Abstract
On July 5, 2018, the National Medical Products Administration of China (NMPA) made an unannounced inspection on Changchun Changsheng Biotechnology Co., Ltd. (Changchun Changsheng). 1 It was found that Changchun Changsheng made false records for producing freeze-dried rabies vaccine (Vero cells) for human use, which was a serious violation of the Good Manufacturing Practice for Medical Products (GMP). Later, on July 15, NMPA issued an Announcement on Changchun Changsheng Producing Freeze-Dried Rabies Vaccine (Vero Cell) for Human Use While Breaking Laws and Regulations (No. 60, 2018). 2 NMPA ordered the Jilin 3 Food and Drug Administration (JLFDA) to draw back the GMP Certificate, No. JL20180024, from Changchun Changsheng in the announcement. It was also announced that the products under the unannounced inspection were still in the factory and under effective control. On July 22, the head of NMPA stated that JLFDA had conducted an investigation on the enterprise, and the suspects comprising a director and other senior managers were handed over to the police department for criminal investigation. It was also announced that the China Food and Drug Administration (CFDA) 4 had found valence problems in a batch of pertussis vaccine produced by the enterprise at a sampling inspection. Xi Jinping and Li Keqiang urged cracking down on any involved entity or body and that the State Council should send a special group to conduct the investigation. 5 The special investigation group held a conference in Jilin to deliver the instructions from Xi Jinping and Li Keqiang, and to hear the investigating reports made by the Jilin provincial government, JLFDA, Central Commission for Discipline Inspection (CCDI) and State Supervision Commission, 6 the Ministry of Public Security, National Health Commission, and China Securities Regulatory Commission. 7
After an almost three-month investigation, NMPA issued a Written Decision of Administrative Penalty against Changchun Changsheng on October 15, 2018. 8 Listed within were eight unlawful acts conducted by Changchun Changsheng, including making the products by blending two or more batches of original liquid, 9 falsifying the batch number and the production date of the 184 batches of products, 10 using original liquid exceeding the stipulated storage period for making freeze-dried rabies vaccine (Vero cells) for human use, failing to carrying out thermostability experiments for the 386 batches of product made in 2016 and 2017, 11 having not presented the change of main manufacturing equipment (centrifugal machine) to the provincial FDA for the record, destroying the original records of production from 2014 to July 2018 and falsifying production, valent test, and thermostability records, 12 submitting falsified information related to the involved products to the National Institute for Food and Drug Control in order to obtain the certificate of compliance, and destroying relevant evidence by changing and disposing of the video storage card(s) of internal surveillance camera(s) and some PC hard drives after the first unannounced inspection of NMPA. Based on these acts, NMPA invalidated the drug approval certificate for Changchun Changsheng to produce rabies vaccine (National Pharmaceutical Approval No. S20120016) and the approval certificate for biological products wholesale, and fined Changchun Chang RMB 12,030,000. JLFDA confiscated the illegal income of RMB 1.89 billion, fined Changchun Changsheng RMB 7.21 billion as three times the value of the illegal products, and ordered that the 14 persons responsible for the above-mentioned acts shall not conduct pharmaceutical production and business. 13
1. Frequent Occurrences of Bad Vaccines in China
Changchun Changsheng is not the first case in China that gave rise to public worries about the quality of vaccine products. In 2004, Suqian Medical Products Administration of Jiangsu Province (SMPAJP) investigated in secret and found that Suqian Maternal and Child Health Hospital purchased more than 6,000 doses of nine types of vaccine from a person without a Drug Dealing Certificate (DDC). The company that was operated by Zhang Peng has a drug storehouse with less than 20m2 and the vaccine was stored in two refrigerators, one of which was not even plugged in. It was estimated by SMPAJP that over 3,000 infants were inoculated with these vaccines. 14
On June 16, 2005, the Center for Disease Control and Prevention of Dazhuang Town, Si County, Anhui Province inoculated 2,500 elementary and middle school students with Hepatitis A vaccine. From June 17 to 26, there were 216 students suffering from such symptoms as dizziness, chess tightness, nausea, etc., and a six-year-old girl was dead. After investigation, it was found that the supplier of the vaccine did not own a DDC and that some village doctors had not been trained for inoculation.
