Yang Yu,Shi Yu,Hu Rongbo,Tian Lijuan

(School of Business Administration,Shenyang Pharmaceutical University,Shenyang 110016,China)

Abstract Objective To study the origin and development,framework and content of the EU-RMP (European Drug Risk Management Plan) so as to provide a reference for China’s drug risk management plan (RMP).Methods Literature research and comparative research were used in this paper.Through searching Chinese and foreign literature,the website of European Medicines Agency (EMA) and the Guideline on Good Pharmacovigilance Practices (GVP),in-depth understanding of the EU-RMP content and requirements,some lessons were extracted for our reference.Results and Conclusion All departments should cooperate closely in the preparation of RMP in China.Then,the risk control measures should be further enriched to reduce the risks.Besides,the rules for implementing RMP should be clarified to promote the risk management of the whole life cycle of drugs and maintain the safety of patients’ medication.

Keywords:risk management plan; risk minimization; EU

On September 30,2018,the National Medical Products Administration (NMPA) issued the“Announcement on Direct Reporting of Adverse Reactions by Drug Marketing License Holders”,requiring drug marketing authorization holders (MAHs)to take effective measures for drug varieties that may have safety risks.For example,they should formulate a risk management plan (RMP)[1].The newly revised“Drug Management Law” also clearly requires MAH to develop a post-marketing RMP to strengthen the continuous management of marketed drugs.Besides,it also stipulates the punishment measures for MAHs if they fail to formulate RMPs or fail to carry out postmarketing research and evaluation.It can be seen that drug RMP in China has gradually risen to the legal level,highlighting the government’s emphasis on risk management after drug listing.

RMP is a specific description of the drug risk management system.It should not only clarify the risks that may occur in the use of drugs,but also explain the control measures to deal with and reduce the risks.In recent years,with the continuous advancement of the reform of China’s drug review and approval system,the new drug review process has been optimized.Therefore,it is fast for innovative drugs to be approved for marketing in China.To ensure the safety of drug use for patients,regulatory departments must improve the post-marketing risk management system of innovative drugs.Meanwhile,marketing authorization applicant (MAA) is required to submit more risk management information when applying for innovative drugs.

The European Union (EU) adopted the safety information description of ICH-E2E as early as 2005 and introduced the concept of RMP[2].The European Medicines Agency (EMA) released the first version of the RMP writing template in 2006,and the latest version was released in October 2018.At present,the EU has provided the basis and support for the smooth development of RMP in terms of system establishment and template norms.China can learn from the advanced experience of the EU to refine the implementation rules of RMP.This can improve the construction of post-marketing risk management system and keep the balance of risks and benefits throughout the life cycle of drugs.

1 Overview of RMP

As a specific description of the drug risk management system,RMP describes the risks that may occur in the use of drugs,such as the identified adverse reactions or the potential ones.In addition,it is to study how to deal with and reduce the drug risk,such as the warning information on the packaging or a risk identification and evaluation system established early in the clinical trial as well as various drug safety information.These are used as the basis for postmarket risk management.

2 The origin and development of EU-RMP

In 2005,the EU adopted the ICH-E2E recommendation.After combing with its own experience and the opinions of experts and the public,it issued guideline for the Risk Management System of Human Drugs[3].The core of the guideline is the EU risk management system based on EU-RMP,which provides guidance for MAA/MAH to introduce the risk management system to regulators in the form of RMP.In October 2012,the EU issued regulations 1027/2012/EU and 2012/26/EU to revise the previous regulatory framework for drug risk management,and proposed more EU pharmacovigilance actions and regulatory requirements.This has greatly increased the number of RMPs submitted by MAH.In 2012,the number of RMPs submitted to the EMA for listing increased by more than three times from the previous year,and the RMP permit for initial listing increased by 24%[4].In June 2012,the EU issued the “Guideline for the Fifth Module of the Pharmacovigilance Code-Risk Management System”,which was revised twice in 2014 and 2016.Then it was officially promulgated and implemented on May 31,2016.The contents of each part of RMP give detailed interpretation and suggestions,which put forward specific requirements for MAH submission and update of RMP.

EMA provides a detailed RMP template for MAA/MAH.It is now required that all drugs should submit an RMP when applying a marketing permit.MAA/MAH can consult EMA for any RMP related issues before submitting the application[5].The RMP summary of the drug approved for marketing will be open to everyone on the EMA website.

3 Overview of EU-RMP content

The main purpose of EU-RMP is to describe the drug safety issues.Through the study of the pharmacovigilance plan and the dynamic evaluation of the risk information,EU-RMP can determine whether the drug risk will be effectively avoided to achieve the goals of minimizing drug risk and maximizing patient benefits.The contents mainly include the following parts (Fig.1).

