Availability, prices and affordability of essential medicines in Zhejiang Province, China.

OBJECTIVE: To evaluate the availability, prices, and affordability of essential medicines in Zhejiang Province, China.
METHODS: The survey was carried out in Zhejiang Province in 2018 following the methodology of the World Health Organization (WHO) and Health Action International (HAI). This method is an international standard method.Data on 50 medicines were collected from public health facilities and private pharmacies. Medication prices were compared with international reference prices to obtain a median price ratio. The affordability of medicines was measured based on the daily wage of the lowest-paid unskilled government worker. In private pharmacies, the mean availability of Originator Brands (OBs) and Lowest-priced Generics (LPGs) was 36.7% and 40.3%, respectively.
FINDINGS: The effects of the mean availability of OBs and LPGs were seen in private pharmacies. Correspondingly, the average availability of OBs and LPGs was 41.8% and 35.1% in the public sector, respectively. In the public sector, the median price ratios (MPRs) were 5.21 for generics and 13.49 for OBs. In the private sector, the MPRs were 4.94 for generics and 14.75 for OBs. Treating common diseases with LPGs was generally affordable, while treatment with OBs was less affordable.
CONCLUSIONS: In Zhejiang Province, low availability was observed for medicines surveyed in the public and private sectors. Price differences between originator brands and generics in both sectors are apparent. OBs were more expensive than LPGs in both the public and private sectors. Low availability affects access to essential medicines. Policy measures should be taken to improve the availability of essential medicines.

Introduction

Medicines, especially essential medicines, play a significant role in health care [1]. Though health care is a basic human right [2], this fundamental right cannot be met without fair access to essential medicines. Essential medicines satisfy the health care needs of the population [3]. They are selected based on disease prevalence, evidence of efficacy and safety, and comparative cost-effectiveness [4]. In China, the national essential medicine system was implemented in 2009 [5].

In Zhejiang, all medicines stocked by public health care institutions are procured by the Bureau of Drug Price Bidding, Zhejiang Provincial Department of Health. The procurement complies with the requirement of the province's unification. All the medicines were distributed with zero mark-up [6].

Zhejiang, located in eastern China, has a population of 56.57 million and has 11 cities. It is among the top-five provinces in China in terms of economic development. In Zhejiang, total expenditure on health care in 2019 was 2.11% of gross domestic product (GDP), just under the 5% level recommended by the World Health Organization (WHO). Meanwhile, in recent years, some essential medicines with low prices and high quality are short in supply. For instance, in 2017, there was an acute shortage of mercaptopurine tablets. The present study aimed to examine the availability of essential drugs. Few surveys have evaluated the availability and affordability of medicines in Zhejiang Province, China. This was the context in which we conducted this study. This survey can help us to understand the availability and affordability of essential medicines in Zhejiang Province.

Survey areas

For the price and availability survey, Hangzhou, the capital city of Zhejiang Province, was chosen as the major urban center, and an additional five areas (Ningbo, Shaoxing, Huzhou, Taizhou, and Jiaxing) within one day of travel of Hangzhou were randomly selected. We investigated price components in two areas: Hangzhou (the main urban center) and Taizhou (far from the urban center) to collect the price markups in the supply chain.

Data collection and entry

Six well-trained data collectors visited medicine outlets and collected data on medicine prices (procurement price and patient price in public sector outlets, and patient price in private sector outlets) and availability, using standardized price collection forms. No specific permits were required for the described field studies. Three trained personnel entered the data into the standardized WHO/HAI Excel Workbook using a double-entry technique. Five data collectors visited key informants along the drug supply chain and collected price component data. Then, we entered this information into the WHO/HAI Excel workbook.

Ethics statement

The study was approved by the Ethics Committee of People's Government of Zhejiang Province, and Zhejiang Food and Drug Administration approved the study before data collection. The participants were informed of the aims of our study prior to participation. All participants provided signed written informed consent forms.