On February 6, 2009, Dalian JGAD Bio-products Co. Ltd. was found to have illegally added nucleic acid into 11 batches of freeze-dried rabies vaccine (Vero cells) for human use, which broke the falsification-preventing rule in the Pharmaceutical Administration Law. 15 The virus antigen contained in the freeze-dried rabies vaccine with nucleic acid added is 51% less than that contained in vaccines without added nucleic acid. Until February 22, 2009, 326,400 doses of freeze-dried rabies vaccine were recalled, with 33,400 doses left unaccounted for.
At the end of December 2009, a five-year old child in Guo Tang village of Laibin City was bitten by a dog and inoculated with a dose of rabies vaccine at the village health center. Twenty-one days later, he died of rabies. It was found after investigation that the rabies vaccine was made from hot water and some medicine. It involved 13 village health centers and 20 individual clinics, and more than 1,000 does of rabies vaccine for human use, evaluated as RMB 330,000, were found.
On March 17, 2010, nearly 100 children were reported to have died or been disabled from vaccine injections. The parents of these children kept asking poignant questions, such as why did my child suffer from Japanese encephalitis after being inoculated with the vaccine? Did all this result from an illegal operation or because the vaccine was exposed to high temperatures? It is a pity that this remains an unresolved case, and that the journalist reporting this news, Wang Keqin, was even forced to quit the job. 16
On December 3, 2009, NMPA made an announcement that seven batches of rabies vaccine for human use, amounting to 215,800 doses, produced by Hebei Fu'er Bio-pharmaceutical Co., Ltd. and Jiangsu Yanshen Biotechnology Co., Ltd. from July to October 2008, were found to be unqualified. It was reported that Jiangsu Yanshen Biotechnology Co., Ltd. willfully added a substance during production which greatly lowered the vaccine's effectiveness. The aim of the addition was to reduce the production cost. 17
In 2012, the police of Weifang seized 42,494 doses of vaccine, evaluated as RMB 120 million, which included influenza vaccine, hepatitis vaccine, rabies vaccine, and varicella vaccine. The vaccines were stored in foam boxes with some ice and transported through logistics or express delivery. 18
On March 2016, the police department of Shandong province announced that it had uncovered a case of illicit vaccines worth RMB 0.57 billion in April 2015. Twenty-five types of second-category vaccines for children and adults were stored without strict cold-chain compliance and were transported and sold to 24 provinces and nearly 80 cities and counties, including Anhui, Beijing, Fujian, Gansu, Guangdong, Guangxi, Guizhou, Hebei, Henan, Heilongjiang, Hubei, Jilin, Jiangsu, Jiangxi, Chongqing, Zhejiang, Sichuan, Shanxi, Shanxi, Shandong, Hunan, Liaoning, Inner Mongolia, Xinjiang, etc.
Pang Hongwei and her daughter, without any approval from the drug administration department, purchased vaccines worth of RMB 0.26 billion online from over 100 salesmen of approved pharmaceutical companies and businessmen conducting illegal vaccine business, and sold them for RMB 0.31 billion, making an illicit income of RMB 50 million.