Fig.1 Framework of EU-RMP

3.1 Safety regulations

The safety regulations are the core and foundation of the EU-RMP and they are divided into three parts.An important identified risk refers to a risk that will have a significant impact on the product’s benefit-risk balance and/or an impact on public health.An important potential risk refers to data suggesting that there may be a causal correlation between the adverse event and the drug of interest,but this correlation has not been confirmed.The important missing information refers to the gap in understanding of the drug safety knowledge for the intended users or a specific target group.Therefore,it is hard to prove whether the drug safety characteristics are different from those shown before.Further research and evaluation are needed for the expected risks in the described group and the unstudied group.

Safety regulations are applicable to the study of safety issues after drug approval.However,with the gradual accumulation of safety information,there may be a transition between three categories(important identified risks,important potential risks,and important missing information).The dynamic adjustment of risks in EU-RMP is shown in Fig.2.In this process,the newly identified risk signals will be introduced into RMP,or a new safety certificate will remove the quantified risks from RMP.It is expected that the uncertain safety issues will be resolved throughout the entire life cycle.

Fig.2 Dynamic adjustment of risks in EU-RMP

3.2 Pharmacovigilance plan

Pharmacovigilance plans are divided into regular and additional plans.The regular pharmacovigilance plan refers to a series of major activities that meet the pharmacovigilance laws and regulations stipulated by the EMA,such as signal detection,literature review,preparation of periodic safety update reports,and questionnaire surveys of specific adverse events,etc.When the regular pharmacovigilance plan cannot meet the needs of daily work,enterprises should develop an additional pharmacovigilance plan,that is,formulating an implementation plan for each risk,including the research in the pharmacovigilance plan,such as post-market safety studies,intervention or non-interventional safety research,registration items and clinical research.

3.3 Risk minimization authorization (RMA)

3.3.1 Overview of RMA

After the enterprise formulates routine and additional pharmacovigilance plans and discovers drug risks,the next step is to take RMAs,including conventional RMAs and additional RMAs,to reduce the risk level or prevent the possibility of adverse reactions related to drug exposure.Among them,conventional RMAs are mainly aimed at product packaging and instructions,such as using small packages,controlling the quantity of drug dosage units,or adding safety information to the instructions.In addition to conventional tools,additional tools can be used to minimize risks,including educational materials (guidelines for healthcare professionals and patients/ caregivers,etc.),letters (dear doctor letter),patient risk identification (patient logs),training materials (training materials for healthcare professionals,list of prescribers),mandatory monitoring items or patient registration,etc.

3.3.2 Evaluation of RMA

For safety issues summarized based on risks,utility evaluation should be conducted according to the process of Fig.3 to determine whether it is necessary to take RMAs.

Fig.3 Evaluation of the effectiveness of RMAs

The utility evaluation of RMAs usually adopts the method of investigation to evaluate whether doctors are aware of the risks and the measures to be taken.Process indicators mainly investigate whether the drug meets the target population,and examine the effectiveness of RMAs by evaluating clinical knowledge and clinical medication behavior.Meanwhile,outcome indicators mainly consider whether the risk is actually reduced through the severity and incidence of adverse reactions.The ultimate goal of examining these two indicators is to reduce the occurrence of similar events,which can help doctors prescribe correctly and convey risk information to patients accurately.

4 Submission and maintenance of RMP in China

At present,China has only issued RMP writing requirements for special drug varieties.In 2008,the launch of high-risk variety management plan marked the start of constructing a drug risk management system by China’s drug regulatory authorities[6].In 2009,Center for Drug Evaluation (CDE) launched“Risk Management Plan for Traditional Chinese Medicine Injection (Trial)”[7],starting a systematic translation and transformation of foreign technical guidelines.On September 13,2018,CDE issued the “Format and Content Requirements for the Risk Management Plan for Applying for Anticancer Drugs”,requiring Chinese RMP should be submitted when enterprises apply for antitumor drugs (including chemical drugs and biological products) for the first time in China[8].The main contents include the following aspects (Fig.4).

Fig.4 Framework of RMP for anti-tumor drugs in China

The RMPs of China and the EU are based on the ICH E2E pharmacovigilance plan.From the above,it can be seen that the RMP framework of anticancer drugs in China is roughly the same as that of the EU,which includes product overview,safety overview,pharmacovigilance activities,the effectiveness after marketing,risk minimization measures and appendix.In terms of safety overview,considering that drug safety information may dynamically change between important identified risks,potential risks,and missing information,RMP of China’s anti-tumor drugs also supplements the risks that need further evaluation.For important identified risks,the frequency,severity and outcomes of the risks should be further studied.For important potential risks,the causal correlation between adverse events and the drug of interest should be evaluated in depth.For important missing information,groups with significant safety issues (children,the elderly,pregnant women or breastfeeding women,etc.) should be clarified.In addition,both China and the EU require enterprises to submit RMPs at the same time when submitting a listing application.The materials to be submitted include the original and all revised versions of RMP,the previous evaluation results,and the implementation status of various studies covered by RMP.Only when the registration application and the RMP submitted by the applicant are approved at the same time,the drugs can be sold on the market.In addition,MAA is responsible for the RMP both in China and the EU.MAA is required to keep in touch with regulatory departments to revise and update RMP according to the newly discovered risks.

