Purchase of Carbapenems in Vietnam, a Low

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Address for correspondence: Dr. Vu Quoc Dat, Department of Infectious Diseases, Hanoi Medical University, No. 1 Ton That Tung Street, Dong Da District, Hanoi, Vietnam. Department of Tropical Diseases and Harm Reduction, Hanoi Medical University Hospital, No. 1 Ton That Tung Street, Dong Da District, Hanoi, Vietnam. E-mail: [email protected], [email protected]

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DOI: 10.4103/WHO-SEAJPH.WHO-SEAJPH_76_21

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AbstractIntroduction: Carbapenems are the last-resort antibiotics used for the treatment of multidrug-resistant bacterial infections. We reported the expenditure and prices of carbapenems in public healthcare institutions in Vietnam. Materials and Methods: Data on carbapenem procurement were obtained from tender-winning bids from provincial health authorities and public hospitals from 2013 to 2018. We use the anatomical therapeutic chemical index 2019 and the defined daily doses (DDDs) to describe the purchase (in number of DDD) and the price of carbapenem (presented in US dollar per DDD). Results: There are four available carbapenems in Vietnam between 2013 and 2018. Imipenem/cilastatin was the most common purchased antibiotic, accounting for 50.7% of total carbapenem consumption. The vast majority of carbapenem purchase (in DDD) was imported (79.1%). By 2018, among available carbapenems, the average price of doripenem was the highest (US $85.25/DDD), followed by meropenem (US $39.4/DDD), imipenem/cilastatin (US $36.5/DDD), and ertapenem (US $24.5 per DDD). The average carbapenem price decreased by 6.3% annually. The price of doripenem (P = −0.8518, r = 0.0313) and meropenem (P = 0.8875, r = 0.0183) had a significant correlation with the number of manufacturers in the market. The price variability and the number of manufacturers of doripenem (P = 0.8173, r = 0.047) and meropenem (P = −0.8116, r = 0.499) also had a strong positive correlation. Conclusion: The price of carbapenems in the Vietnam pharmaceutical market was high. Monitoring the price and consumption of last-resort antibiotic are needed to ensure availability of antibiotics in the setting with high burden of antibiotic drug resistance.

Keywords: Antibiotic, antimicrobial, carbapenem, drug price, Vietnam

Purchase of Carbapenems in Vietnam, a Low- to Middle-Income Pharmaceutical Market with a High Burden of Antimicrobial Drug Resistance

Original Research

Ninh Thi Nhu Quynh1, Vu Quoc Dat1,2

1Department of Infectious Diseases, Hanoi Medical University and 2Tropical Diseases and Harm Reduction, Hanoi Medical University Hospital, Hanoi, Vietnam

How to cite this article: Quynh NT, Dat VQ. Purchase of carbapenems in Vietnam, a low- to middle-income pharmaceutical market with a high burden of antimicrobial drug resistance. WHO South-East Asia J Public Health 2021;10:12-7.

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IntroductionIn 2019, the WHO declared that antimicrobial resistance (AMR) is one of the top 10 global public health threats facing humanity.[1] Carbapenems are considered as “last-line agents” or “antibiotics of the last resort” for the treatment of patients with severe infections of suspected multidrug-resistant (MDR) bacteria.[2] The consumption of carbapenem has been increased due to the emergence of MDR organisms. In a review of trends of antibiotics consumption in 71 countries from 2000 to 2010, the usage of carbapenem had risen 45% over 10 years.[3]

Vietnam is one among the countries with a fast-growing threat of AMR, which is related to the irrational use of antibiotics at all levels of the healthcare system, in aquaculture and livestock production, and in the community.[4,5] In a study of 16

hospitals with approximately 25,000 clinical isolates in Vietnam between 2012 and 2013, the proportion of the third-generation cephalosporin-resistant Escherichia coli was 56%.[6] The point prevalence survey in 2233 patients in 12 hospitals between 2017 and 2018 showed that 52% of inpatients were colonized with carbapenem-resistant Enterobacteriaceae.[7] The report of antibiotic purchase in 30 hospitals and 52 provincial departments of health in Vietnam in 2018 showed that the expenditure on carbapenems contributed significantly to the antibiotic treatment budget (10.2%).[8] Because carbapenem is essential for the treatment of infections due to MDR pathogens, when the drug resistance rate increases, the high cost of last resource antibiotics can threaten the national healthcare budgets.[9] In countries without universal healthcare, the high cost of prescription poses an additional threat of