Until March 26, 2018, 91 judgements in relation to the 2016 Shandong illicit vaccine case could be searched on China Judgement Online; 137 persons were convicted of crimes such as illegal business operation, abuse of authority, destruction and forgery of evidence, corruption, and intentional disclosure of state secrets. 19
2. Why the Problem of Bad Vaccine Frequently Happens in China
These cases show that, no matter what lessons we have learned from bad vaccines, they never cease to be produced. China has set up strict regulations for producing vaccines. In accordance with the regulations set in the Provisions for Drug Registration, Specification for Vaccine Storage and Transportation, Measures for Drug Business and License, etc., vaccine manufacturers shall meet the standard of Good Manufacturing Practices (GMP), and apply to provincial FDAs for Drug Business Licenses if they pass inspection. Then the manufacturers shall obtain Good Supply Practices (GSP) authentication. The approved manufacturer may sell the second-category vaccine to the Center for Disease Prevention and Control (CDC), Inoculation Departments, or other vaccine wholesale enterprises, and shall transport the vaccine in accordance with related storage and transportation regulations to ensure the quality of the vaccine. However, the above-stated approval and license obtained by the manufacturer Changchun Changsheng did not prevent it from producing bad vaccines, which indicates that the creation of bad vaccines may occur at any stage of production and distribution. 20 Although strict approval, production, and distribution procedures have been regulated, the problem of bad vaccines seems out of control. It is known to all that a vaccine, like any medicine, could cause a serious reaction. But the risk of a vaccine causing serious harm or death is extremely small. 21 The most urgent problem for China is not the risk of a qualified vaccine, but how to make sure that the production and distribution of vaccines is under control. This results from several causes.
First, the classification of vaccine. As the vaccine was classified into first- and second-category, 22 the second category made CDC and its staff become the salesman for the manufacturers. Budgetary shortfalls and the policy of allowing CDC to raise funds by itself made paid service for vaccination become the focus of its work.
Second, rent seeking due to the lack of effective supervision. It can be seen from the above-mentioned cases that some government officials played an important role in offering an umbrella or facilitating the illicit manufacturing or distribution process. In accordance with Article 7 of the Regulation for Vaccine Circulation, Precaution, and Inoculation, and Article 4 of the Specification for Vaccine Storage and Transportation, NMPA is responsible for supervising and regulating the quality and circulation of vaccine in the whole country, and provincial, autonomous regional, and municipal FDAs are responsible for it in their administrative regions, which means that supervision and administration is completely within the grasp of FDA. The regulations did not point out how to supervise the behavior of FDA. So, if the charging person is involved with manufacturing or distributing bad vaccine, there is no effective measure to prevent it except for criminal charges.
Third, fear of accountability causes officials to be reluctant to uncover a “bad thing.” Since there is no clear legal accountability set for the administration in charge, political accountability would sometimes be mixed with legal accountability. Where there is some “bad thing” that occurs, many officials in charge would be held responsible even if they have done their job. After Changchun Changsheng, the Party group meeting of State Administration for Market Regulation (SAMR) 23 decided on August 17, 2018, two months before the administrative punishment decision for Changchun Changsheng, to dismiss some officials from the positions of NMPA, including Ding Jianghua, previous head of the Department of Drug and Cosmetics Supervision and director of Food and Drug Inspection Center; Dong Runsheng and Sun Jinglin, previous deputy heads of the Department of Drug and Cosmetics Supervision; Ye Guoqing, previous head of the Special Drug Regulatory Administration, a division in the Department of Drug and Cosmetics Supervision; Guo Xiuxia, previous consultant at the Special Drug Regulatory Administration; and Wang Youchun, deputy dean of the National Institute for Food and Drug Control. The charge was obscure, which went as inappropriate regulatory administration, ineffective direction, a lack of strict checks, and neglect of official duties. Where so many officials are held politically responsible for a bad vaccine case without definite charge, it provides a disincentive for officials to find the real problem and accept their legal responsibility.
Finally, the punishment for those violating drug administration regulations is not strict enough to generate deterrent force. Article 47 of Regulation on the Administration of Circulation and Inoculation of Vaccines 2005 provides that “as for the problem that the injury is caused by unqualified vaccine, it shall be solved in accordance with Pharmaceutical Administration Law.” But Article 75 of Pharmaceutical Administration Law (2015 amendment) stipulates that as for an enterprise or other entity engaged in producing or selling falsified medicine or manufacturing or selling inferior drug with serious circumstance, the executive or other staff in direct charge shall be forbidden to carry out drug manufacture or business. Even if a crime is convicted, as Article 141 and 142 of Criminal Law stipulate, the punishment is 3 to 10 years' imprisonment for serious harm caused to human body or health. The attraction of high profit brought by illegal vaccine production and sales may seduce some people to challenge the low cost of violations.
