MAO Xiao-fang, YANG Yue(School of Business Administration, Shenyang Pharmaceutical University, Shenyang 110016, China)

Analysis of the Roles and Obligations of Pharmaceutical Industry in Pharmacovigilance

MAO Xiao-fang, YANG Yue
(School of Business Administration, Shenyang Pharmaceutical University, Shenyang 110016, China)

Objective To clarify the roles and obligations of pharmaceutical industry in pharmacovigilance and to provide references of supervision for the authorities which will contribute to enhancing effective interaction both in information communication and implementation of decisions between industries and the authorities. Methods Provisions related to obligations of pharmaceutical industry in the context of current laws and regulations were analyzed. Results and Conclusion Pharmaceutical industry should submit RMP and PSUR to ensure drug quality and truthfulness of promotional materials, monitor ADRs of products, conduct postmarketing study and risk communications as well as risk interventions.

industry; pharmacovigilance; obligation

1 Research background

Drug safety and pharmacovigilance is an important topic in global pharmacy. As a new subject with rapid development, its conception is accepted and applied by more countries and regions. In 2002, WHO explained“pharmacovigilance” comprehensively and systematically in an article titled “The Importance of Pharmacovigilance: Safety Monitoring of Medicinal Products”. Pharmacovigilance is the science and activities to detect, assess, understand and prevent adverse effect of drugs and other problems[1].

There are many risk factors such as drug ADRs, design and manufacturing defects, the circulation of inferior products on the market and irrational drug use. The reality that drug isn’t absolutely safe forces people to seek balance between the benefits and risks of drugs. It can ensure that the benefit outweighs the risk which is the ultimate goal for drug safety and pharmacovigilance.

Pharmacovigilance is based on laws, regulations and a series of guidance. It’s supervised by government and implemented by R&D department and production department, involving clinical personnel, epidemiologists, researchers, marketing staff and patients[2]. This article intends to clarify the roles and obligations of pharmaceutical industry in pharmacovigilance and help them change the passive attitude of accepting regulatory requirements into having pharmacovigilance monitor actively. For those benefit-risk ratio imbalanced products, industry should actively collect and make scientific utilization of pharmacovigilance information, conducting pharmacovigilance and risk management activities in order to ensure drug safety at source.

2 Analysis of the responsibility in drug safety and pharmacovigilance

Drug safety and pharmacovigilance is closely related to those people who are exposed to medical interventions[3]. In order to meet the challenge faced by pharmacovigilance, all parties should maintain cooperation and communication to understand their demands for a successful benefit-risk communication. Pharmacovigilance activities consist of many stakeholders including government, industry, health professionals and patients. The obligations of each party are summarized in the following tabular form. The details are shown in Table 1.

3 The roles and obligations of pharmaceutical industry in pharmacovigilance

Pharmacovigilance runs through the life cycle of product. The work of industry involves many aspectsincluding drug development, clinical trails, authorization application, manufacture, product positioning and sales, ADR monitoring as well as post-authorization study. Generally speaking, the roles and obligations fulfilled by industry can’t be replaced. Pharmacovigilance is helpful to risk characterization and reduce risks. By analyzing the measures taken by industries for the target of reducing risks and maximizing benefits, at the stage of pre-marketing and post-marketing, we conclude the roles and obligations of industry in pharmacovigilance as follows:

Table 1 Analysis of subject of liability in drug safety and pharmacovigilance

3.1 Submitting risk management plan (RMP)

At the stage of clinical trials, the “Guidance of Drug Safety and Risk Management for Human Trial” provides that safety and risk control from protocol design to implementation should be strengthened. It requires sponsors and clinical researcher along with experts from safety risk management committee review protocol carefully and establish drug risk management plan according to drug properties.

At the stage of applying for authorization, as the supporting document of “Regulations for the Registration and Management of Drug”, “Regulations on Prioritizing New Drug Registration” aims at encouraging new drug research and strengthening risk control management. Article 18 provides that applicants applying for special approval must have related risk control plans and schemes at the stage of application for clinical trails and manufacture. The regulations also requires industries have exit mechanism for prioritizing new drug registration and article 20 also gives some regulations in principle. Design of exit mechanism promotes risk control in every aspects and it is the crucial measure for risk control[4].

