In­jec­tions of Fear

With the pro­duc­ers of in­ef­fec­tive vac­cines un­der in­ves­ti­ga­tion, China’s lat­est med­i­cal scan­dal has grown pub­lic dis­trust in the do­mes­tic vac­cine mar­ket

NewsChina - - COVER STORY - By Li Mingzi, Yang Zhi­jie and Zhou Tian

In mid-july, Changchun Chang­sheng Bio-tech Co of North­east China's Jilin Prov­ince, a ma­jor vac­cine pro­ducer listed on the Shen­zhen Stock Ex­change, came un­der fire af­ter in­ves­ti­ga­tors found it had forged records for hu­man ra­bies vac­cines and supplied in­ef­fec­tive DPT (diph­the­ria, whoop­ing cough and tetanus) vac­cines to the do­mes­tic mar­ket – vac­cines used as part of the na­tion­wide manda­tory in­oc­u­la­tion of ba­bies and chil­dren.

A pub­lic out­cry fol­lowed the rev­e­la­tions, which went vi­ral on so­cial me­dia and once again placed the du­bi­ous safety of vac­cines through­out China in the spot­light. Both Chi­nese Pres­i­dent Xi Jin­ping and Premier Li Ke­qiang ex­pressed con­cern over the is­sue, urged reg­u­la­tors to in­ves­ti­gate and said the truth should be dis­closed in a timely man­ner and the per­pe­tra­tors pun­ished “se­verely.”

Shortly af­ter, the po­lice bureau in Changchun, Jilin, launched an in­ves­ti­ga­tion that re­sulted in nu­mer­ous ar­rests of top com­pany of­fi­cials. Then an­other ma­jor vac­cine pro­ducer, Wuhan In­sti­tute of Bi­o­log­i­cal Prod­ucts Co Ltd was also found to have pro­duced sub­stan­dard DPT vac­cines.

It was not a rou­tine inspection but a tip-off from an ex-chang­sheng em­ployee that re­vealed ir­reg­u­lar­i­ties in the com­pany's vac­cine pro­duc­tion, prompt­ing China's drug watch­dog, the State Drug Ad­min­is­tra­tion (SDA), to carry out a spot check on July 15th. The inspection found the com­pany had fab­ri­cated pro­duc­tion records for freeze-dried ra­bies vac­cines for hu­man use, the SDA said. Since the process used to make ra­bies vac­cines vi­o­lated man­u­fac­tur­ing stan­dards, the SDA re­voked Chang­sheng's Good Man­u­fac­tur­ing Prac­tice (GMP) li­cense to pro­duce the vac­cine.

The com­pany has since been un­der in­ves­ti­ga­tion by the China Se­cu­ri­ties Reg­u­la­tory Com­mis­sion for vi­o­lat­ing rules and for ir­reg­u­lar­i­ties in in­for­ma­tion dis­clo­sure. Un­der pres­sure, Chang­sheng re­called its ra­bies vac­cines and apol­o­gized to the pub­lic for the in­ci­dent, telling in­vestors that it might be delisted. Chang­sheng's stock price plum­meted by more than half its value since mid-july.

The is­sue es­ca­lated when a few days later, the pub­lic learned that the SDA'S sam­pling in­spec­tions in Oc­to­ber 2017 had also found a batch of DPT vac­cines pro­duced by Chang­sheng did not meet po­tency stan­dards, and pro­duc­tion was sus­pended. It was only on July 20 that the Jilin Food and Drug Ad­min­is­tra­tion fi­nally fined Chang­sheng 3.44 mil­lion yuan (US$ 0.5m) for its mis­con­duct. Ev­i­dence of the pro­duc­tion records, their where­abouts and whether these sub­stan­dard vac­cines had been re­called was still un­clear.

The SDA an­nounced on July 22 that 252,600 doses of

Chang­sheng's in­ef­fec­tive DPT vac­cines – which in­oc­u­late chil­dren against diph­the­ria, whoop­ing cough and tetanus – were all sold to China's east­ern prov­ince of Shan­dong. Ac­cord­ing to SDA ex­perts, the sub­stan­dard DPT vac­cine could make peo­ple more vul­ner­a­ble to the dis­eases, but it was un­likely to di­rectly threaten peo­ple's health.

Ac­cord­ing to the lat­est press re­lease from Shan­dong Pro­vin­cial Cen­ter for Disease Con­trol and Preven­tion, a to­tal of 215,184 chil­dren in eight cities in­side Shan­dong had been given the sub­stan­dard DPT vac­cines. The SDA said a plan to reinoc­u­late those af­fected chil­dren was worked out in Fe­bru­ary this year. How­ever, this was not pub­licly re­leased.