3. How Shall China Solve the Problem?
On November 11, 2018, SAMR issued for public comment a comprehensive draft Vaccine Administration law. 24 The draft aims at solving some issues stated above, but is not enough to build an organic system to solve the problem of bad vaccines. Some regulations try to take various measures to strengthen the regulation of vaccine manufacture, storage, and circulation. Staff qualifications are required in Article 21: the staff in key positions of a vaccine manufacture enterprise shall be checked for their qualification, the legal representative and the major executive shall have good credit records, and the executives for production management and quality management and the staff at other key positions shall have relevant professional backgrounds.
Furthermore, the draft also reinforces the administration of vaccine circulation and inoculation. Article 39 states that the price of non-state-planned vaccine may be reasonably set by the licensee of vaccine marketing, who shall distribute the vaccine to provincial CDCs while the latter distribute the same to the inoculation center(s). Article 40 stipulates that the process of vaccine storage and transportation shall conform to the stated regulations and shall be managed under stipulated temperatures in order to ensure vaccine quality.
Furthermore, severe punishment is provided for in the forms of civil, criminal, and administrative penalties for the licensee of vaccine marketing and its related entities, including the manufacturer, salesman, and even the supervising department. It is specified in Article 84 that the person inoculated may claim punitive compensation against the salesman if he knows that the vaccine is unqualified; in Article 86, that criminal liability against violators is available; and Article 86 also states that those breaking vaccine administration regulations shall be punished in the more severe way regulated in the Drug Administration Law.
In addition, the supervising department and local government are assigned corresponding responsibilities. Article 96 provides that the supervising department shall be responsible for failing to perform, or being negligent in the performance of, its duties and any resulting serious consequences. If the department participates, covers up, or connives with the criminals, employs trickery, hides facts, intervenes or impedes investigation, or helps to forge, hide, or destroy evidence, the department's officials may be held liable for these acts. Article 97 provides that the leader of the local government shall be held accountable in accordance with pertinent laws, regulations, and Party disciplines for unsatisfactory leadership, abuse of power, being negligent or perfunctory in discharging responsibilities, and/or for causing serious damage to the lives and property of the country and people.
The draft has learned some lessons from previous cases involving bad vaccines and addresses such issues as manufacture, storage, and distribution of vaccines, and the collusion of supervising department, local government, and the manufacturer and salesman. However, it is not intended to solve the root of the problem of bad vaccines.
Vaccines are ultimately like other products, the quality of which is best cultivated in a free and mature market. The market can play the most important role in ensuring safety and quality. Since people pay for second-category vaccines, they should have the right to select from which CDC to get the inoculation, as the CDC is a commercial institution for such vaccine. If the government requires very high market-entry qualifications, the enterprise would incur more transaction costs to obtain the vaccine license, which in turn reduces the money available to be spent on quality control. It would be better to attract more high-quality enterprises from abroad to help form and cultivate a fully competitive market, where competition for customers will drive improvements in quality and safety.
The other issue to be addressed is to clarify the responsibility of the officials. If officials have done their jobs, it is unfair to ask them to take responsibility for bad vaccines. Legal responsibility or culpability should not be mixed with political responsibility. If the officials do not need to worry about unexpected political risks, they can focus on performing their duties in line with the law. Severe punishment is, of course, a good means to disincentivize them from conducting or turning a blind eye to illicit behavior, but is not enough to keep them clearly focused on ensuring quality regulation and administration. There must be clear direction for officials and a structure and rules that support them in overseeing vaccines and vaccination. In a word, China should think in a systematic way in order to solve the problem of bad vaccines, not just take band-aid or stopgap measures.