Pharmacovigilance System for Pharmaceutical Enterprises in EU: Regulation and Its Enlightenment

ZHANG Hao, LIU Si-qi, WU Zhi-ang

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

Pharmacovigilance System for Pharmaceutical Enterprises in EU: Regulation and Its Enlightenment

ZHANG Hao, LIU Si-qi, WU Zhi-ang

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

Objective To provide references for China’s pharmaceutical enterprises by studying the pharmacovigilance system in EU, which is one of the most advanced and comprehensive monitoring system. Methods The contents and methods of pharmacovigilance system for pharmaceutical enterprises in EU were introduced based on the framework of social regulation. Results and Conclusion The social regulations of pharmacovigilance system include the set up of qualification system, information disclosure system and certification system. Establishing a scientific and reasonable pharmacovigilance system is an important measure for the government to control the drug risks and it is also an effective way to ensure drug safety after listing.

manufacturing enterprise; pharmacovigilance system; social regulation

The World Health Organization defines the purpose of pharmacovigilance as scientific research that can discover, evaluate, understand and prevent the adverse effects of drugs[1]. The content of pharmacovigilance includes: (1) detection of unknown ADRs and their interactions; (2) discovering the trends of drug adverse reactions; (3) analyzing risk factors for adverse drug reactions; (4) assessment the risk and benefit, release information, promote the pharmaceutical supervisory and administrative and guide clinical medicine[2].

Social regulation[3]is the rule that government takes to control externality which may affect personal safety and health risks. In recent years, due to Roche enterprise’s cover-up drugs adverse reactions and other drug safety incidents, various countries used different measures to strengthen enterprise pharmacovigilance system. This paper analyzes the pharmacovigilance system implemented by European Medicines Agency (EMA) based on social regulation theory to provide references for the improvement of China’s drug risk management.

1 The introduction of social regulation theory

Social regulation is the law designed by government to control pollution generated from production process, developing health and safety standards in the workplace, limiting product information range that sellers provide to consumers by advertisement or other media, establishing rules to protect consumers from fraud and discrimination by sellers[4]. The range of social regulation is wide and it involves in production, consumption, safety, health, hygiene, environmental protection and information in the process of trading. Social regulation is a universal rule that can be applied to all industries and enterprises.

1.1 The theoretical basis of social regulation

1.1.1 Problems of externality

Externality refers to the phenomena that certain economic behaviors affect the society and result in personal cost conflicting with social costs. It includes positive externalities and negative externalities. Negative externality refers to a positive impact on economic behavior. Externality can make market inefficient and that is why government should make the social regulation.

1.1.2 Information asymmetry issue

Information asymmetry or incompletion can cause negative effects and moral hazard problems, which will seriously affect fair trade and result in low efficiency of themarket. Therefore, government should regulate asymmetric information of the industry.

1.1.3 Public goods

Public goods refer to the goods such as services or resources that are non-excludable and non-rivalrous in that the individuals can not be effectively excluded from using. These characteristics of public goods can lead to market configuration failure. Therefore, the supply of public goods has become an important function of government.

1.1.4 Non-value goods

The so-called non-value goods mean that they can not be allocated by the competitive market mechanisms due to the moral and ethical norms. A typical example is drugs and weapons. This “non-value goods” would bring harm to society and the government should control them[5].

1.2 The subject and object of social regulation

The subject of social regulation refers to the government, which develops and implements social regulation. The object of social regulation refers to the market. The market includes two parts; one is the organizations and individuals who achieve economic interests through participating in business activities, such as enterprise, corporate etc, and the other is the goods in the markets. For example, the manufacturers’ products and services are the object. In China, the subject of social regulation include the following departments, such as the General Administration of Quality Supervision, Inspection and Quarantine, the State Administration of Work Safety, the Ministry of Health, China Food and Drug Administration, the State Administration of Traditional Chinese Medicine and so on.

1.3 Contents of social regulation

The purpose of social regulation is to limit market failure caused by rectifying public goods, non-value goods, externalities and information asymmetry. Social regulation includes the following items: (1) To provide public goods by the government such as education (Education Act), health, science and technology, social welfare, fire protection, environmental protection and some quasi-public projects concerning health and hygiene (drug law, medical law, infectious disease control). (2) To prohibit the non-value goods and advocate the consumption of normal goods. (3) To rectify externality such as pollution, industrial disasters, labor disasters, disease, traffic accidents, etc. (4) To mitigate information asymmetry by releasing some laws such as Product Safety Act and Food Safety Law, etc[6].

1.4 Methods of social regulation

1.4.1 Certification system

Certification system refers to the confirmation of certain professional knowledge, experience, skills and other indicators provided by the government to a person who is able to complete some work such as health, safety and environmental protection, etc. The three forms are as follows: (1) Approving those who have qualification for a certain job and prohibiting the disqualified people from engaging in the job such as doctors, lawyers. (2) Setting the certification for certain practitioners such as manager and supervisor. (3) Notarizing people with certain professional knowledge and skills and awarding the certificate.

