicas de segurança e eficácia, bem como do necessário registro da substância como medicamento no órgão  regulador, nos termos da legislação sanitária. No Supremo Tribunal Federal, a ausência de evidências científicas e a utilização de legislação para criar exceção casuísta levaram à declaração de inconstitucionalidade da norma pela maioria dos votos. O estudo registra, todavia, certa indisposição do Poder Judiciário em incorporar no processo decisório a avaliação das autoridades de regulação e fiscalização em saúde como fonte da correta avaliação da segurança e eficácia de medicamentos. Em conclusão, o testemunho dos pacientes sobre as perspectivas de cura ou redução do sofrimento, somado à ausência de provas nos processos judiciais sobre os riscos do consumo da fosfoetanolamina, foram cruciais para tais decisões.

This article analyzed the judicialization of phosphoethanolamine in Brazil, based on an exploratory study of court decisions in the district of São Carlos/SP after the supply of the substance was interrupted by the University of São Paulo. The study cataloged the arguments contained in the Direct Action of Unconstitutionality 5,501/DF that deemed Law 13,269/2016, which authorized the production and prescription of synthetic phosphoethanolamine for any type of câncer (malignant neoplasm) unconstitutional, while the clinical studies were not completed. The results indicated that the judges authorized the use of the substance based on the patients' testimony about the positive impacts of the use of phosphoethanolamine on their health and the absence of side effects. The judges were aware of the lack of scientific evidence of safety and efficacy, as well as the obligation to register the substance as a medicine by the regulatory agency, according to health legislation. In the Supreme Court, the mentioned lack of scientific evidence and the strategic use of legislation to create a case-by-case exception led to the declaration of unconstitutionality of the Law by a majority of Ministers votes. The study registers, however, a certain unwillingness of the Judiciary to incorporate in the decision-making process the evaluation of the health regulatory agency as a source of the correct evaluation of medicines. In conclusion, the convinced patients' testimony about the perspectives of cure or reduction of suffering added to the absence of evidence in the legal proceedings regarding the risks of the consumption of phosphoethanolamine was crucial to the judicial decisions.

The 'false hope' argument in discussions on expanded access to investigational drugs: a critical assessment.

When seriously ill patients reach the end of the standard treatment trajectory for their condition, they may qualify for the use of unapproved, investigational drugs regulated via expanded access programs. In medical-ethical discourse, it is often argued that expanded access to investigational drugs raises 'false hope' among patients and is therefore undesirable. We set out to investigate what is meant by the false hope argument in this discourse. In this paper, we identify and analyze five versions of the false hope argument which we call: (1) the limited chance at benefit argument, (2) the side effects outweighing benefits argument, (3) the opportunity costs argument, (4) the impossibility of making informed decisions argument, and (5) the difficulty of gaining access argument. We argue that the majority of these five versions do not provide normative ground for disqualifying patients' hopes as false. Only when hope is rooted in a mistaken belief, for example, about the likelihood of benefits or chances on medical risks, or when hope is directed at something that cannot possibly be obtained, should it be considered false. If patients are adequately informed about their odds of obtaining medical benefit, however small, and about the risks associated with an investigational treatment, it is unjustified to consider patients' hopes to be false, and hence, to deny them access to investigational drug based on that argument.

A lacuna regulatória de medicamentos órfãos impacta na disponibilidade de alternativas terapêuticas no Brasil?

Introdução: A regulação de registros específicos para os chamados "medicamentos órfãos" tem sido uma estratégia das maiores agências de medicamentos do mundo para fomentar o acesso e monitoramento de tratamento para doenças e agravos de pouca prevalência ou interesse mercadológico. Objetivos: Esse estudo visou identificar o perfil dos medicamentos que se enquadram nessa categoria internacionalmente explorar possíveis lacunas de registro gerados pela ausência de uma norma sanitária específica no Brasil. Métodos: Foram analisadas as bases de dados de registro de medicamentos órfãos de países da União Europeia e dos Estados Unidos da América e os resultados foram comparados com a base registros da Agência brasileira. Resultados: Foram identificados 369 medicamentos registrados como órfãos nos órgãos europeu e estadunidense totalizando 801 indicações clínicas. A maior parte dos medicamentos registrados no âmbito internacional era de agentes anti-neoplásicos e imunomoduladores (N=135; 36,59 %) e de medicamentos que agiam no aparelho digestivo e metabolismo (N=48; 13,01 %). Dos medicamentos órfãos registrados e comercializados no âmbito internacional, quase metade, 177 (47,97 %), não apresentavam registros ativos no Brasil e atendem a 327 indicações clínicas (40,82 %). Conclusão: O Brasil deve analisar afundo os impactos da ausência de um fluxo de registro medicamentos órfãos, que pode afetar diretamente no acesso de tratamento para determinadas doenças raras e negligenciadas.