Statistical analysis

Using the standardized WHO/HAI methodology, we conducted a study on the availability, prices, and affordability of 50 medicines in Zhejiang Province, China [7]. Among the medicines selected in this study, 12 belonged to the global core list medicines recommended by WHO/HAI, and the other 38 were selected as supplementary drugs. The supplementary medicines were determined according to the local disease burden, the 2012 National Essential Medicine List (NEML) [8], local needs, and the opinions of experts. Other factors were also taken into account; for instance, each medicine selected for the supplementary list had to have an international reference price. During the study, we investigated and collected the prices of Originator Brands (OBs) and Lowest-priced Generics (LPGs) for 50 drugs and then compared these prices with international reference prices (IRPs). OBs are products of the same specification produced by the originator manufacturer of the drug, and LPGs are the cheapest generic drugs found by the University research institute. This study adopted the standard sampling survey method provided by the WHO/HAI to determine the cheapest LPGs. Our research focuses on sample surveys, and surveys are conducted in the form of questionnaires. In the hospitals and pharmacies surveyed, if there is no OB, a generic drug with the same name and dosage form will be used as an LPG for research. If there is no generic drug with the same name and dosage form, there is no universal substitute, and it will be displayed as “0” in the table.

All data for this study were collected from March to May 2018. Data collection included six cities in Zhejiang Province. In each area surveyed, five public pharmacies were selected from the list provided by the Health and Family Planning Commission of Zhejiang: one main hospital, two secondary hospitals, and two primary hospitals by convenience sampling. Private pharmacy outlets were randomly selected based on their active registration status and scale [7]. The private pharmacy sample included 30 pharmacy outlets. The availability of individual medicines is calculated as the percentage (%) of medicine outlets where the medicine was found. The availability of medicines was recorded on the day of data collection.

To facilitate comparisons among countries, medicine prices obtained during the survey are expressed as median price ratios (MPRs), referring to the ratio of a medicine’s median unit price across outlets to the median unit price in the Management Sciences for Health 2015 Price Indicator Guide [9]. The Management Sciences for Health 2015 Price Indicator Guide was chosen because of the frequency of its updates, ease of access, and relative stability.

On the basis of the standard WHO/HAI methodology [7], the affordability of core medicines for common diseases in Zhejiang Province was assessed. The affordability was calculated by comparing the total cost of medicines prescribed at a standard dose with the daily wage of the lowest-paid unskilled government worker, which was RMB 68.9655 per day at the time of the survey, based on figures from Zhejiang Province Human Resources and Social Security Department [10].

Results

Availability

In public pharmacies, the mean availability of OBs and LPGs was 41.8% and 35.1%, respectively. In the private pharmacies, the average availability of OBs and LPGs was 36.7% and 40.3%, respectively. Separate availability analysis of 38 medicines listed on the NEML indicated that the mean availability in private sector retail pharmacies was 35.0% for OBs and 39.5% for LPGs, while average availability in the public sector was 41.4% for OBs and 35.4% for LPGs.

We refer to Table 1, Table 1 shows the availability of individual medicines in the public and private sectors. As shown in the table, the availability of the selected medicines in both public and private pharmacies was low. Among the OBs, amlodipine and atorvastatin had the highest availability in both sectors.

Table 1

Availability of individual medicines in public pharmacies and private pharmacies.