1.4.2 Inspection and identification system

Inspection and identification system refer to the examination of the products safety. Enterprises have the obligation to implement a variety of inspections, including regular check, check before and after use.

1.4.3 Information disclosure system

Information disclosure system means that the regulatory agencies have the right to request enterprises that may have information asymmetry to release data and information of their products and services in detail as possible to consumers or regulatory agencies should develop relevant regulations that consumers have the rights of claiming products and services information. For example, regulatory agencies request some food packaging should indicate the ingredients, storage methods, manufacturer, origin, expiration date and other relevant information.

1.4.4 Benchmarking and certification system

Benchmarking and certification system refer to security standard to ensure the safety of products, equipments, operations and management such as the structure, strength and materials. All the products that are not checked or marked without safety standard signs mustbe prohibited from sale and use[7].

2 Analysis of the EMA pharmacovigilance based on social regulation

From July 2012, EU began to implement new pharmacovigilance regulation. In order to promote the implementation of the new regulation, EU has established the pharmacovigilance practice guideline as the new pharmacovigilance principles and it is also the basic framework of EU pharmacovigilance system. The pharmacovigilance practice guideline covers 16 modules, such as the pharmacovigilance system, inspection system, risk management system, ADR monitoring system and security information communication, etc. The new version of pharmacovigilance practice guideline stipulated that drug regulatory agencies, enterprises and EMA members should be responsible for maintaining pharmacovigilance system. The pharmacovigilance of enterprises was reinforced with the help of certification and inspection system. EMA plays a central role in coordinating the work and makes the overall pharmacovigilance system run more procedurally and smoothly.

2.1 Head of pharmacovigilance licensing system

The person in charge of pharmacovigilance in an enterprise refers to a full-time staff in the pharmaceutical enterprise. According to the third paragraph of article 8 of European Union directive 2001/83/EC, when the pharmaceutical companies submit the licensing applications for new drugs, a detailed description of pharmacovigilance should be provided as well. The head of the pharmacovigilance in the enterprise must prove he has the certificate and will be approved by relevant department. In some European Union member states, there are clear regulations pointing out the members should set full-time personnel responsible for pharmacovigilance to ensure drug safety.

According to EU pharmacovigliance practice guideline, the head of pharmacovigliance in an enterprise should have management skills, or the relevant knowledge of medicine, pharmacy, epidemiology and biostatistics. Before being appointed by an enterprise, the pharmacovigilance leader’s qualifications should be assessed, for example, his education background and his knowledge of pharmacovigilance requirements. The enterprise should provide relevant and appropriate training for the appointed person and make a record of the training before the authorization[8].

2.2 Pharmacovigilance inspection system

Pharmacovigilance inspection system is the most important management taken by EMA for pharmaceutical enterprises. By establishing Pharmacovigilance inspection system, EU can monitor whether the pharmaceutical marketing license holder carries out the pharmacovigilance regulations. It can encourage the license holders to follow the rules and at the same time it is a deterrent to the fraud listed licensors.

At present, EU countries such as Germany, Britain, Switzerland and Sweden have carried out the pharmacovigilance inspection system. Inspection work should be done by inspectors appointed by the executive authority of the member state. The main purpose of pharmacovigilance inspection is to encourage the marketing authorization holders, systems and facilities to fulfill its pharmacovigilance related duties such as confirming, recording and dealing with illegal behaviors that threats public health. Then, the government can take action based on the results. The inspection includes checking plans, places, regulatory action and sanctions.

At the appropriate time, the relevant member states shall take necessary measures to ensure that marketing authorization holders are subjected to an effective punishment based on the inspection results. The European Commission 658/2007 regulations authorized the Commission to impose fines on marketing authorization holders if they can’t perform their duties in accordance with the Listing Regulation No.726/2004. As part of the overall transparency of pharmacovigilance system, the implementation and results of pharmacovigilance inspection as well as the process and evaluation of the results should be made public[9].

2.3 Information disclosure system

2.3.1 Enterprises information disclosure

For the listed drug safety supervision, drug regulatory authorities and pharmaceutical enterprise have the information asymmetry problem which affects the efficiency of the drug regulatory agency. Information disclosure regulation is applied by EMA. At present, in addition to ADR and PSUR, the enterprises should release drug safety information on enterprises’ official websites including the new drug risk and production suspension.

2.3.2 Person in charge of pharmacovigilance information disclosure

EMA required enterprises should submit drug information such as the data of ADE to the authorities in time. The drugs risk information must be accurate and complete to avoid duplicate submission process. The listed license holder should communicate with the regulatory authorities effectively about new risks or the changing risks, pharmacovigilance file, risk management system, risk minimization actions, updating periodic safety reports, corrective and preventive actions and safety studies after the authorization. Drug information should be updated by the listed license holders and they should communicate with health care professionals and patients on relevant information as well[10].