SUMMARY Introduction: The regulation of specific registrations for the so-called "orphan drugs" has been a strategy of the largest drug agencies in the world to promote access and monitoring of treatment for diseases and conditions of low prevalence or market interest. Aims: This study aimed to identify the profile of drugs that fall into this category internationally and explore possible gaps in registration generated by the absence of a specific health standard in Brazil. Methods: Orphan drug registration databases from countries of the European Union and the United States of America were analyzed and the results were compared with the database of the Brazilian Agency. Results: A total of 369 drugs registered as orphans in European and US agencies were identified, totaling 801 clinical indications. Most of the drugs registered internationally were antineoplastic agents and immunomodulators (N=135; 36.59 %) and drugs that acted on the digestive system and metabolism (N=48; 13.01 %). Of the orphan drugs registered and marketed internationally, almost half, 177 (47.97 %), did not have active registrations in Brazil and meet 327 clinical indications (40.82 %). Conclusion: Brazil must analyze in depth the impacts of the absence of an orphan drug registration flow, which can directly affect access to treatment for certain rare and neglected diseases.

Introducción: La regulación de registros específicos para los denominados "medicamentos huérfanos" ha sido una estrategia de las agencias de drogas más grandes del mundo promover el acceso y seguimiento del tratamiento de enfermedades y condiciones de poca prevalencia o interés de mercado. Objetivos: Identificar el perfil de las drogas que entran en esta categoría a nivel internacional explorar posibles lagunas en los registros generadas por la ausencia de un estándar sistema de salud específico en Brasil. Métodos: Las bases de datos de registro de medicamentos huérfanos de países de la Unión Europea y Estados Unidos da América y los resultados fueron comparados con la base de registros de la Agencia Brasileña. Resultados: Se identificaron 369 medicamentos registrados como huérfanos en órganos europeos y americanos, totalizando 801 indicaciones clínicas. La mayor parte de los medicamentos registrados a nivel internacional fueron agentes antineoplásicos e inmunomoduladores (N=135; 36,59%) y fármacos que actuaron en el aparato digestivo y metabolismo (N=48; 13,01%). De medicamentos huérfanos registrados y vendidos internacionalmente, casi la mitad, 177 (47,97 %), no tenía registros activos en Brasil y atendió 327 indicaciones clínicas (40,82%). Conclusión: Brasil debe analizar en profundidad los impactos de la ausencia de un flujo de registro de medicamentos huérfanos, que puede afectar directamente el acceso al tratamiento para ciertas enfermedades raras y desatendidas.

Trend of drug clinical trials in mainland China from 2009 to 2020.

With the development of linnovative regulations on drug clinical trials in mainland China, the quantity and quality of drug clinical trials have gradually improved over the past decade. Based on the information of the clinical trials from the online drug clinical trial registration platform of National Medical Products Administration, we reviewed the data of drug clinical trials in mainland China from 2009 to 2020. A total of 8,593 clinical trials have been conducted during this period. The annual number of clinical trials has been increasing gradually, and peaked in 2017. There were 2,127, 1,051, 1,551, and 156 phases I, II, III, and IV clinical trials respectively. In addition, there were 3,441 bioequivalence studies. Trials for anti-tumor drugs ranked the highest (19.45%), followed by trials of drugs for infections and infestations (12.96%) and those for cardiovascular diseases (9.00%). Meanwhile the number of the clinical trial sites also increased annually. However, there were only 116 and 130 clinical trials of drugs for children and rare diseases respectively. The geographical distribution of the sites was uneven. This mapping review provides an overall look of clinical trials in China, which may be useful for domestic and international sponsors.

Analysis on the expression of drug standards and related issues in the newly revised Drug Administration Law / 中国药房

OBJECTIVE To sort out and analyze the expression and provisions of drug standards in the text of the newly revised Drug Administration Law ，and to explore the connotation and legal positioning of drug registration standards so as to provide reference for the rational application and interpretation of relevant provisions of drug standards in Drug Administration Law . METHODS Through the review of the evolution of drug standard management in China ，the legal provisions of drug standard in the Drug Administration Law were analyzed. Comparative study and literature research methods were used to analyze the legal expression and connotation of drug standards. RESULTS & CONCLUSIONS There were different expressions about “national drug standards ”“drug standards ”and“quality standards ”in the current provisions of the newly revised Drug Administration Law ； the legal position of the provincial-level standard for the preparation of Chinese herbal pieces was not clear ，and there may be insufficient legal regulation in the enforcement of drug administration. It is necessary to make an administrative interpretation for the content of relevant drug standards and provisions ，and further clarify the legal attributes of drug standards in the processing of provincial Chinese herbal pieces in order to promote the standardized management of Chinese herbal pieces.

[The medical social aspects of improving accessibility of medications in conditions of necessity of prevention and treatment of diseases dangerous to immediate neighborhood].

The article presents a review of essential approaches of increasing accessibility of medicinal preparations in conditions of need in prevention and treatment of diseases representing danger to immediate neighborhood.

Update on the ESCEO recommendation for the conduct of clinical trials for drugs aiming at the treatment of sarcopenia in older adults.