Besides, “Basic Technical Specifications for TCM and Natural Medicine Injection” can be used as a policy reference document, article 1 and 6 in clinical contents provide that the risk control plan written in accordance with post-authorization study should be submitted together with other materials.

By comparison, European Medicines Agency specifies the content and format of RMP in Good Pharmacovigilance Practices. RMP consists of seven modules including product overview, safety specification, pharmacovigilance plans, post-marketing efficacy studies, risk minimization measures and summary of risk management plan[5].

3.2 Ensuring drug quality[6]

Drug possesses commodity attribute, “Product Quality Law” explicitly stipulates the liability of product quality. Especially the third chapter on the obligation of manufacturer and sellers provides that manufacturers are responsible for their products quality and adulteration is forbidden. Drug is also a special commodity, from the very beginning article 1 of “Pharmaceutical Administration Law” explains the purpose which is to strengthen drug administration and to guarantee drug quality.

In terms of manufacturing and obligation for industries to ensure the drug quality, article 8, 9, 11, 12 and 51 respectively provide from several aspects such as conditions for pharmaceutical enterprises, GMP, API and excipients meeting the requirements of medicinal use, quality inspection before delivery, package materials and container, etc. “Drug Administration Law” and GMP specifications give guidance on implementation steps in a practical way. For the pharmaceutical excipients, relevant regulations on strengthening pharmaceutical excipients supervision and management issued in 2012 clearly stipulates pharmaceutical enterprises must bear main liability of quality problems due to illegal usage of excipients[7].

3.3 Guaranteeing the reliability of the promotional materials

Pharmaceutical enterprises publicize drug properties and popularize medical knowledge with drug instruction (or label) and advertisements. Article 3 of Regulations on drug instruction and labels points out that drug labelsshould be based on drug instruction, and its content shall not exceed the scope of the instruction. Printed words and signs promoting product can’t imply curative effect which may mislead the public. According to different readers, drug advertisements are divided into two types. One is OTC advertisements on mass media, the other one is prescription advertisements on medical journals. In terms of ads, article 3 and 4 of “Advertisement Law” and article 60 of “Pharmaceutical Administration Law” state that the content of drug ads must be truthful and legal, and shall not resort to any falsehood. Article 14 of “Advertisement Law” also specifies that drug and medical devices ads can’t contain any unscientific assertion or guarantee. In addition,“Drug Advertisements Review” can regulate pharmaceutical industries to advertise drugs by some compulsory measures like suspending drug sales or repealing advertising approval number.

3.4 Monitoring ADRs of products

ADR monitoring should be carried out at the stage of clinical trails. A complete scheme of clinical trials should consists of record of adverse events and reporting methods, handling practices, follow-up ways, time and prognosis for serious adverse events (SAEs). Article 41 of “Regulations for Registration and Management of Drugs” requires that researchers should report any SAEs in clinical trials to authority within 24 hours. Article 25, 26 and 39 of “Good Clinical Practice” specify that researcher must treat those subjects who suffer from ADRs and report the event to Institutional Review Board and authority. Article 47 requires that clinical research supervisor should record all AEs and report them within scheduled time.

Article 71 of “Pharmaceutical Administration Law”provides that the government applies a system of report to adverse drug reaction which indicates industry is the main ADR reporting subject. It requires manufacturer often investigate drug quality and efficacy and report related SAEs without delay. In addition, article 67 of “Regulations for Registration and Management of Drugs” stipulates manufacturing industry should investigate the new drug for its ADRs in monitoring period, reporting them to authority every year. “Regulations on ADR Reporting and Monitoring” give practical and technical guidance to industry on how to properly conduct ADR monitoring.

3.5 Submitting periodic safety update report (PSUR)

Article 36 of “Regulations on ADR Reporting and Monitoring” requires industry should periodically summarize and analyze ADRs and monitor materials of their products. They should gather safety information abroad and perform benefit-risk assessment for periodic safety update report (PSUR)[8]. Article 37 and 38 set boundaries according to new drug monitoring period, submission time, frequency and the delivered agency for domestic and imported drugs. However, the regulation doesn’t discuss further how to prepare for PSUR including format, submission means and core content. In 2012, CFDA issued PSUR preparation practice based on ICH E2C (R1) titled Post-authorization PSUR and it aimed at normalizing and instructing industry to prepare for PSUR so that it can improve industry’s assessing capacity.