Name of medicine	Public pharmacies		Private pharmacies
	OBs availability (%)	LPGs availability (%)	OBs availability (%)	LPGs availability (%)
Albendazole	66.7	0	96.7	40.0
Amitrityline	0	46.7	0	23.3
Amlodipine	93.3	63.3	80.0	96.7
Amoxicillin	0	43.3	0	63.3
Atenolol	0	0	0	0
Atorvastatin	93.3	43.3	80.0	60.0
Azithromycin	26.7	66.7	20.0	63.3
Bisoprolol	66.7	40.0	50.0	16.7
Captopril	0	56.7	6.7	63.3
Cefalexin	0	10.0	0	13.3
Ceftriaxone injection	66.7	6.7	0	0
Cefuroxime	30.0	40.0	13.3	33.3
Cetirizine	23.3	26.7	20.0	80.0
Chlorphenamine Maleate	0	56.7	0	80.0
Ciprofloxacin	0	6.7	0	10.0
Clarithromycin	6.7	30.0	3.3	60.0
Clomipramine	3.3	16.7	0	3.3
Clopidogrel	93.3	26.7	53.3	26.7
Co-trimoxazole suspension	0	0	0	3.3
Diazepam	0	3.0	0	0
Diclofenac Sodium	23.3	6.7	73.3	13.3
Digoxin	0	86.7	0	43.3
Diphenhydramine	0	3.3	0	3.3
Doxycycline	0	46.7	0	16.7
Enalapril	3.3	26.7	3.3	63.3
Erytromycin	0	23.3	0	3.3
Gliclazide	3.3	16.7	40.0	73.3
Glimepiride	70.0	56.7	56.7	83.3
Hydrochlorothiazide	0	86.7	0	40.0
Ibuprofen	0	20.0	0	36.7
Irbesartan	86.7	66.7	80.0	93.3
Levofloxacin	0	53.3	0	26.7
Lisinopril	0	3.3	0	10.0
Lortadine	43.3	20.0	80.0	96.7
Losartan	40.0	66.7	76.7	63.3
Mebendazole	23.3	0	13.3	3.3
Metformin	66.7	56.7	63.3	40.0
Metronidazle	0	73.3	0	76.7
Mupriocin	50.0	40.0	73.3	60.0
Nifedipine	0	53.3	0	86.7
Nimodipine	53.3	6.7	16.7	6.7
Omeprazole	20.0	73.3	43.3	86.7
Oseltamovir	60.0	53.3	3.3	0
Paracetamol	23.3	23.3	3.3	56.7
Promethazine HCL	0	13.3	0	6.7
Propranolol	0	46.7	0	33.3
Salbutamol inhaler	70.0	0	40.0	50.0
Sertraline	46.7	46.7	16.7	6.7
Simvastatin	43.3	53.3	66.7	53.3
Tinidazole	0	46.7	0	46.7

Note: 0 means the drug was not obtained in the pharmacy.

We refer to Table 2, Table 2 lists the availability of medicines in the public pharmacies and the private pharmacies. Twenty-eight OBs were found in the public sector and 23 in the private sector, while 45 LPGs were found in the public sector and 46 in the private sector. In the public sector, only 13 OBs and 16 LPGs had >50% availability. In the private sector, only 13 OBs and 21 LPGs had>50% availability.

Table 2

Availability of medicines in the public sector and the private sector.

Availability	Public facilities		Private pharmacies
	Originator brand	Lowest-priced generic	Originator brand	Lowest-priced generic
Medicines not found in any outlets	22	5	23	4
Medicines found in fewer than 25% of outlets	9	15	11	15
Medicines found in 25 to 50% of outlets	6	14	3	10
Medicines found in 50 to 75% of outlets	9	14	7	12
Medicines found in more than 75% of outlets	4	2	6	9

N = 50.

Price

Prices of the public pharmacies

We refer to Table 3.

Table 3

Prices in the public sector compared to international reference prices.

	Lowest-priced Generic (times)
MPR	5.21
25th percentile MPR	2.77
75th percentile MPR	8.44
Minimum MPR	0.15
Maximum MPR	43.89

The results in Table 3 indicate that generic products in the public sector were generally sold at more than five times the international reference prices. Half of these were sold from 2.77 times (25th percentile) to 8.44 times (75th percentile) more than their reference prices. There was a large difference between the minimum MPR of 0.15 (captopril) and the maximum MPR of 43.89 (omeprazole).

Price of private pharmacies

We refer to Table 4 and Fig 1, The results in Table 4 show that prices in the private sector are much higher than the international reference prices. Of the originator brand products, omeprazole was found to be the highest priced at over 130 times the international reference price. Four originator brand products are over 40 times more expensive than their international reference prices. They also have the highest-priced generic products. The diagram below illustrates the MPRs of these four medicines in the private sector.