BACKGROUND: In 2016, an expert working group was convened under the auspices of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and formulated consensus recommendations for the conduct of clinical trials for drugs to prevent or treat sarcopenia. AIMS: The objective of the current paper is to provide a 2020 update of the previous recommendations in accordance with the evidence that has become available since our original recommendations. METHODS: This paper is based on literature reviews performed by members of the ESCEO working group and followed up with face to face meetings organized for the whole group to make amendments and discuss further recommendations. RESULTS: The randomized placebo-controlled double-blind parallel-arm drug clinical trials should be the design of choice for both phase II and III trials. Treatment and follow-up should run at least 6 months for phase II and 12 months for phase III trials. Overall physical activity, nutrition, co-prescriptions and comorbidity should be recorded. Participants in these trials should be at least 70-years-old and present with a combination of low muscle strength and low physical performance. Severely malnourished individuals, as well as bedridden patients, patients with extremely limited mobility or individuals with physical limitations clearly attributable to the direct effect of a specific disease, should be excluded. Multiple outcomes are proposed for phase II trials, including, as example, physical performance, muscle strength and mass, muscle metabolism and muscle-bone interaction. For phase III trials, we recommend a co-primary endpoint of a measure of functional performance and a Patient Reported Outcome Measure. CONCLUSION: The working group has formulated consensus recommendations on specific aspects of trial design, and in doing so hopes to contribute to an improvement of the methodological robustness and comparability of clinical trials. Standardization of designs and outcomes would advance the field by allowing better comparison across studies, including performing individual patient-data meta-analyses, and different pro-myogenic therapies.

Overview on the Amendments of Provisions for Drug Registration in China.

The revised Provisions for Drug Registration was promulgated by the State Administration for Market Regulation of China in March 2020 and came into force on July 1, 2020. This article describes the history of the drug registration management system in China, explains the background of the revision of the Provisions for Drug Registration in 2020, and introduces the main modifications of the Provisions for Drug Registration in 2020 in the aspects of registration classification, application for clinical trial on drug, application for drug marketing authorization, accelerated procedure for drug registration, working timeline, and supervision and administration. This article is intended to give a brief overview for those who wish to submit a drug registration application in China or for those who would like to get more acquainted with drug registration in China.

Construction of Post Competency Evaluation Index System for Drug Registration Specialist / 中国药房

OBJECTIVE：To esta blish a sc ientific and objective post competency evaluation index system for the drug registration specialist. METHODS ：By searching the competency model literature of drug registration and registration related documents，combined with Spencer ’s Competency Dictionary and Hay ’s Competency Dictionary ，post competency evaluation index system for drug registration specialist was formulated preliminarily. Through two rounds of Delphi expert consultation ，experts in related fields of drug registration were consulted by letter ，the evaluation indexes were screnned and revised ，and the weight of the indexes was calculated by using the superior order diagram method. Based on questionnaire survey ，232 drug registration personnel were selected as research objects ，and then exploratory factor analysis ，confirmatory factor analysis and internal consistency reliability analysis were used to test the constructed evaluation index system. RESULTS ：The post competency evaluation system of drug registration specialist covered 4 core dimensions （registered professional ability ，relationship management ability ，professional development ability ，personal comprehensive quality ），11 sub-scales，and 41 measurement items ；the weight of the index was confirmed. The establishment process of the evaluation system showed that the expert consultation had high enthusiasm and good coordination；exploratory factor analysis and confirmatory factor analysis had proved the scientific rationality of the index system. CONCLUSIONS：The post competency evaluation index system for drug registration specialist is comprehensive ，integrated and scientific，can provide reference for evaluation and management of the drug registration specialist practice.

Estimating the utilisation of unregistered antimicrobials in Australia.

OBJECTIVE: To identify and estimate the usage of unregistered antimicrobial drugs in Australian clinical practice. METHODS: A descriptive pharmaco-epidemiological study, utilising three data sources: analysis of Special Access Scheme (SAS) applications for unregistered antimicrobials included in clinical guidelines over a five year period, analysis of antimicrobials dispensed from South Australian public hospital pharmacy departments over a two year period and analysis of National Antimicrobial Utilisation Surveillance Program (NAUSP) data for reported inpatient usage of unregistered antimicrobials in Australian hospitals over the last 5 years. RESULTS: 59 unregistered antimicrobials were identified using the mixed methods. 18,362 Special Access Scheme applications were submitted between May 2012 and April 2017 to access the 20 unregistered antimicrobials identified in the Therapeutic Guidelines® (eTG complete); 51.4% were determined by the prescriber to be for life-threatening indications. Annual applications more than doubled over the five years. 34 unregistered antimicrobials were dispensed from South Australian public hospitals between July 2015 and June 2017. On average, 1.1% of total antimicrobial usage (Defined Daily Doses) per month was accessed via the SAS, of which 87.7% were for outpatients or discharged patients. 34 unregistered antimicrobials for systemic use identified in the NAUSP database were used in Australian hospitals between 2013 and 2018. CONCLUSION: The use of unregistered antimicrobials in Australian clinical practice is not uncommon. With increasing antimicrobial resistance, there will be a continued reliance on older less-used antimicrobial agents and an increasing need for novel drugs, therefore regulatory pathways need to facilitate security of supply and assurance of medicine quality and safety.