A Closer Look at Bioequivalence Trials in China and the Increased Need for Reliable CROs

2 / October 2017 © Informa UK Ltd 2017 (Unauthorized photocopying prohibited.)

October 2017 / 3© Informa UK Ltd 2017 (Unauthorized photocopying prohibited.)

China’s 13th five-year plan 2016–20 will move the country into the center of the international stage of drug development, where they will be global innovators in the industry and more competitive than ever with foreign firms.1 The country is focused on developing innovative drugs within China and are actively discussing ways to reduce clinical trial durations and address quality concerns. China is continuing to build upon their 12th five-year plan, which prioritized drug safety and the expansion of their pharmaceutical sector2. While technology and innovation are the focus of the 13th five-year plan, the country will still heavily rely on their strong generic drug market and set a standard to produce high quality drugs, as well as generics, for their 1.4 billion population and the rest of the world.

Generics in China are sold at a better price, but are not always as dependable and effective as the respective global innovator drug. In response to data fraud findings in 2015 and 2016, the China Food and Drug Administration (CFDA) has insisted that its approved generic drugs be retested. Citizens need to be reassured that these generics are just as good as the innovator drug and anyone using false data will be criminally punished. Generics companies are being required to conduct new bioequivalence (BE) tests, and therefore there is a significant rise in BE trial activities. The expected costs for these studies is expected to increase 10-fold.3

BE tests have largely been done by Contract Research Organizations (CROs). These organizations reportedly offered a “no win, no fee” service for drug applications, and have been a catalyst to a clinical trial system that fosters corruption.4 This entire business model must change, as quality and good clinical practice become critical and penalties for malpractice and forgery become more severe. Not only are the sponsors going to be blacklisted, but so will investigators and clinical research sites.5 China is a member of the International Council for Harmonization (ICH) and has taken a “zero tolerance” approach to clinical trial fraud, therefore there is more pressure than ever for pharmaceutical companies, investigators/trial institutions, and CROs to improve drug quality and reporting.

Examples of data fraud include findings from over a year ago when the CFDA discovered unreliable test results from BE trials conducted by Zhejiang University First Hospital (Zhejiang-08). Both Cefuroxime Axetil (GlaxoSmithKline) and amlodipine (Sumitomo Dainippon) trial results dating back to October 20116 were inspected by regulators and the agency found discrepancies where the study products were not equivalent to the originator drug.7

Cefuroxime Axetil is a cell wall synthase inhibitor that is used to treat bacterial skin infections, otitis media, respiratory infections, and urinary tract

Introduction

Christina DeRuzzaAssociate DirectorSitetrove and Chinatrove

1. Central Compilation & Translation Press (2016) The 13th five-year plan for economic and social development of the People’s Republic of China (2016–2020). Available from: http://en.ndrc.gov.cn/newsrelease/201612/P020161207645765233498.pdf. [Accessed September 15, 2017.]2. China Food and Drug Administration (January 20, 2012) Notice of the State Council on Issuing the “12th Five-year Plan” for National Drug Safety National Development. Available from: http://www.sfda.gov.cn/WS01/CL1749/69672.html. [Accessed September 15, 2017.]3. Wang B, Davidson A (2017) An overview of major reforms in China’s regulatory environment. Regulatory Rapporteur, Vol 14 (7/8), 5–9. Available from: https://www.ppdi.com/-/media/Files/PPDI-Files/news/PPD-In-The-News/2017-July-Regulatory-Rapporteur-Major-China-Reforms-Wang-Davidson.ashx [Accessed September 15, 2017].4. Woodhead M (2016) 80% of China’s clinical trial data are fraudulent, investigation finds. BMJ, 355:i5396. Available from: http://www.bmj.com/content/355/bmj.i5396 [Accessed September 15, 2017].5. FDAnews Drug Daily Bulletin (2016) China FDA Frames Sanctions for Data Falsification. Available from: http://www.fdanews.com/articles/178213-china-fda-frames-sanctions-for-data-falsification [Accessed September 15, 2017].6. China Food and Drug Administration (2016) Notice of the General Administration of the People’s Republic of China on the Approval of Six Drug Registration Applications of 7 Enterprises (No. 92 of 2016). Available from: http://www.cfdi.org.cn/resource/news/7492.html [Accessed September 15, 2017].