Table 4

Prices in the private sector compared to international reference prices.

	Originator Brand	Lowest-priced Generic
MPR	14.75	4.94
25th percentile MPR	7.67	2.02
75th percentile MPR	25.12	9.30
Minimum MPR	1.91	0.19
Maximum MPR	134.45	28.75
Number of medicines included	22	36

Fig 1

MPRs of these four medicines in the private sector.

We refer to Table 5, The results in Table 5 show that the patient price in the public sector is 13.41 for OBs, lower than that in the private sector while for LPGs it is 5.21, higher than that in the private sector.

Table 5

MPRs for medicines found in both the public and private pharmacies.

Product type	MPR public sector patient prices	MPR private sector patient prices	% difference private to public
OBs (21)	13.41	14.85	10.7%
LPGs (32)	5.21	4.94	-5.3%

Affordability

The affordability was calculated using the median prices collected during the survey [7]. Table 5 shows the affordability associated with the seven common diseases. OB products were generally less affordable than the lowest-priced medicines in both the public and private sectors. However, in the private sector, some treatment costs were high. For instance, treating peptic ulcer with omeprazole required 5.2 days’ wages. The treatment course of omeprazole is 4–8 weeks.

We refer to Table 6.

Table 6

Affordability of core medicines for common diseases in public sector and private sector.

Disease Condition	Drug name	Product Type	No. of units a day	Duration (days)	Day’s wage (Public pharmacies)	Day’s wage (Private pharmacies)
Asthma	salbutamol	Originator	200	as needed	0.3	0.3
		Lowest-priced	200	as needed	NA	0.3
Diabetes	Metformin	Originator	3	30	1.5	1.6
		Lowest-priced	3	30	0.6	0.8
Hypertension	Captopril	Originator	2	30	NA	NA
		Lowest-Priced	2	30	NA	NA
	Bisoprolol	Originator	2	30	2.5	2.5
		Lowest-Priced	2	30	1.8	1.8
Hypercholesterolaemia	simvastatin	Originator	1	30	1.3	1.3
		Lowest-Priced	1	30	0.4	0.8
Depression	amitriptyline	Originator	3	30	NA	NA
		Lowest-Priced	3	30	0.2	0.2
Adult respiratory infection	amoxicillin	Originator	3	7	NA	NA
		Lowest-Priced	3	7	0.2	0.3
	ciprofloxacin	Originator	2	7	NA	NA
		Lowest-Priced	2	7	NA	NA
	ceftriaxone	Originator	1	1	0.7	NA
		Lowest-Priced	1	1	NA	NA
Ulcer	omeprazole	Originator	1	30	4.6	5.2
		Lowest-Priced	1	30	1.7	0.8

Note: NA, not available.

Duration: Duration of treatment course over a one-month period.

Discussion

Some studies on access to essential medicines have been conducted in China using the WHO/HAI methodology [11-13]. The present study is the first to apply this methodology to the availability of essential medicines in Zhejiang Province in China. The findings of this study offer a report on the availability, prices, and affordability of essential medicines in Zhejiang Province in China. We conducted this survey in six cities in Zhejiang Province. The results suggest that the availability of 50 essential medicines is low in the public and private sectors. In private pharmacies, the mean availability of OBs and LPGs was 36.7% and 40.3%, respectively. The average availability of OBs and LPGs was 41.8% and 35.1% in the public sector. Compared with the study of Minghuan Jiang et al. [12], our findings showed a higher availability of essential medicines in both the public and private sectors. Their study showed that, in Shaanxi Province, the mean availability of OBs and LPGs was 12.9% and 29.5% in private pharmacies, respectively [11]. The mean availability of OBs and LPGs was 7.1% and 20.0% in public hospitals.

