Research Progress in FDA’s Focus Areas of Regulatory Science for Drugs and Suggestions for China

Gong Jingran ,Chang Senhao ,Chang Yingnan ,Chen Yuwen＊

(1. School of Business Administration, Shenyang Pharmaceutical University, Shenyang 110016, China;2. Research Institute of Drug Regulatory Science, Shenyang Pharmaceutical University, Shenyang 110016, China)

Abstract Objective To sort out the focus areas of FDA’s scientific supervision and to achieve corresponding results,so as to provide some suggestions for the scientific research and innovation of drug supervision in China.Methods Indepth research was carried out in the fields of safety evaluation tools,clinical trial innovation,new methods of product quality evaluation,information science and so on.Results and Conclusion The research foundation of drug supervision related technology in China is weak,and a systematic supervision system has not been formed.Learning from the scientific experience of drug supervision in the United States,we can promote the development of the focus areas of drug supervision in China.Besides,we should improve the standard management ability while perfecting the regulations and standards system.Lastly,we should establish a system for government and industry-university-research to realize the full-cycle supervision of drugs.

Keywords: research progress;focus areas of regulatory science (FARS);drug

The promotion and innovation of scientific supervision is the foundation of the core mission of the U.S.Food and Drug Administration (FDA)to protect and improve public health.Research on scientific supervision plays a critical role in decisionmaking,ensuring the safety and efficacy of medical products and promoting public health.Therefore,they develop new tools and methods to obtain the data needed for innovation,which not only improves the evaluation of supervision,but also meets medical and public health needs.As a result,it greatly promotes the development of scientific supervision.For example,FDA uses electronic medical records to realize realtime post market monitoring,which is real-world data(RWD) dynamic supervision.

By combing the focus areas of FDA drug regulatory science,we can draw on its advanced experience and innovative thinking to put forward some suggestions,which will promote the development of focus areas of drug regulatory science in China.

1 Focus areas of regulatory science (FARS)of FDA

Although the scientific progress of FDA enables the entry of innovative products into the market to improve public health,it needs to keep up with the pace of science and technology.The FARS is intended to identify the key areas for innovation or strengthening investments in regulatory scientific research to support FDA’s regulatory and public health mission.To stay ahead of evolving regulatory needs,FARS is designed to be regularly updated to ensure that FARS includes the most current topics of FDA’s research and fulfills regulatory responsibilities.In 2011,FDA developed a strategic plan for regulatory science that identified eight focus areas[1].In 2013,a ninth focus area was added[2].In 2020,FDA recognized that the science and technology underpinning FDA-regulated products had made significant progress since 2011.

1.1 Preclinical safety prediction

Quantitative structure activity relationship(QSAR) model is a set of molecules with known toxicity,which deduces the relationship between drug structure attributes and whether they cause some biological effects.In 2015,FDA decided to use QSAR model to predict the mutagenicity of impurities found in drugs,replacing the traditional experimental methods.In the same year,FDA issued a guide describing how the model could be used.QSAR model is valuable to screen the toxicity of candidate drug molecules before animal testing.In 2016,the QSAR computational toxicology consulting service of FDA/Center for Drug Evaluation and Research (CDER)provided CDER safety reviewers with QSAR analysis and structural similarity-based assessment,helping reviewers solve insufficient experimental results and understand post market safety signals.

1.2 Clinical evaluation and individualized treatment innovation

1.2.1 Virtual physiological human(VPH)model

The VPH model is a global virtual community designed to create computer models of human health and diseases[1].The VPH provides computing and data infrastructure modeling while considering the complexity of processing medical data.The longterm goal of VPH is to create “digital twins” of patients,a personalized computer model of the patient that mimics their physiological or pathological characteristics.The ultimate goal of VPH is to create virtual patients,or computer trials in virtual populations,where patients manage their own health.Computer models of physiology or pathology are applied in medicine in a variety of ways.Model individuation can help predict the disease progression or treatment outcome and play an important role in doctors’ decision-making.

1.2.2 New biomarkers

Biomarkers are some biochemical indexes that can be objectively measured and evaluated.They are usually special small molecules,proteins,and nucleic acid sequences.The current biological state of the body can be obtained by measuring biomarkers[3].Biomarkers of patients are measured before treatment for the selection of clinical trial subjects.Changes in biomarker indicators after treatment can predict or identify safety problems related to candidate drugs.Microarray technologies are used in basic and clinical research,including the identification of biomarkers for drug efficacy and safety.If microarray technology is fully transformed into clinical application,standards and quality control measures must be formulated and implemented.

Biomarker qualification program (BQP) identifies the biomarkers used for auxiliary diagnosis or drugs development,regulatory and review.It supports the development and verification of new biomarkers in cooperation with stakeholders,providing a biomarker review procedure framework to support regulatory decisions,and the results interpreted within a given context of use.With the continuous development of drug development tool (DDT) qualification,8 biomarkers have obtained DDT qualification[4].

1.3 Product quality evaluation

Due to the increasing proportion of targeted therapy,combination products,biological agents,and generic drugs in regulatory submissions,drug quality assessment is becoming more and more complex,which needs to be analyzed by assessment and analysis technology.