Chang­sheng chair­woman and ma­jor­ity share­holder Gao Jun­fang did not an­swer re­peated calls from Newschina on July 23. Around 11am a po­lice car was seen driv­ing into the com­pany. An em­ployee in the Chang­sheng sales depart­ment told Newschina a vac­cine re­call had been un­der­taken to meet the drug author­ity's in­ves­ti­ga­tion. “The au­thor­i­ties re­quired a re­call of all of Chang­sheng's vac­cine prod­ucts af­ter the re­cent event, not just the prob­lem­atic ones,” the source said.

“Once the GMP cer­tifi­cate was re­voked, the com­pany could no longer con­duct any pro­duc­tion or sales ac­tiv­i­ties,” said Zhao Nan, a health colum­nist with five years' ex­pe­ri­ence in the vac­cine in­dus­try. “The com­pany was or­dered to re­call all its prod­ucts for test­ing, and even if they were found to be up to stan­dard, they had to be de­stroyed.”

Pub­lic Anger

The vac­cine scan­dal fu­eled wide­spread pub­lic anger, par­tic­u­larly af­ter the pre­vi­ous DPT case was dis­closed. The nine-month gap be­tween the drug author­ity's in­ves­ti­ga­tion into the sale of a quar­ter of a mil­lion doses of vac­cine and the pub­lic be­ing told about it was a source of par­tic­u­lar ire. Fur­ther­more, Chang­sheng failed to men­tion it in its 2017 an­nual re­port.

Af­ter the dis­clo­sure, an­other in­ef­fec­tive batch of DPT vac­cines sur­faced – this one from Wuhan In­sti­tute of Bi­o­log­i­cal Prod­ucts Co Ltd in Hubei Prov­ince – which was dis­cov­ered in Novem­ber 2017. Ac­cord­ing to the SDA, spot checks in Novem­ber 2017 found that due to a tem­po­rary fail­ure of the pack­ag­ing equip­ment, 400,520 doses pro­duced by the com­pany failed to meet qual­ity stan­dards.

These re­cent dis­clo­sures were in­ter­preted by the pub­lic as more ex­am­ples of fab­ri­cated vac­cines, which have been a long-run­ning is­sue in China. There were calls on Weibo, China's twit­ter equiv­a­lent, to boy­cott do­mes­tic vac­cines.

In­dus­try in­sid­ers were con­cerned about whether the fi­nal in­ves­tiga-

tion would give the pub­lic, and in par­tic­u­lar the chil­dren who had taken sub­stan­dard vac­cines, a clear ex­pla­na­tion. “From a sci­en­tific per­spec­tive, it needs to be clar­i­fied whether the vac­cines were ef­fec­tive – and whether re-in­oc­u­la­tion was re­quired, and if so by how many doses,” said Tao Lina, an in­dus­try in­sider and vac­cine ex­pert.

Ac­cord­ing to the China Se­cu­ri­ties Jour­nal, a pa­per, the Chang­sheng spot check con­ducted by the State drug reg­u­la­tor in 2017 was the re­sult of a tip-off from a com­pany em­ployee who re­ported that there were prob­lems with sub­stan­dard con­tain­ers dur­ing the vac­cine cell fer­ment­ing process. Wang Yuedan from Pek­ing Univer­sity Health Sci­ence Cen­ter told Newschina: “Once the con­tainer stan­dard is changed, the con­di­tions for cul­tur­ing cells are changed, and the amount of anti­gen might not meet the stan­dard.” SDA staff did not re­spond to de­tailed ques­tions from Newschina, only say­ing, “the in­ves­ti­ga­tion is on-go­ing and yet to be an­nounced of­fi­cially.”

Mao Qun'an, the Na­tional Health Com­mis­sion's disease con­trol chief, said on July 17 that those who had not yet fin­ished tak­ing the whole course of Chang­sheng ra­bies vac­cines could choose a ra­bies vac­cine from an­other com­pany in­stead. But for those who have taken the whole course, no author­ity could give ad­vice on what to do.

“The great­est fear is that there will be pub­lic dis­trust of vac­cines in gen­eral,” Zhao added. It was im­por­tant that peo­ple did not blame vac­cines them­selves, which are ex­tremely im­por­tant to pre­vent­ing the spread of disease. “How­ever, the scan­dal and fer­ment­ing pub­lic fury to­wards it may re­sult in se­ri­ous dis­trust of the do­mes­tic im­mu­niza­tion pro­gram, and if peo­ple start to shun vac­ci­na­tions the con­se­quences could be dis­as­trous.”