4 / October 2017 © Informa UK Ltd 2017 (Unauthorized photocopying prohibited.)

7. Yang B (2016) China Probe Reveals Widespread Drug Data Violations At Major Study Centers. Pink Sheet. Available from: https://pink.pharmamedtechbi.com/PS118643/China-Probe-Reveals-Widespread-Drug-Data-Violations-At-Major-Study-Centers [Accessed September 15, 2017].8. DeRuzza C (2017) Heads Up: New CFDA-Certified Hospitals Coming Soon to Chinatrove! Available from: https://pharmaintelligence.informa.com/resources/product-content/chinatrove-blog [Accessed July 15, 2017].9. China Food and Drug Administration (2017) Notice of the General Administration of the People’s Republic of China on the Consultation on the Opinions on Encouraging the Reform of Clinical Trial Management of Innovative Medical Devices. Available from: http://www.sfda.gov.cn/WS01/CL0778/172568.html [Accessed September 15, 2017].10. Yang B (2017) Clinical Data Forgers Face Harsh Punishment In China. Pink Sheet. Available from: https://pink.pharmamedtechbi.com/PS121341/Clinical-Data-Forgers-Face-Harsh-Punishment-In-China [Accessed September 15, 2017].

From Chinatrove, we can quickly confirm that the site inspected, Zhejiang University First Hospital (Zhejiang-08), is one of the 630 hospitals8 currently approved for clinical trial work by the CFDA. Zhejiang-08 will be able to continue running trials for infections for the next three years, and its cardiology certification expires at the end of this year (December 12, 2017). CFDA certifications are granted for a period of three years, after which hospitals must reapply for renewal. (This policy has been under review since May 2017 and the CFDA is moving towards expanding the number of clinical trial sites by replacing trial site pre-certification with registration9.) Zhejiang-08 has new bioavailability studies planned for both cefuroxime axetil (ChiCTR-IIR-17011314/TrialTroveID-302094) and amlodipine (ChiCTR-IIR-17010570/TrialTroveID-295843). While ongoing/planned trials in these CFDA certified hospitals may be one indicator for GCP

and comprehensive test results, we still cannot be certain.

Clinical data forgery continues to be prevalent in China – in June alone another 135 New Drug Applications were withdrawn. Since BE and other Phase I trial results are not required to be published, we need more transparency in these results, as well as increased inspections of institutions and CROs conducting the study10. CROs could be the catalyst for change and a key contributor to comprehensive testing and honest drug reporting in BE studies.

In this paper we will explore the BE trial landscape in China, where the BE studies are being run, which CROs are involved, and finally identify some additional data sources to aid in final site selection in China.

infections. The second drug requiring further testing, amlodipine is an L-type calcium channel antagonist that treats hypertension and coronary artery disease.

According to Trialtrove, there were four completed BE tests in China on generics for cefuroxime axetil, and there are now two planned trials: 1. CTR20170203 at The First Affiliated Hospital

of Nanchang University (Jiangxi-01), sponsored by United Laboratories; and 2. CTR20170670 at The Affiliated Hospital of Qingdao University (Shandong-13), sponsored by Brilliant Pharmaceutical Co. There is a lot of activity in BE trials for amlodipine, as shown in Figure 1. Additional trial sites for these BE tests on amlodipine include the most active BE study site, Jilin University - First Affiliated Hospital (Jilin-02).

Figure 1. Total bioequivalence trials for amlodipine

Source: Trialtrove®, September 2017

Completed

Planned

Closed

Open

Temporarily Closed0 1 2

Number of Clinical Trials

Tria

l Sta

tus

3 4 5 6 7 8 9 10

9

4

2

2

1

October 2017 / 5© Informa UK Ltd 2017 (Unauthorized photocopying prohibited.)