1.3.1 Key core technologies

FDA invests in core science and technology such as high-throughput sequencing,high-resolution nuclear magnetic resonance and mass spectrometry,multicolor flow cytometry,and ultra-high resolution confocal microscope to support drug regulation[2].Mastering key technologies,FDA scientists conduct cutting-edge research using new technologies that drug applicants are or will use.Based on scientific regulatory decision-making and the formulation of policies and guidelines,the use of new technologies is critical for the practical experience of innovative drug evaluation.

1.3.2 Nanotechnology

Compared with traditional small molecule drugs,nano drugs have advantages in pharmacokinetics,passive or active targeting,reducing toxic and side effects,such as improving the solubility of insoluble drugs and effectively improving the bioavailability of drugs.All countries in the world regard nano drug therapy as the key support and development direction in the field of biomedicine.

FDA has established Nanotechnology Core Centers,which provides technicians with medical devices to conduct product evaluation and safety research.Scientists in this center study the safety of products using nano materials,establishing methods to evaluate the quality and effectiveness of nano materials,identifying pre-clinical safety evaluation standards for products containing nano materials.At present,51 kinds of nano drugs have been approved to enter the clinic[5].

1.4 Using information science to monitor drug safety

FDA obtains information from various sources such as product submission,inspection report,adverse reaction event report,confirmed patient data provided by health care,investigation,and basic scientific research results.In addition to integrating the data of patient results,the predictive safety assessment tool combines the post market data with other information sources to develop new methods and data sources for post market regulatory.

1.4.1 Array Track TM genomics tool

Array TrackTMis a key bioinformatics tool for receiving and analyzing data in the voluntary genome data submission program,which promotes the application of toxicological genome data in drug development and evaluation[6].Initially,Array TrackTMcould only receive DNA microarray data.In 2008,FDA improved Array TrackTMto accept,analyze and manage the pharmacogenomics data review of ultrafine arrays,including proteomics,metabolomics,and whole genome joint research data.

1.4.2 Nonclinical information management system(NIMS)

NIMS is a software tool,which includes a nonclinical research data repository.FDA receives data on a single platform for review,approval,analysis,and data visualization[1].With the development of nonclinical data standards,NIMS has become a part of the transformation of nonclinical review,providing standard and dynamic data views and functions for reviewers.In addition to improving the efficiency of review,the resource base allows cross-cutting research and analysis,improving review science and safety prediction research.

2 Research progress of regulatory science in China

In April 2019,the National Medical Products Administration (NMPA) launched the first nine key projects of China’s scientific action plan for drug regulatory.These projects focused on the reform of drug evaluation and approval system,closely followed the frontier of international drug regulatory,innovated regulatory tools,standards and methods,which effectively solved some problems restricting China’s drug regulatory.They also comprehensively improve the modernization level of drug regulatory[7].After two years,the first focus projects achieved some good results,103 new regulatory tools,methods and standards were studied and formulated,of which 31 were released[8].

On June 28,2021,NMPA released the second batch of 10 focus projects of drug regulatory action plan,further improving the ability and level of drug regulatory to accelerate the innovative products to better meet the demand of public health.According to the goal of becoming the best pharmaceutical power by 2030,China’s drug regulatory science should focus on problems of drug regulatory from the aspect of drug life cycle,such as drug review and approval,inspection,monitoring and evaluation.Then,it can determine the research focus[8].

2.1 Artificial intelligence

The application of model and simulation(M&S) covers drug discovery,preclinical and clinical research,approval,and life cycle management.In August 2020,the Center for Drug Evaluation(CDE) released the first “Guidance of Model-driven Drug Development (Draft)”,which guided drug development through M&S quantitative evaluation.

Artificial intelligence learns medical literature and relevant data through natural language processing (NLP),discovering the relationship between compounds and diseases,finding targets and shortening the target discovery cycle.Chiatai Tianqing and Alibaba cloud are cooperating to adopt AI pharmacy.Compared with traditional computeraided drug design methods,this new method can improve the screening accuracy by 20%[9].At present,AI is used in drug research,auxiliary diagnosis,virtual assistant and so on.AI virtual assistant developed by domestic enterprises has been used before,during and after diagnosis[10].In the future,some products will be made into lightweight applications and integrated into the information system,which can connect the information of different links.

2.2 Cell and gene therapy

In recent years,many countries and regions have taken cell and gene therapy as the key research direction in the field of biomedicine.NMPA has required experts in the field of scientific research and supervision to conduct in-depth research on the regulatory system and risk classification of cell and gene therapy products.It has preliminarily established preclinical research,clinical safety and efficacy evaluation system,verification and testing technical specifications,covering cellular immunotherapy products and other gene therapy products based on viral vectors.