In a state­ment on Au­gust 3, the World Health Or­ga­ni­za­tion's (WHO) China office ex­pressed con­cern over im­proper prac­tices by Chi­nese vac­cine man­u­fac­tur­ers and en­cour­aged Chi­nese cit­i­zens to “con­sider this event in the con­text of the im­por­tance of im­mu­niza­tion as a pub­lic health in­ter­ven­tion, and the achieve­ments over sev­eral decades of China's suc­cess­ful, life-sav­ing im­mu­niza­tion pro­gram.”

“There are many Chi­nese peo­ple alive to­day who would not be, if not for im­mu­niza­tion. While the events at Changchun Chang­sheng Life Sci­ences Ltd should never have hap­pened, the fact that the anom­alies [of the DPT vac­cine] were de­tected by the reg­u­la­tors – and re­sponded to quickly and ro­bustly once so – shows that the reg­u­la­tory author­ity's sys­tem of checks and bal­ances to pro­tect pop­u­la­tion health is work­ing,” added the WHO in the state­ment, which did not men­tion the fact that a whistle­blower had re­vealed the anom­alies with the ra­bies vac­cine.

Part of a Pat­tern

In­side China, pri­vate drug com­pa­nies have boomed and since the GMP cer­tifi­cates be­gan be­ing pro­moted by the State drug reg­u­la­tor, do­mes­tic drug com­pa­nies have started to go global. Be­fore 2005, im­ported vac­cines dom­i­nated the Chi­nese mar­ket. It was in 2006 that Liaon­ing Chengda Biotech­nol­ogy Co., Ltd be­came the first do­mes­tic pro­ducer for ra­bies vac­cines for hu­man use. The au­thor­i­ties adopted com­pul­sory tests and rec­ti­fi­ca­tion pro­cesses for each batch of vac­cine that en­tered the mar­ket.

De­spite the reg­u­la­tions, nu­mer­ous scan­dals over fake vac­cines have erupted since then. In late 2016, a case of fake ra­bies vac­cines in Hei­longjiang Prov­ince was un­cov­ered. In Fe­bru­ary 2009, 11 batches of freeze-dried ra­bies vac­cines for hu­man use pro­duced in 2008 by Liaon­ing Dalian Jin­gang Andi Biotech Co Ltd were found by the au­thor­i­ties to have il­le­gal ad­di­tives of nu­cleic acid, a ma­te­rial which could en­hance the vac­cine's po­tency if the ef­fec­tive con­tent of the vac­cine is lower than the stan­dards. Ac­cord­ing to Tao Lina, adding nu­cleic acid, a prac­tice not ap­proved in China, could lower pro­duc­tion costs by one-third. In De­cem­ber 2009, a to­tal of seven batches of more than

210,000 doses of ra­bies vac­cine for hu­man use by Jiangsu Yan­shen Biotech Co Ltd and He­bei Fuer Drug Co Ltd were found to not meet na­tional po­tency stan­dards. Later on, ac­cord­ing to Jiangsu Pro­vin­cial Food and Drug Ad­min­is­tra­tion and the lo­cal pub­lic se­cu­rity depart­ment, Jiangsu Yan­shen had bro­ken the law by us­ing in­fe­rior ma­te­ri­als, fab­ri­cat­ing records, and evad­ing su­per­vi­sion. Their sub­stan­dard vac­cine prod­ucts were sold to more than 21 of China's prov­inces.

These fab­ri­cated ra­bies vac­cines claimed lives, like the five-year-old boy who was bit­ten by a dog in a ru­ral vil­lage in Guangxi Zhuang Au­ton­o­mous Re­gion in De­cem­ber 2009. He died three weeks later, de­spite be­ing ad­min­is­tered a ra­bies vac­cine at a lo­cal health cen­ter. In­ves­ti­ga­tions re­vealed a to­tal of 13 town­ship level health cen­ters and 20 vil­lage level health cen­ters had pur­chased vac­cines through il­le­gal mar­ket chan­nels. More than 1,000 doses of in­ef­fec­tive ra­bies vac­cines were con­fis­cated. Eight peo­ple were ul­ti­mately sen­tenced to prison.