3.6 Conducting post-marketing study

Article 33 of “Pharmaceutical Administration Law”and article 40 of “Rules of Drug Administration Law”specified that drug regulatory authorities should conduct reevaluation work in principle. “The Five-year Plan for Drug Safety” was also proposed to establish and perfect post-authorization drug reevaluation system. As the main body of post-marketing reevaluation, pharmaceutical enterprise should continue to fulfill its obligations to sponsor and organize the post-marketing study, and it should consistently trace and evaluate drug safety and efficacy. “The Twelfth Five-year Plan for Drug Safety”requires that industry should be the main body to carry out the industry-university-research cooperation. “Drug Reevaluation Regulation” draft issued in 2007 states drug reevaluation falls into three types: regular reevaluation, cause reevaluation and other reevaluation. Pharmaceutical industry is liable for the previous two reevalustions.

3.7 Carrying out risk communication and intervention

Risk communication and intervention are basic activities for risk management, and they’re always powerful means to make drug benefit outweigh its risk in pharmacovigilance. Risk communication is a process in which decision-makers and other stakeholders share risk as well as risk management information. The regulatory authority and manufacturing industry are liability bodies while pharmaceutical sales enterprises, health professionals and the public are subjects of communication[9].

In China, the intervention adopted by enterprises for risks consists of:

(1) Pre-marketing study and approval should be suspended: Article 42 of “Regulations for Registration and Management of Drug” stipulates some situations whenapplicants need to modify protocol suspend or terminate clinical trails. Article 43 specially emphasizes that CFDA will require applicants to modify protocol, suspend or terminate clinical trails once unexpected ADR or SAE occurs in clinical trails on a large scale or there is evidence that the drugs used in clinical trails have serious quality problems. Article 70 of “Drug Administration Law”regulates that clinical trails with false documents shall not be approved and a warning shall be given to the applicant. In serious cases, the drug applied for clinical trails shall not be accepted in 3 years.

(2) Revising drug instruction: Article 8, 12 and 13 of “Regulation on Drug PI and Label” stipulate that enterprises actively apply for revising PI in accordance with CFDA requirement which is judged on the basis of ADR information and reevaluation results. Enterprises should add warnings and notify the revised contents to sales companies, users and other parties.

(3) Suspending manufacture, sales and use, repealing approval documents: Article 41 of “Drug Administration Law” and article 45 of “Regulation on ADR Reporting and Monitoring” specify the situation.

(4) Drug recall: Article 5 of “Regulations on Drug Recall” provides that enterprises should establish and perfect recall system, collecting relevant safety information, conducting investigation and assessment of drugs with potential safety hazard. And these drugs should be recalled finally. After investigating and assessing potential safety hazard, enterprises should carry out classified recalls based on severity of potential safety hazard.

Except for the above measures, PSUR Preparation Practice also stipulates other interventions adopted by enterprises due to safety reasons, including suspending clinical trails, dosage modification, changing targeted patients and indications, altering dosage form or restricting administration routes.

4 Conclusion

Drug safety is the first duty for enterprises and they undertake much work such as R&D, marketing authorization and manufacture, ADR monitoring and drug reevaluation. There is no doubt that pharmaceutical enterprises hold much safety information concerning their products. When enterprises provide consumers with drugs and they must guarantees their safety and efficacy. So it’s vital to perform a list of pharmacovigilance activities on drug safety.

Pharmaceutical enterprises in China haven’t been familiar with the concept of pharmacovigilance. Due to poor innovation capacity and insufficient fund, most enterprises haven’t set up drug pharmacovigilance system[10]. ADR monitoring work is allocated to salesmen and quality control staffs[11]. On the whole, enterprises do not have the awareness of risk management and they passively conduct pharmacovigilance activities. Therefore, It’s of significance to clarify the roles and obligations of pharmaceutical industry in pharmacovigilance and to realize attitude transformation. It also provides a new idea of supervision for authority and helps enhance effective interaction in information communication and implementation of decisions between industry and authority.

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Author’s information: YANG Yue, Professor. Major research area: Pharmaceutical laws and drug policy. Tel: 13998236315, E-mail: yyue315@126.com