The scale of clinical research on stem cells and immune cells in China is second only to the United States,and it is one of the countries that has the largest number of clinical research on cell and gene therapy.Preliminary research results have been achieved in some fields[11].As of April 30,2021,the CDE had approved 71 clinical trials of cell and gene therapy products (according to the acceptance number).Relying on the scientific research platform of drug regulatory,the Center for Drug Evaluation,NMPA has formulated 17 technical guiding principles,of which 4 guiding principles have been released and 12 guiding principles have been completed for public comment.On June 23,2021,NMPA announced that axicabtagene ciloleucel injection,a CAR-T cell therapy product of fosun kite was officially approved for marketing[12].This marks the first CAR-T therapy approved in China and the sixth CAR-T cell therapy approved in the world.

2.3 Quality evaluation of nano drugs

Nanoscience is a strategic emerging field with innovation initiative in China.In Clinical Trials database and drug clinical trial registration and information disclosure platform,nearly 300 drugs under research have adopted nano dosage forms to carry out clinical trials,and 54 nanotechnology related pharmaceutical products have been launched[13].The research of nanomedicine in China is at a critical stage from quantity to quality change now.More products will be submitted for listing in the future.

Due to the particularity of nano drugs,although there are standards for nano materials,there are no standards for nano drugs.The National Center for Nanoscience has explored new methods for the preparation and characterization of standardized samples of nanoproducts,achieving the detection sensitivity of pg and fg levels.After successfully developing two nano-inhibitors of immune checkpoint through the design of a diphilic polypeptide,personalized nano-tumor vaccine has made progress[14].The CDE puts forward basic requirements and evaluation principles for quality control,non=clinical safety evaluation and pharmacokinetics of nano drugs.

2.4 Post marketing drug safety monitoring

Active safety monitoring is the process of continuously and actively collecting electronic health data and evaluating the safety of marketed medical products.RWD is the main data collected in active monitoring to obtain more reliable information and ensure drug safety of patients.Based on the research of post-marketing drug regulatory norms of RWD,a literature database of RWD safety research and global post-marketing drug safety regulatory literature database of were established.

In order to promote the construction of drug information traceability system and guide enterprises to carry out drug traceability code,NMPA Information Center has completed the consultation drafts of two standards,namely,“Specification for Printing Drug Traceability Code” and “Specification for Displaying Consumer Query Results of Drug Traceability Code”.In addition,the pharmacovigilance evaluation model of marketing license holders based on big data is explored.

3 Proposals

China continues to strengthen drug regulatory.However,the research foundation of drug regulatory related technology is weak,and researchers’professional ability needs to be improved.In addition,the contradiction between regulatory demand and research ability is serious because a systematic regulatory science system has not been formed.By combing the research progress in focus areas of FDA’s drug regulatory science,we can draw on its experience to put forward the following suggestions.

3.1 Improving the regulations and standards system and the standard management ability

Regulatory policies determine the resource orientation of the industry.The government needs to issue detailed guidelines,which is in line with international standards.At present,the products under research and application in the field of cell and gene therapy involve a lot of genetic modification in vitro,and such transduction and modification tools have an important impact on product quality and safety.Therefore,it is necessary to formulate guidelines for such tools in pharmaceutical production to make the technical requirements more flexible.It can also be combined with other technical guidelines to provide comprehensive technical guidance for product.

3.2 Improving the review and approval system and the technical review ability

In terms of guiding principles for non-clinical research of cell and gene therapy products,there is no standard trial program applicable to all products in China.According to the principle of case-by-case analysis,communication with reviewers at early or key nodes runs through the whole approval process of cell and gene therapy products.Domestic CAR-T products obtain clinical data evaluated by clinical specialty at the time of application.If the risk is considered controllable,and applicant can provide evidence of the effectiveness and safety,some nonclinical research data can be exempted.

A three combinations of evaluation evidence system of traditional Chinese medicine theory,human experience of traditional Chinese medicine and clinical trials should be set up.Meanwhile,an expert evaluation committee of ancient famous traditional Chinese medicine preparations and prescriptions should be formed to promote the reform of evaluation and approval of traditional Chinese medicine.Based on the experience of three combination review and approval,we will gradually explore the guiding principles for the review of ancient traditional Chinese medicine preparations and classic prescriptions and formulate the technical guiding principles that meets the characteristics of traditional Chinese medicine.

3.3 Improving the information system and enhancing full-cycle digital regulatory

The regulatory of drug review and approval should be strengthened through information technology.Meanwhile,the security of network information must be guaranteed to improve the quality and efficiency of drug review and approval continuously.In addition,we should also pay attention to the informatization of the pilot construction of the scientific regulatory system of the drug examination center.We will incorporate various measures into the evaluation information system to enhance the rigid constraints on the implementation of measures and improve the scientific regulatory and evaluation.

3.4 Establishing a system of government, industry,university, and research institutions to realize fullcycle regulatory

Based on multi-party sharing of high-quality data resources,the government can guide enterprises to carry out scientific and technological innovation and help the public obtain accurate drug information.The industry will effectively transform the results on a large scale to improve drug accessibility.Research institutions can develop new technologies to help transform achievements.Patients should give timely feedback on the clinical effect of new drugs to achieve full-cycle regulatory.Based on professional training,the construction of drug evaluation team can be further strengthened.Enterprises should cooperate with the government in drug evaluation,actively carrying out personnel recruitment,strengthening the construction of professional and technical team by improving its promotion system.