On January 17, 2019, the Chinese government issued the “National Organized Drug Centralized Procurement and Use Pilot Program,” marking the beginning of the Chinese government's formal implementation of the centralized drug procurement policy, which has greatly reduced the prices of drugs in China. This policy is labelled the “4+7” centralized procurement policy. The Chinese government forces bid-winning companies to lower the price of medicines. The bid-winning medicines of bid-winning companies can gain more market share leading to lower medicine prices through large purchases.

There are three reasons for these findings. First, the low profit margins of essential drugs have prompted the public and private sectors to support other high-profit equivalent alternative drug treatment schemes. In Zhejiang Province, public medical institutions adopt a zero-margin drug sales policy; that is, the purchase price is the same as the price patients pay [14]. In the past, medical institutions could increase the price of drugs by 15% on the basis of purchase prices. Because of the lack of sales profits, medical institutions are more inclined to seek profits in equipment inspection or operation, and the willingness to increase the supply of drugs is significantly reduced. Second, the government's essential drug policy prohibits the sale of essential drugs by medical institutions at premium prices, and by allocating funds to hospitals to maintain their operations, government subsidies usually only account for 10% of operating expenses [15]. It can be said that hospital pharmacies are now the pure-cost expenditure units of medical institutions, so they tend to reduce the scale of drug supply. In China, public pharmacies do not charge for prescription reviews and also do not charge preparation service fees for drugs sold to patients. Their profit comes from the premium between the purchase and sale of medicines, which is very different from how pharmacies in the United States and other countries operate.

Although some hospitals have charged pharmaceutical services because pharmaceutical services in Zhejiang or China are still in their infancy, general hospitals do not have the ability to provide better pharmaceutical services, so only a few hospitals in individual areas charge pharmacist service fees [16]. The essential drug list is an important guideline for the implementation of an essential drug system. China has implemented an essential drug system for several years. Primary medical institutions have achieved full coverage of essential drugs. With the progress of medical and health system reforms, the next goal of the essential drug system is inevitable. It is to increase the use rate of essential medicines in secondary and tertiary hospitals. Third, most essential medicines are commonly used medicines, which are the main target of price reduction in recent years. The profit margin is relatively small, which makes enterprises unenthusiastic about maximizing profits. The “4+7 bulk quantity purchasing policy” means that, with the approval of the Central Committee for Comprehensive and Deepening Reform, the state organizes a pilot project of centralized drug purchasing, covering 11 cities in Beijing, Tianjin, Shanghai, Chongqing and Shenyang, Dalian, Xiamen, Guangzhou, Shenzhen, Chengdu, and Xi'an. If we take the “4 + 7” bidding purchase as an example, average reduction of more than 50%, the highest drop in drugs reached 92%. In this year's bidding and procurement, the “4 + 7” model is also being followed up in areas outside the pilot project. It is generally believed that the prices of essential drugs will continue to fall. Prices have declined since the “4 + 7” policy, which reduces the burden on patients, but the shortage of drugs is also increasing. For example, the Chinese government has established a drug shortage–monitoring mechanism [17], and provinces have issued their own drug shortage catalogs [18].

The “4+7” policy is a national policy, but the provinces will make appropriate adjustments according to their actual conditions to better realize the availability and affordability of essential medicines [19]. For example, on the December 6, 2019, the National Medical Security Administration of China issued the “Opinions on Doing a Good Job in Current Drug Price Management.” Article 1 of Chapter 3 states that in case of drug shortages, operators are allowed to quote their prices directly online. The medical institution purchases at the online price or further negotiates with the operator for purchase. On June 28, 2020, the Zhejiang provincial government issued the “Zhejiang Province to Enhance the Function of the Centralized Pharmaceutical Procurement Platform to Promote the Reform of the Full Coverage of Medical Insurance and Drug Payment Standards.” Chapter III noted that for clinical needs, public medical institutions are entitled to fair negotiations with enterprises to determine the purchase price within the limit of 1% of the settlement amount of drugs in the previous year and purchase products themselves through the provincial drug equipment purchase platform, if there are no online traded products within the platform or they cannot be purchased at the set price within the platform [20].