Submitted: 12-Apr-2021 Revised: 30-Jul-2021 Accepted: 11-Aug-2021 Published: 15-Jan-2022

[Downloaded free from http://www.who-seajph.org on Tuesday, January 18, 2022, IP: 49.206.122.78]

Quynh and Dat: Prices of carbapenems in Vietnam

WHO South-East Asia J Public Health | Volume 10 | Issue 1 | January-June 2021 13

unaffordable out-of-pocket costs for individual patients.[10] The WHO recommended monitoring antibiotic prices to understand the access to antibiotic in the country, inform policymaker in improving accessibility and affordability of antibiotics, and also monitor the impact of antibiotic stewardship.[11] However, the standard routine monitoring of medicine prices is not reported regularly in Vietnam. This study aimed to describe the purchases and prices of carbapenem in healthcare institutions in Vietnam over the last 6 years.

Materials and MethodsEthics

This study was not implemented on human beings or animals. We did not offend any ethical standard of human experience as well as animal studies.

Study design

By the end of 2019, Vietnam had 1150 public hospitals which were structured into central, provincial, district, and district levels throughout 63 provinces. The process of bidding for contracts to supply medications to public health facilities follows the Vietnam Ministry of Health guidance.[12] Annually, health facilities basing on their use of medication over the previous 12 months and the anticipated demand for drugs in the current year develop the plan and call for drug bidding.

Data on the price and characteristics of procured carbapenem antimicrobials in Vietnam were taken from the successful tenders from 2013 to 2018 for provincial departments of health and hospitals in Vietnam as published on the website of the Drug Administration of Vietnam. We searched the official homepage of the Drug Administration of Vietnam for databases of successful bids from 2013 to 2018. The data for each tender included the name of the active ingredient, trademarks, formula, manufacturer, country of origin of the manufacturer, measuring unit, bid quantity, unit price, total value, bidders, time of binding, suppliers and brand name/generic name, and healthcare facilities/hospital names. We included in this analysis all available carbapenem antibiotics (J01DH carbapenems) as defined by the classification of anatomical therapeutic chemical (ACT)/defined daily dose (DDD) index.[13] These antibiotics procured were mostly for dispensing for inpatients in the hospital sector.

Price calculation

All the analyses used the standard unit of each active substance. We applied DDD as the standard unit based on the ATC index with DDDs 2021.[13] The DDD is recommended by the WHO as a measurement unit of drug consumption.[13] It is defined as the assumed average maintenance dose of a drug per day administrated to a 70 kg adult for its main label indication. DDD was proved to be an estimate and comparison of drug consumption between

population groups and is widely used in pharmacoeconomic studies. The DDD for a given drug was a unique code and specified for each active ingredient. DDD may change depending on the routes of administration of the same drug when there is a substantial difference in bioavailability.

In this analysis, the “price” of each antibiotic was a monetary value of a winning product in each successful bid and calculated based on DDD unit. We calculated the total number of DDD by dividing the total volume per transaction by DDD value of each carbapenem. All prices of carbapenems were adjusted for inflation[14] using CPI to 2019 price and converted to US$ with the exchange rate of 2019 (US$1 = 23,050 VND).[15] The ratio of the highest to the lowest price of antibiotics per DDD (high/low [H/L] ratio) was calculated to report the variation of antibiotics price.[16]

Statistics

Data analysis of this descriptive study was performed by using Microsoft Excel (Office 365, version 1909, Microsoft Corporation, Redmond, Washington, USA) and Stata Statistical Software: Release 15 (College Station, TX: Stata Corp LLC). We used the Pearson’s correlation coefficient to assess the association between the variation of antibiotics prices, the number of manufacturers, and the H/L ratio per year.

ResultsOur analysis included 1628 successful biddings related to carbapenems over 6 years (2013–2018) from a total of 215 healthcare institutions. We identified only four available carbapenems out of 9 carbapenems as included in the ACT during the study period, namely meropenem (J01DH02), doripenem (J01DH04), imipenem/cilastatin (J01DH51), and ertapenem (J01DH03).

The annual average budget and the number of DDD for all carbapenem in our study institutions were 12.06 million US dollars and 888324 DDD, respectively [Table 1]. In all institutions for a period of 6 years, imipenem/cilastatin and meropenem accounted for the largest proportion of carbapenem’s budget (34.6%, US$23,290,427/US$72,361,337.7 and 41.5%, US$30,446,222.7/US$72,361,337.7, respectively) with the corresponding numbers of DDD of 50.7% (2,704,557/5,329,946.4) and 35.6% (1,901,867/5,329,946.4), respectively. The detailed proportion of budget and the quantity of each carbapenem (in DDD) are shown in Figure 1.