Fig.5 Management process of RMP in drug life cycle

RMP is an effective means to prolong the life cycle of drugs.In order to ensure the safety of public medication and the balance of risks and benefits of the entire life cycle of drugs,China refers to the risk management plan system of the EU.

Generally speaking,RMPs must be prepared before the clinical trials are carried out.They can identify risks in preclinical studies and confirm benefits in phase I and phase II clinical trials.Besides,RMPs must be submitted at the time of first submission of the listing applications.After the approval of the drug,drug safety information should be collected with the gradual advancement of Ⅳ clinical research.Meanwhile,RMAs should be formulated and implemented to reduce risks and retain benefits.Then,based on the results of the RMA effectiveness evaluation,we can decide whether to reassess the risk-benefit balance and make adjustment to improve this balance.

5 Suggestions for promoting RMPs in China

5.1 The development and implementation of RMP requires cross-sectoral cooperation

RMP is one of the means for enterprises to build a risk management system.Since the formulation of RMP runs through the entire life cycle of drugs,crosssectora cooperation is required.It requires information and opinions from both pre-clinical scientists,clinical research teams,epidemiologists,registration and legal departments,as well as the participation of the marketing and sales departments.When the benefitrisk ratio of drugs changes during the implementation of routine and additional risk minimization measures,MAH,quality management department,technology development department and other departments should actively monitor drug safety and evaluate the riskbenefit ratio so that patients can use safer and more effective drugs as soon as possible.

5.2 Enriching risk control measures

In order to reduce the risk of drugs,Chinese pharmaceutical enterprises usually adopt control measures such as revising labels and instructions,recalling/suspending product sales.On this basis,it is recommended to learn from the experience of the EU,and at the same time,we can gradually enrich the risk control measures after considering the differences in China’s medical system and public health literacy.For patients,it is recommended to develop specific instructions,warning cards and drug treatment guidelines,etc.For medical personnel,it is recommended to provide them with letters/education materials,including communication letters and nursing guidelines.In addition,for drugs that have significant efficacy but accompanied by great risks,if none of the existing RMAs can minimize their risks,feasible plans can be taken to limit the use of drugs,such as conducting specific trials on patients to ensure that they abide by the strict clinical standards.Meanwhile,the distribution of drugs is restricted and only the registered pharmacies with permit can dispense drugs.Some information of patients,such as follow-up measures as well as the acceptance and understanding of drug risks from doctors,pharmacists and patients can be collected through specific data systems.

In addition,the efficiency,flexibility and accessibility of risk control measures must be ensured.Under the premise of not increasing the burden of medical institutions,risk control measures that match the severity of the risks can be taken to evaluate the implementation effect of RMAs as soon as possible.The higher the degree of risk,the more frequently the control measures should be evaluated to minimize patients’ risks while benefiting to the largest degree.

5.3 Formulating relevant management methods to clarify the application scope and update requirements of RMP

Because RMP is a dynamically changing document,the applicant should update the risk information in RMP in a timely manner to ensure the benefits of the product outweighing the risks with appropriate pharmacovigilance activities and RMAs.However,at present,China has not yet clarified the scope of the application of RMP and the requirements for updating,including the circumstances,the content and the procedures.It is recommended that NMPA should stipulate relevant management measures as soon as possible to provide guidance for the submission of RMP.

First of all,it is necessary to refine the scope of the application of RMP.Not all drugs are required to submit RMP,and they should be classified according to the risk level.RMPs are required for new drugs and drugs with emerging safety risks.Generic drugs should be consistent with the RMP of their reference preparations[9].Secondly,MAH should update the RMP in time according to the safety data of the product.Specific circumstances include the following items such as significant changes in the dosage,administration route,production process or indications during the drug registration process.Besides,drugs with new active ingredient or new biological agents applying for listing should submit RMPs,too.Product safety information leading to greater risks than benefits should submit RMP as well.Lastly,MAA/MAH actively requesting confirmation of a drug safety issue should submit RMP.The updated contents should include the followings but they are not limited to them.(1) They are new safety information,additional pharmacovigilance plan or RMAs,and the effectiveness evaluation of RMAs defined in RMP.(2)The updated RMP should be submitted to the National Center for ADR Monitoring.At the same time,it should be submitted to CDE and the provincial drug administration for record.

In short,in order to protect public health,proactive drug safety monitoring should be conducted to evaluate the risk-benefit balance in real time.Then,the cross-departmental cooperation in the preparation of RMP should be implemented.Besides,risk control measures should be enriched and RMAs that match the severity and degree of hazard must be adopted.The scopes of the application and updated requirements of RMP should be clarified.And the implementation rules of RMP should be refined.Lastly,the construction of risk management system should be perfected after listing.