A closer look at BE studies in ChinaAccording to Trialtrove, there are 820 BE trials in China: 423 completed, 13 terminated, 249 ongoing, and 135 planned. BE trials are rarely terminated,

and the planned trial activity is largely driven by the generic companies.

Figure 2. Bioequivalence trial counts, overall and by sponsor type

Note: Trial counts by sponsor type represent each study for that sponsor type, including collaborative research.

Source: Trialtrove®, September 2017

11. China Food and Drug Administration (2013) Notice of the State Food and Drug Administration on Carrying out the Evaluation of Consistency in the Quality of Generic Drugs. Available from: http://www.sfda.gov.cn/WS01/CL1749/78516.html [Accessed September 15, 2017].12. China Food and Drug Administration (2015) Announcement of the State Food and Drug Administration on the Record Management of Bioequivalence Tests for Chemical Drugs (No. 257 of 2015). Available from: http://www.sfda.gov.cn/WS01/CL0087/136520.html [Accessed September 15, 2017].

Industry (Generic)

Industry (Non-generic)

Academic

ALL

0 100 200

Trial Count

300 400 500 600 700 800 900

Completed Terminated Ongoing Planned

BE clinical trial activity has greatly changed since 2010. As seen in Figure 3, BE trials started to pick up in 2013 and 2014, after the CFDA’s initiation of Generic Quality Consistency Evaluation in 201311. BE studies reached record highs in 2016 after the CFDA required retesting of generics and implemented a new registration system for BE studies12. Since then, sponsors have registered their trials at the “Chemical Drug BE trials registration information platform” (http://www.chinadrugtrials.org.cn). So far in 2017, overall BE trial activity is the same as

2016. However, while industry-generic companies continue to expand BE testing in 2017, non-generic and academic sponsored trials are down from the previous year. Please note that this information is limited to trials where trial start dates were published and it therefore does not include all BE trials in Trialtrove (59%: 487 of 820 trials). The largest sponsors in the past and today are generic companies, followed by industry (non-generic) and academic (Figure 3).

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Figure 3. Bioequivalence trial activity in China, overall and by sponsor type, 2010–17

When we look at the top sponsors overall, academic sponsors appear to lead at 98 studies, followed by Jiangsu Chia Tai Tianqing Pharma (41 studies) and other industry (29 studies), as shown in Figure 4. However, a large proportion of academic sponsored trials are completed, and there is small difference

between the level of active trials in academic and Jiangsu Chia Tai Tianqing sponsorship. Following the trends in sponsor type (Figure 2), we see that most of these sponsors are China-based industry companies specializing in generics.

Note: Trial counts by sponsor type represent each study for that sponsor type, including collaborative research.

Source: Trialtrove®, September 2017

140

120

100

80

60

40

20

0

Trial Start Date

2010 2011 2012 2013 2014 2015 2016 2017

Tria

l Cou

nt

Total# of New Trials

Academic

Industry (Non-generic)

Industry (Generic)

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When we zoom in on international company sponsors, Johnson & Johnson (J&J) leads the way (five studies) followed by Novartis and Pfizer with four studies each (Figure 5). However, only J&J and Merck & Co currently have active BE trials which include ongoing and planned research. J&J’s active trials include a planned trial for allergic rhinitis

drug, Xisimin (loratadine). It also has a planned BE trial for Risperdal (risperidone), which has been launched globally. Risperdal is a 5-HT2A and dopamine D2 antagonist, developed by Janssen for the treatment of schizophrenia and the behavioral and psychological symptoms of dementias, such as Alzheimer’s disease.