Regarding the purchased amount of carbapenem in DDD, imipenem/cilastatin was the most commonly used (50.7%, 2704556.8/5,329,946.4), followed by meropenem (35.6%, 1,901,866.5/5,329,946.4), ertapenem (12.2% 648,120/5,329,946.4), and doripenem (1.5%, 75,403.3/5,329,946.4). The overall trend on the shares of carbapenem consumption was



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stable over the study period [Figure 1]. By 2018, among carbapenems, the average price per DDD of doripenem was the highest (US $85.25/DDD), followed by meropenem, (US$39.4/DDD), imipenem/cilastatin (US$36.5/DDD) and ertapenem (US$24.5/DDD) [Table 2]. There was large variability in price per DDD range for imipenem/cilastatin (H/L ratio ranged from 2.74 to 10.85) and meropenem (H/L ratio ranged from 4.53 to 12.93) over years.

79.1% of carbapenems DDD (4,211,663/5,329,947) were procured from international manufacturers (67 companies), and only 21% of DDD (1,118,283.7/5,329,946.6 DDD) were supplied by domestic producers (13 companies). Carbapenems supplied by international manufacturers accounted for 89.5% of the total budget (US$ 72,361,337.7) and 79.1% of the total DDDs procured.

The changes in the price of carbapenems from these manufacturers are displayed in Figure 2. In general, there was a sustainable decrease of carbapenem price by approximately 6.3% per year (decreased by 8.3% for meropenem, 5.0% for imipenem/cilastatin, 1.9% for ertapenem, and 4.1% for doripenem, annually). Carbapenem price and the number of purchasers have a strong negative correlation, especially doripenem, ertapenem, and imipenem/cilastatin [Figure 3]. There were negative correlations between the numbers of purchasers and the prices of doripenem (r = −0.817, n = 6, P = 0.047), ertapenem (r = −0.725, n = 6, P = 0.104), imipenem/cilastatin (r = −0.871, n = 6 P = 0.024), and

meropenem (r = −0.179, n = 6, P = 0.734). Pearson’s correlation between price and number of manufacturer of doripenem (r = −0.8518, n = 6, P = 0.0313) was reversible with meropenem (r = 0.8875, n = 6, P = 0.0183). In the meanwhile, the correlation between price variability (H/L ratio) and the number of manufacturer of doripenem (r = 0.8173, n = 6, P = 0.047) and meropenem (r = −0.8116, n = 6, P = 0.0499) were reversible.

DiscussionThis was the first study to describe the change in carbapenem drug price between 2013 and 2018 in Vietnam, a country with a high level of consumption of antibiotics. The carbapenem prices reduced by 6.3% per year, and it was associated with an increased number of bidders.

Our study showed that carbapenems were expensive compared to the GDP of Vietnam. The average daily cost of carbapenem treatment in Vietnam was US$50.6 (range from US$20.61 for ertapenem to US$120.8 for doripenem) which was more than 7 times the daily income of Vietnamese people (the US $7.4/day), while the average daily cost of carbapenem treatment in the US was just double the daily incomes (US$134–245 vs. daily income of US$172).[17] In 2015, the price of imipenem/cilastatin provided by global drug facility for Peru, South Africa, and the Dominican Republic was US$11.4, US$15.6, and US$19.7 per DDD, respectively.[16] The high price of carbapenems posed an economic burden

Table 1: Characteristic of sampled sitesCharacteristics 2013 2014 2015 2016 2017 2018Proportion of healthcare institutions with carbapenem purchase*

60.4% (29/48)

71.0% (27/38)

50.9% (27/53)

80.6% (50/62)

50.9% (83/163)

57.3% (71/124)

Total DDD number of purchased carbapenem (DDD)

335,662.9 450,626.6 982,698.1 795,559.5 1,166,842 1,598,557.4

Total budget for carbapenem in sampled health institutions (US $)

$5,264,389 $6,971,621 $16,969,372 $9,851,523 $15,985,694 $17,318,739

*Number of hospital or health institutes purchasing carbapenem/total sampled healthcare institution. DDD: Defined daily dose

Figure 1: Proportion of total defined daily doses and expenditure of carbapenem from 2013 to 2018