This study has several limitations. First, we use the research method based on WHO/HAI, which may diverge from the real situation in Zhejiang Province. A better method may need to be developed in the future. Second, the relevant data are only applicable to the date of data collection and may not reflect the average availability over time. Finally, this study analyzes the price components of essential medicines in China using the standardized WHO/HAI method. However, only some medicines were included in the analysis. For confidentiality reasons, some data have errors and are missing.

Conclusion

In Zhejiang Province, the supply of drugs surveyed by the public and private sectors is inadequate. The price difference between the original brands and generic drugs in the two industries is obvious. In the public and private sectors, OBs are more expensive than LPGs. Relevant measures should be taken to improve the supply of essential drugs.

First, the government should increase subsidies for health insurance, investment in this field has been increasing in recent years. For example, in 2019, in Zhejiang Province, the basic medical insurance income is each worker’s basic medical insurance allotment, the income of the basic medical insurance fund for Chinese workers and urban and rural residents increased by 9.94% year on year, and the income of the basic medical insurance fund for urban and rural residents increased by 7.71% year on year. Second, the government should improve the availability and affordability of essential medicines in public pharmacies. Now, some of the measures, such as lowering the barriers for pharmacies to enter the health care system and allowing them to sell essential drugs at higher prices than medical institutions, should be effective. Third, allowing pharmacists in public pharmacies to charge pharmaceutical service fees will significantly improve the income structure of public pharmacies and encourage pharmacists to provide more types of drugs and better pharmaceutical care, instead of paying attention to drugs with high premium prices. The good news is that the service fees pharmacists charge for drug preparation may be recognized by law. Article 5 of the second draft of the pharmacist law of the People's Republic of China, adopted by the Chinese government on June 18, 2020, required pharmacists to provide pharmaceutical professional technical services to patients, which indicated that pharmacists’ service charge is likely to become a reality in the future.

In this study, we studied the affordability of medicines for seven common conditions. As shown, most LPGs for these common diseases were affordable in both sectors. The improvement in people's living standards enables them to afford high medical expenses.

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14 May 2020

PONE-D-19-30034

Availability, prices and affordability of essential medicines in Zhejiang Province, China

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Reviewer 2 comments

Availability and affordability of medicines is an interesting topic. This paper repeats an identical format and analysis from two other provinces of China (Shaanxi and Jiangsu) in a third province (Zhejiang), which in turn use a 2003 methodology developed by WHO and Health Action International. which was applied in 50 countries studies by 2008. Subsequent to the publication of the comparative results from the WHO study, the methodology has also been used to analyze the same parameters for pediatric drugs, diabetes drugs, cardiovascular drugs, drugs for noncommunicable diseases etc in multiple countries (Nepal, Nigeria, Ethiopia, Anhui province of China, Bangladesh, among many others). Given that China has 32 provinces/municipalities/autonomous regions, there is obviously a lot of scope for many such surveys to be conducted in China. This paper does innovate slightly by relating the results to the “4+7” policy although the way this is presented is a bit difficult for the reader to follow.

There are some methodological issues that would be important to address:

1. It’s not clear why Tables 1 and 2 are presented separately, since the availabilities in Table 3 and the price summaries in Tables 4 and 5 appear to be based on the combined data.

2. Tables 1 and 2 at times use “0” and other times “-“ in the columns. Initially I assumed that “-“ meant not applicable and that these items were excluded from Table 4 but that appears not to be the case, and probably “0” and “-“ actually mean the same thing.

3. Table 4 has a note below the table stating this applies to 37 medicines (although the superscript “a” does not appear in the table, so I am guessing here). There is no reason given for this, since there are more than 37 LPG drugs available in that sector according to Tables 1 and 2.

4. Similarly, in Table 5 has a line in the table this time indicating that the comparisons 22 and 36 medicines, however this does not seem to equate to the number of cases where the drug was available in the private sector. Some explanation would be desirable.