Figure 4. China’s top sponsors for bioequivalence trials

0 10 20 30 40 50 60 70 80 90 100

Trial Count

Source: Trialtrove®, September 2017

Yangtze River Pharmaceutical

Sichuan Kelun Pharmaceutical

Jiangsu Hengrui Medicine

Shenzhen Salubris Pharmaceutical

Qilu Pharmaceutical

Zhejiang Huahai Pharmaceutical

Jiangsu Hansoh Pharmaceutical

CSPC Pharmaceutical

Other Industry Sponsor

Jiangsu Chia Tai Tianqing Pharma

Academic

Active BE Trials Total BE Trials

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The most highly BE tested drugs are included in Table 1. Most BE trials test generics; however, three of the top six drugs are originator drugs (highlighted in bold). The top originator drug, agomelatine (S-20098; Novartis/Servier), is predominantly being tested in active BE studies; it is a once-daily oral melatonin 1/2 agonist and 5-HT2C antagonist, developed by Servier for the treatment of depression. The drug is launched in several

European countries, has Phase III status in the US, and is registered in China. Currently, there are three active trials for agomelatine in China, sponsored by Sinchua Xinsidun (two planned trials) and Nanjing Healthnice Medical Technology (one ongoing trial). Additional BE tests are being conducted on generics to agomelatine; these active BE trials are sponsored by ReYoung Pharma and Hefei Xinfeng.

Figure 5. Top international sponsors of bioequivalence trials in China

Note: Active trials include ongoing and planned BE trials.

Source: Trialtrove®, September 2017

Johnson & Johnson Pfizer Merck & Co.Novartis GlaxoSmithKline

Active BE TrialsTotal BE Trials

5

3 3 3

4 4

1

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Table 1: Top drugs tested for bioequivalence in China

Source: Trialtrove®, September 2017

Note: Active trials include ongoing and planned BE trials. When the company is included in a drug name, the primary drug is a generic. Otherwise the primary drug listed is the originator drug.

The disease areas with the greatest number of BE trials, and perhaps with the greatest incentive to create generics, include: hypertension (115 of 820), respiratory infections (95 of 820), and bacterial skin infection (71 of 820). Amlodipine is the primary hypertension drug requiring BE testing; this includes four hypertension BE trials and multiple BE trials on generic versions of the drug. As previously mentioned, the rise in BE trials for amlodipine has been due to data fraud findings in a trial conducted at Zhejiang-08.

In addition to approved China-manufactured

generic drugs, there are also a few imported drugs (approved abroad but not yet approved in China) that require BE tests to check for racial differences. For example, mizolastine (MKC-431; Sanofi-Synthelabo) is being evaluated by J&J in BE tests, comparing single-dose administration of domestic (made in China) mizolastine tablets and imported mizolastine tablets given at the same dose in healthy volunteers (NCT01928316 /TrialTroveID-192708). Mizolastine is a potent and selective H1 receptor antagonist, developed by Sanofi as an antiallergic and antiasthmatic agent to treat allergic rhinitis and urticaria.

Primary Drugs Total BE Trials Active BE Trialsagomelatine 4 3

amlodipine 4 0

glimepiride (tablet) 4 2

levetiracetam, Nanjing H&D Pharmaceutical Technology Co 4 0

sarpogrelate hydrochloride, Tianjin Chase Sun Pharmaceutical 4 4

tenofovir disoproxil fumarate, Zhejiang South Ocean 4 0

amlodipine besylate + atorvastatin calcium, Beijing Jialin 3 0

celecoxib, Jiangsu Chia Tai Qingjiang 3 2

clopidogrel bisulfate, Shenzhen Salubris Pharmaceuticals Co. 3 1

dexlansoprazole, Jiangsu Hansoh Pharmaceutical 3 3

duloxetine hydrochloride, Fujian Leephick Pharmaceutical Group 3 1

irbesartan, Zhejiang Kinglyuan Pharmaceutical 3 1

lamivudine, Lonzeal Pharmaceuticals 3 1

levetiracetam, Chongqing Shenghuaxi Pharmaceutical Co. 3 0

linezolid, Jiangsu Hansoh Pharmaceutical 3 2

montelukast sodium, Jiangsu Vanguard Pharmaceutical 3 0

paclitaxel 3 2

pramipexole hydrochloride, Simcere 3 0

tenofovir disoproxil fumarate, Anhui Anke Biotechnology 3 3

tenofovir disoproxil fumarate, YaoPharma 3 0

10 / October 2017 © Informa UK Ltd 2017 (Unauthorized photocopying prohibited.)