Table 2: Price of available carbapenems in vietnamActive ingredient 2013 2014 2015 2016 2017 2018Doripenem

Number of samples 2 1 5 12 16 18Number of bidders 2 1 4 10 14 11Number of manufacturer 1 1 2 3 5 4Average price per DDD (minimum-maximum) (US$)

$112.80 (112.80-112.80)

$100.70 (100.70-100.70)

$96.56 (91.28-97.88)

$93.43 (73.14-114.15)

$88.94 (78.96-110.27)

$85.25 (67.56-106.50)

H/L ratio 1.00 1.00 1.07 1.56 1.40 1.58Ertapenem


$27.66 (25.81-28.40)

$25.28 (20.74-27.28)

$26.13 (20.61-27.11)

$26.41 (26.41-26.41)

$25.40 (21.93-25.51)

$24.54 (21.18-24.64)

H/L ratio 1.10 1.32 1.32 1.00 1.16 1.16Imipenem/cilastatin

Drug samples 68 68 107 136 159 90Number of bidders 27 27 40 48 57 48Number of manufacturer 26 17 14 21 19 13Average price per DDD (minimum-maximum) (US$)

$46.16 (27.76-76.13)

$39.41 (7.41-73.14)

$40.05 (6.76-72.68)

$34.21 (6.52-70.80)

$32.38 (8.87-68.39)

$36.47 (9.06-66.05)

H/L ratio 2.74 9.87 10.75 10.85 7.71 7.29Meropenem


$78.67 (31.61-143.22)

$72.81 (18.98-137.60)

$69.43 (13.10-136.74)

$59.75 (10.54-133.19)

$58.64 (9.95-128.66)

$39.40 (7.87-124.26)

H/L ratio 4.53 7.25 10.44 12.64 12.93 15.79H/L: High/low, DDD: Defined daily dose

Figure 2: The price changes of selected carbapenems from 2013 to 2018 (the data included only drugs that were available in the market for 6 consecutive years)



16 WHO South-East Asia J Public Health | Volume 10 | Issue 1 | January-June 2021

Figure 3: Correlation between the average price per defined daily doses of carbapenem and the number of bidders from 2013 to 2018 in Vietnam

on poor people with severe multiresistant infections and limited the treatment options of the physicians. Among four available carbapenems in Vietnam, imipenem/cilastatin was the most commonly utilized carbapenem (53% of number carbapenem DDD), while in the US, meropenem was the most commonly used (49%) followed by imipenem/cilastatin (21%) and ertapenem and doripenem (15% for each).[18]

In the period between 1990 and 2015, Vietnam still imported 90% of pharmaceutical consumption.[19] With carbapenem, only 10.53% of total consumption was produced by domestic companies. European countries were the leading exporter to Vietnam in terms of spending on antibiotics.[8] Currently, many domestic companies are not capable of pursuing the research and development of patent drugs, and they can only manufacture generic drugs.[8] Vietnamese drug manufacturers seem to target less-advanced and competitive markets to benefits from low barriers to entry.[19]

In a study on the pricing and manufacturers of oral antibiotics in the US from 2013 to 2016, 70/81 (86.4%) formulas did not have “substantial price increases”[20] while our study showed that the price of 7/7 selected formulas decreased in 6-year consecutive period. We found that the price of brand name carbapenems was two to three times higher than generic drugs of the same substance. Although existing evidence shows that generic and brand name drugs are equally effective,[21] many physicians doubt this. Policymakers can adopt more price regulations and behavioral interventions to promote the use of generic drugs.

Our study has some limitations. First, we reported data of the period 2013–2018 because of the availability which may be outdated. Our major limitation is that this study may not include complete data of carbapenem purchases in Vietnam because healthcare institutions can publish their data on the institutional website or elsewhere. However, our study included carbapenem purchase in all levels of

the healthcare system, including tertiary, secondary, and primary institutions and largest institutions in Vietnam; we believe that we include almost all carbapenems available in the Vietnam market.

In conclusion, the high price of carbapenems in the Vietnam pharmaceutical market is likely to affect the treatment options as patient-shared decisions. Especially, under the high burden of antibiotic resistance, patients with hospital-acquired infections who required carbapenems tend to be limited to access to the medications. Our study emphasizes the need for monitoring the antibiotic consumption and implementing antibiotic stewardship to preserve antibiotic sources.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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Purchase of Carbapenems in Vietnam, a Low

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