In March 2016, po­lice in Shan­dong Prov­ince dis­cov­ered 22 types of il­le­gal vac­cines – in­clud­ing those for in­fluenza, hep­ati­tis B and ra­bies – with a mar­ket value of more than 570 mil­lion yuan (US$83.44 mil­lion), which were sent un­re­frig­er­ated to more than 20 pro­vin­cial re­gions, in­clud­ing An­hui, Bei­jing and Fu­jian. Since then, the cir­cu­la­tion of vac­cines has gained the at­ten­tion of reg­u­la­tors who have im­posed stricter rules on lo­cal gov­ern­ment pro­cure­ment pro­ce­dures, and im­proved mon­i­tor­ing of what is called the “cold chain” for vac­cine trans­porta­tion.

Ex­perts in­ter­viewed by Newschina claimed there was lit­tle dif­fer­ence be­tween the qual­ity of do­mes­ti­cally pro­duced vac­cines and im­ports. Ac­cord­ing to the 2017 An­nual Re­view of Bi­o­log­i­cal Prod­uct Is­su­ing in China, re­leased by the Na­tional In­sti­tutes for Food and Drug Con­trol, seven batches of ra­bies vac­cines for hu­man use failed to meet do­mes­tic stan­dards, with one batch pro­duced by a do­mes­tic com­pany, and the rest im­ported from other coun­tries. The re­port found “this in­di­cates the is­su­ing pro­cesses could ef­fec­tively pro­hibit sub­stan­dard vac­cine prod­ucts to en­ter the do­mes­tic mar­ket.”

“Ad­dress­ing this re­cent vac­cine scan­dal is­sue, the au­thor­i­ties should dis­close the in­ves­ti­ga­tion re­sults in a timely man­ner and pun­ish any crimes,” sad Tao Lina, adding that the best way to re­build trust was trans­parency and real action from the gov­ern­ment.

Chang­sheng's trans­gres­sions could date back as early as 2014. In Au­gust, in­ves­ti­ga­tors told the Xin­hua News Agency the com­pany be­gan to vi­o­late rules on vac­cine pro­duc­tion and na­tional drug stan­dards as early as April of that year. In ad­di­tion to the ear­lier dis­clo­sure, in­ves­ti­ga­tors found an­other sub­stan­dard batch of 247,200 doses of DPT pro­duced by Chang­sheng. On Au­gust 7, the SDA is­sued na­tion­wide free re-in­oc­u­la­tion pro­ce­dures to lo­cal pro­vin­cial gov­ern­ments for those who had taken half the course of Chang­sheng's ra­bies vac­cines – say­ing they could sub­sti­tute the rest of the course with a dif­fer­ent brand. As of Au­gust 9, there was no fur­ther in­for­ma­tion on the in­ves­ti­ga­tion or han­dling of the Chang­sheng ex­ec­u­tive per­son­nel.

Then on Au­gust 16, a meet­ing of the Stand­ing Com­mit­tee of the Po­lit­i­cal Bureau of the Cen­tral Com­mit­tee of the Com­mu­nist Party of China presided over by Pres­i­dent Xi Jin­ping heard re­ports of the in­ves­ti­ga­tion and an­nounced pun­ish­ments for the of­fi­cials in­volved.

Vice gov­er­nor of Jilin Prov­ince, Jin Yuhui, who was re­spon­si­ble for the food and drug ad­min­is­tra­tion in the prov­ince, was re­moved from his post. In to­tal, around 40 gov­ern­ment of­fi­cials, in­clud­ing seven at and above the pro­vin­cial level, have been held ac­count­able. Three se­nior of­fi­cials were or­dered to re­sign, in­clud­ing Bi Jingquan, head of the former State Food and Drug Ad­min­is­tra­tion, former Jilin vice gov­er­nor Li Jinxiu, and Changchun Mayor Liu Chang­long.

The Na­tional Health Com­mis­sion also told the pub­lic it would ar­range fol­low-up vac­ci­na­tions for those who had re­ceived the sub­stan­dard shots.

A child gets a vac­ci­na­tion at a clinic in Xing­tai, He­bei Prov­ince, April 2014

Changchun Chang­sheng Bio-tech Co, Au­gust 2018

Su­per­vi­sion staff from the lo­cal Disease Preven­tion and Con­trol Depart­ment of Ron­gan County, Guangxi Zhuang Au­ton­o­mous Re­gion, re­view the stock list for vac­cines, July 23, 2018

Sealed boxes of vac­cines made by Chang­sheng Bio-tech in Tunxi District Disease Preven­tion and Con­trol Cen­ter, An­hui Prov­ince, July 23, 2018

A pri­mary school stu­dent shows his vac­cine cer­tifi­cate for measles in Jiaozuo, He­nan Prov­ince, Septem­ber 13, 2010

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