2.4 Benchmarking and certification system

Benchmarking and certification system is the principal means of social regulation. Parmaceutical enterprises under EU pharmacovigilance also use the certification system. European pharmaceutical enterprises have established a quality system which had gone through the audit and certification.

EU new pharmacovigilance regulation put forward a requirement that the drug manufacturers’ pharmacovigilance system should be audited. This requirement can make the audit process consistent and simple. EU auditing standards are in line with the “International Auditing Standards”issued by the relevant international organizations, which are used to audit pharmacovigilance risks. The audit includes all pharmacovigilance processes and tasks, quality system and cooperation with other departments. It also audits whether the pharmacovigilance activities will be carried out by the subsidiary body or delegated to another agency[11].

3 Enlightment

3.1 Promoting ADR monitoring and reporting system

For the listing drug safety supervision, inspection system is a kind of social regulation model. At present in China, according to Article VI from the “Adverse Drug Reaction Monitoring Management Approach”, China Food and Drug Administration is responsible for adverse drug reaction reporting and monitoring management. Its task is to check pharmaceutical enterprises have carried out the ADR reporting and monitoring system. In addition, China in 2008 began to use the new national ADR monitoring network and the hardware facilities of the system have been able to meet the needs of ADR reports. However, the reporting mechanism and form is not perfect which results in the false information. Therefore, it is necessary to conduct ADR monitoring work based on the analysis of regulation and the current situation.

EU pharrmacovigilance inspection system provides a reference for China. For example, the inspection types can be classified into the routine inspection and specific inspection based on China’s national conditions. Enterprises that make Chinese medicine injections or vaccines should be inspected regularly. The work of drug inspection in national and provincial department must be further refined with corresponding guidelines.

3.2 Promoting enterprises to establish ADR contacts system

At present, China has not established the ADR contacts system, but the provincial drug regulatory departments have started the related research about it and have introduced a relevant guidance. For example, in October 2013, Hainan province established the ADR contacts system and all the pharmaceutical enterprise ADR contactors in Hainan have been registered.

EMA regulated that the pharmacovigilance leader must be certificated. EU pharmacovigilance pratice guideline clearly specified the pharmacovigilance leader should have relevant qualification, and after being assessed by regulatory authority he could be appointed to the position. We should take advantage of the mechanisim of ADR contacts. National or provincial regulatory authorities should have a strict examination for the enterprises’ contacts and we should have the registration and filing system for them as well.

3.3 Strengthening the management of the marketing authorization holders (MAH)

According to the current Drug Administration Law, China takes a “bundling” management mode with the drug listing license and production license. It means the drug approval number is only issued to the enterprise with the pharmaceutical production license. Due to the marketing authorization holders’ sole responsibility for drug safety, it is particularly important to strengthen the supervision of marketing authorization holders. The contents of supervision of the MAH includes to set up a quality assurancedepartment and safety management department equipped with production sales managers, directors of manufacturing GMP and the pharmacovigilance leaders.

EU uses the access system with the separation of the drug listing authorization holders and production license holders. China should establish a system of MAH to take the place of the approval number access pattern. MAH system made it clear that the authorization holder is responsible for drug safety. A drug must have good quality and other civil liabilities.

3.4 Promoting drug safety information disclosure

At present, China’s ADR monitoring system in the pharmaceutical enterprises is at primary stage. It is limited to ADR report and there are a few researches about drug evaluation and risk management. Enterprises are reluctant to disclose too much drug information.

EU requires all pharmaceutical enterprises to disclose drug information to public and the irregularities will be punished. China’s drug regulatory departments shall establish incentive measures to promote the enterprises to report ADR more actively so that the agencies can make a further analysis. The above mentioned ADR contacts should reinforce the communication and cooperation with drug regulatory authorities to monitor the risks.

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[8] EMA. Guideline on Good Pharmacovigilance Practices [EB/OL]. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/02/WC500123206.pdf,2012-02-20.

[9] EMA. Comments Received from Public Consultation on Good Pharmacovigilance Practices [EB/OL]. http://www.ema.europa.eu/docs/en_GB/document_library/Other/2012/12/WC500136234.pdf,2012-12-13.

[10] EMA. Guideline on Good Pharmacovigilance Practices [EB/OL]. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/02/WC500123205.pdf,2012-02-20.

[11] EMA. Guideline on Good Pharmacovigilance Practices [EB/OL]. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500130395.pdf,2012-07-26.

Author’s information: WU Zhi-ang, Professor. Major research area: Drug risk management. Tel: 024-23986542, E-mail: zhiangwu@163. com