Where are BE studies being conducted and what CROs are involved?According to Citeline’s Sitetrove, Beijing has lead the BE study activity in China at 61 investigators, where 32 are currently working on ongoing or planned studies. Next to Beijing, we see the greatest number of BE study investigators in Shanghai, Sichuan, Hunan, and Guangdong (Figure

6). In recent years, ongoing and planned trials are concentrated in Beijing and Shanghai, while the remaining investigators are more evenly dispersed across the country (Figure 7). Only about half of the investigators with BE testing experience are currently involved in a BE study.

Figure 6: Investigators by province: all bioequivalence (BE) trials

Source: Sitetrove®, October 2017

Province Investigator # (All BE Studies)

Beijing 61Shanghai 39Sichuan 22Hunan 20

Guangdong 19Total 296

5

11

13

2

11

16

1911

20

22

8

3

49

83

1911

1

3

3 16

61

October 2017 / 11© Informa UK Ltd 2017 (Unauthorized photocopying prohibited.)

Figure 7: Investigators by province: ongoing and planned bioequivalence (BE) trials

Source: Sitetrove®, October 2017

Province Investigator # (Active BE Studies)

Beijing 32Shanghai 18Sichuan 10Jiangsu 9Tianjin 9Total 133

2

6

4

2

2

9

48

10

4

3

23

12

51

1

13

2

32

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Interestingly, when we look at the trial sites by province, the majority of sites conducting BE studies are in Beijing, Jiangsu, and Shanghai (Table 2). Jilin only has four trial sites conducting BE studies, but their average number of trials per site is the greatest. Jilin-02 has run the most BE trials at 59 total (34 ongoing or planned). Currently, there are no BE studies being conducted in the Guangxi province, but this is not concerning because there was only one trial site available here. Perhaps, this could be a new location for pharma or generic companies to target their next BE study.

Until recently, sponsors had to select a certified CFDA approved facility in order to run a trial in China, including BE research13. As competition increased for generics,14 the CFDA modified its policy in August 2017, allowing BE trial sites to expand to any qualified trial site regardless of its CFDA certification (site requirement changes are currently being

finalized for non-BE clinical trials)15. Today there are several hospitals currently conducting BE studies that are not CFDA certified.

The greatest variance is seen for Heilongjiang, in which BE activity decreased and trials are being conducted at hospitals that are not CFDA approved. One speculation is perhaps that there were some unfavorable inspection results, or that the CDFA approved hospital prefers not to be involved in BE studies at this time for another reason. For 10 provinces, the CFDA trial site requirement did not create many changes in trial site selection because the 630 certified hospitals were already those trial sites that historically performed these studies, and are 100% CFDA certified in the table below. The greatest change in the new certified hospitals actively conducting BE trials today were found in Tianjin, Liaoning, Shanxi, and Jilin (Table 2).

13. Yang B (2017) China Innovation Policy Reform Streamlines Trial Management. Pink Sheet. Available from: https://pink.pharmamedtechbi.com/PS121733/China-Innovation-Policy-Reform-Streamlines-Trial-Management [Accessed October 11, 2017].14. To earn a spot on the centralized drug procurement lists, a company must be one of the first three to complete a BE test for the generic in comparison to the originator drug.15. China Food and Drug Administration (2017) Administration of Quality Supervision, Inspection and Quarantine of the People’s Republic of China on the Relevant Issues concerning the Consistency Evaluation of the Quality and Efficacy of Generic Drugs (No. 100 of 2017). Available from: http://www.sfda.gov.cn/WS01/CL1757/176734.html [Accessed October 15, 2017].

October 2017 / 13© Informa UK Ltd 2017 (Unauthorized photocopying prohibited.)

Table 2: Comparison of trial sites by province: total and active (ongoing/planned) bioequivalence studies

Source: Sitetrove ® and Chinatrove®, September 2017

Total Studies Active Studies Delta

Province # of Sites

# of CFDA Cer-

tified Sites

% Cer-tified Sites

# BE Trials

Avg # of

trials/site

# of Sites

# of CFDA Cer-

tified Sites

% Cer-tified Sites

# BE Trials

Avg # of

trials/site

% Change in cer-tified hospi-

tals

Beijing 27 23 85% 151 6 22 19 86% 74 3 1%

Jiangsu 20 14 70% 106 5 15 10 67% 41 3 -3%

Shanghai 20 15 75% 99 5 12 10 83% 34 3 8%

Guangdong 16 15 94% 38 2 6 5 83% 13 2 -10%

Hunan 12 9 75% 75 6 10 7 70% 37 4 -5%

Liaoning 12 7 58% 67 6 6 5 83% 25 4 25%

Tianjin 10 6 60% 36 4 8 7 88% 19 2 28%

Zhejiang 8 6 75% 33 4 5 4 80% 12 2 5%

Shanxi 8 6 75% 31 4 4 4 100% 11 3 25%

Sichuan 7 5 71% 46 7 5 4 80% 18 4 9%

Shandong 7 6 86% 31 4 5 4 80% 14 3 -6%

Anhui 6 5 83% 14 2 4 4 100% 5 1 17%

Hubei 5 3 60% 34 7 3 2 67% 15 5 7%

Hainan 5 3 60% 23 5 2 1 50% 11 6 -10%

Jiangxi 5 3 60% 21 4 3 2 67% 13 4 7%

Heilongjiang 5 3 60% 7 1 1 0 0% 2 2 -60%

Jilin 4 3 75% 100 25 3 3 100% 56 19 25%

Chongqing 4 4 100% 9 2 1 1 100% 1 1 0%

Hebei 3 3 100% 7 2 2 2 100% 3 2 0%

Henan 3 3 100% 6 2 2 2 100% 4 2 0%

Gansu 2 2 100% 15 8 2 2 100% 9 5 0%

Yunnan 2 2 100% 8 4 2 2 100% 6 3 0%

Fujian 2 2 100% 4 2 1 1 100% 3 3 0%

Inner Mongolia 2 2 100% 4 2 2 2 100% 3 2 0%

Xinjiang 2 1 50% 2 1 2 1 50% 2 1 0%

Ningxia 1 1 100% 6 6 1 1 100% 1 1 0%

Guangxi 1 1 100% 1 1 0 0 0% 0 0 -100%

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16. China Food and Drug Administration (2015) State Administration of Food and Drug Administration Announcement on Clinical Trials of Drug Clinical Trials and Contract Research Organizations (No. 172 of 2015). Available from: http://www.sfda.gov.cn/WS01/CL0087/129060.html [Accessed September 15, 2017].17. Center for Food and Drug Inspection of CFDA (2015) Available from: http://www.cfdi.org.cn/resource/news/7713.html [Accessed September 15, 2017].18. Shanghai Clinical Research Center (2017) Phase I Clinical Research Unit. Available from: http://www.scrcnet.org/PCRU_en.asp [Accessed September 19, 2017].19. Chen S, et al. (2012) China’s new blacklist: the impact for drug and device lawbreakers. Scrip Regulatory Affairs. https://www.cov.com/~/media/files/corporate/publications/2012/09/chinas_blacklist_the_impact_for_drug_device_lawbreakers.pdf [Accessed August 28, 2017].20. China Food and Drug Administration (2012) Notice of the State Food and Drug Administration on Printing and Distributing the “Blacklist” Management Regulations (Trial) of Drug Safety. http://www.sda.gov.cn/WS01/CL0844/74236.html [Accessed August 28, 2017].21. Center for Food and Drug Inspection of CFDA (2017) Notices of discontinued drugs. Available from: http://www.cfdi.org.cn/cfdi/index?module=A001&nty=D16&m1=13 [Accessed September 29, 2017].22. Center for Food and Drug Inspection of CFDA (2017) Notice of the General Administration on the Unqualified Grades of 14 Batch Drugs. Available from: http://www.cfdi.org.cn/resource/news/8335.html [Accessed September 15, 2017].

CRO involvement in BE trialsIn 2015, the CFDA published a list of CROs16 that it was going to inspect. All but Shanghai Clinical Research Center and Beijing Stemexcel Technology are confirmed to be involved in BE trials for further inspection, which will be conducted by the Center for Food and Drug Inspection Unit (CFDI)17 (Table 3). The majority are domestic CROs, except for Parexel and InCROM. Other international CROs on the inspection list with fewer BE trials include Covance, PPD, and ICON.

The CROs’ websites indicate the focus and commitment towards reproducible comprehensive testing. For example, Shanghai Clinical Research Center posts that it “operates in accordance with ICH-good clinical practice (GCP) and Chinese GCP…and has Association of Clinical Research Professionals, [and] USA certified clinical investigators.”18 This CRO’s Phase I unit is located at the CFDA certified hospital, Xuhui Central Hospital

(Shanghai-14).

Currently, there is no confirmation of a single CRO, sponsor, or investigator/trial site blacklist19,20.However, there is some information of drug safety on each province’s food and drug administration webpage, and the CFDI has posted announcements of batches of substandard drugs21. The first notice of unqualified drugs was posted in January 2017 and included seven drugs22.

The CFDA also provided a list of institutions involved in BE tests and Phase I clinical trials to compare with the latest CFDA certifications for approval. A detailed review confirmed each site is currently a CFDA certified hospital (see Annex 1 of CFDA, No. 172 of 2015), so we can reasonably conclude that these sites passed inspection and should be considered for upcoming BE studies.

October 2017 / 15© Informa UK Ltd 2017 (Unauthorized photocopying prohibited.)

23. China Food and Drug Administration (2015) State Administration of Food and Drug Administration Announcement on Clinical Trials of Drug Clinical Trials and Contract Research Organizations (No. 172 of 2015). Available from: http://www.sfda.gov.cn/WS01/CL0087/129060.html [Accessed September 15, 2017].24. Yang B (2017) China FDA Lays Out eCTDs, Bioequivalence, Patent Linkage As Priorities. Pink Sheet. Available from: https://pink.pharmamedtechbi.com/PS120150/China-FDA-Lays-Out-eCTDs-Bioequivalence-Patent-Linkage-As-Priorities [Accessed August 15, 2017].25. China Food and Drug Administration (May 26, 2016) Notice of the General Administration of China on the Implementation of the “Opinions of the General Office of the State Council on Carrying out the Evaluation of Consistency of the Quality and Efficacy of Generic Drugs” (No. 106 of 2016). Available from: http://www.sfda.gov.cn/WS01/CL0087/154042.html [Accessed September 15, 2017].

ConclusionsTo ensure better generics and safety, the CFDA should continue to prioritize a product review technical system with adequate numbers of reviewers and trained site inspectors. This will increase manufacturing site and asset inspections, clarify inspectors’ responsibilities, set up drug master file mechanisms that include data of formulations, quality, and post-marketing safety, and enhance manufacturing process checks to comply with

national and global standards.24

China is well on its way to reaching their goal to retest 289 generic drugs by 201825 and in the process, pharma companies, investigators/sites, and CROs will have moved to meet global GCP standards. CROs will continue to play a critical role in BE testing and help China make better, more affordable drugs.

CRO # of Trials Guangzhou Boji Medical Biotechnological 70

Shenyang Eliving Pharmaceutical Technology 46

Anhui Wanbang Medical Technology 41

Shanghai CARES Biotechnology 28

Beijing Wanquan Sunshine Medical Technology 27

Hangzhou Tigermed Consulting 22

Hefei Heyuan Pharmaceutical Technology 19

Beijing Bionovo Medicine Development 16

Shanghai Clinical Research Organization for Medicines 14

Beijing Cosource Huifeng Pharmaceutical Technology 13

R&G PharmaStudies 12

Beijing Lewei Bio & Tech 11

Simoon Record Pharma Information Consulting 10

Beijing Stemexcel Technology 8

Beijing Tianheng Pharmaceutical Institute 7

Ji’nan Sancai Medical Technology 7

PAREXEL International 7

Shanghai Bestudy Medical Technology 7

China Shijiazhuang Pharmaceutical Group 7

Chongqing Pharmaceutical Research Institute 7

Table 3: Top 20 CROs included in 2015 CFDA inspection list23

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