5. I have an overall concern with the WHO-HAI methodology. The importance of non-availability of the “lowest priced generic” requires careful definition. Is the “lowest priced generic” defined for China (or for Zhejiang province) and if so how? How much difference is there between the prices of the lowest priced generic and the second lowest priced generic for these drugs? What is the policy significance of the lowest-priced one being unavailable in a circumstance where possibility the second lowest-priced one is available, and how does that compare to a situation where the lowest-priced one is considerably less expensive than the next lowest-price one? It is possible that when the WHO originated the methodology back in 2003 fewer generics were available, so this wasn’t as much of an issue as it perhaps is now.

6. How did the authors take account of the fact that the international reference prices were for 2015, while the data were collected in 2018. Do international pharmaceutical prices not change much over three years?

7. Given that the policy issues are the main area in which this paper distinguishes itself from scores (or hundreds) of similar studies, it would be worth getting an English-first-language health expert to read the discussion and conclusion sections and make the policy implications clearer for example the term “subsidies” in the Discussion section sometimes seems to mean government contributions to the hospital budget rather than a subsidy per se; and “The essence of “4 + 7” is to exchange price by quantity” would be better explained “…is to use bulk purchases to drive down prices” or something similar.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Dear Authors,

The topic on medicines access is still relevant and important in many ways. It is good that such studies are still been carried out. However, this article need improvements:

1. Overall the article need language improvement by an expert; thus I will not comment on the matters related to language and grammar.

2. Abstract - Conclusions - affordability is one of the main objs but it was not mentioned.

3. Methods section - you mentioned 'an additional 5 cities' but you only mentioned 4+1 - it is confusing - 5 or 6 cities in total?

4. Methods section - what does 'scale' mean in this context ?

5. many researchers used the WHO/HAI methodology but why this methodology? any strengths/advantages? please explain.

6. Figure 1 - check the spelling for Omeprazole; and the use of cap vs small letter

7. Table 7 - font type - be consistent with the main text; check the use of cap vs small letters for drug name

8. Discussion - does this province use diff policy and regulation from other provinces in China? good for the International readers to understand

9. Discussion - lack of studies from other countries that are relevant; were not included in the discussion

10. Conclusion - sentence 1 - 'inadequate' - what does this clearly mean? shortages? not available?

11. Include recommendations section at the end of the Discussion section - move the ones mentioned in the Conclusion section.

12. Include the strength, limitations and study implications in the last part of the Discussion section

**********

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Reviewer #1: Yes: Professor Mohamed Izham Mohamed Ibrahim, PhD

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10 Jul 2020

Dear Susan Horton

Thanks you very much for your comments and suggestions.

As suggested, We have made amendments to the academic papers, in accordance with the requirements of the academic editors, and responded to the comments made by the reviewers. The details are attached below. Some of our basic research data is written in Chinese, which may be difficult to understand.

We have polished English and revised academic papers.We have revised the manuscript, according to the comments and suggestions of reviewers and editor, and responded, point by point to, the comments as listed below. Some of the references we cited are published in domestic academic journals in China and may not be found in foreign databases.

I would like to re-submit this revised manuscript to PLOS ONE, and hope it is acceptable for publication in the journal.

Looking forward to hearing from you soon.

With kindest regards,

Yours Sincerely

QiuCheng Tao

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

28 Jul 2020

PONE-D-19-30034R1

Availability, prices and affordability of essential medicines in Zhejiang Province,

China

PLOS ONE

Dear Dr. Sun,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Sep 11 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.Please include the following items when submitting your revised manuscript:

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We look forward to receiving your revised manuscript.

Kind regards,

Susan Horton

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Please see REviewer 1's comments below. I also provided responses as Reviewer 2, which I include here.This paper is somewhat improved in methodology following revisions, although the quality of the written English remains an issue. A big disadvantage is that the authors did not provide a “track changes” version of the manuscript and thus it was hard to see whether the changes really had been implemented as requested. I would request that in the next revision a track changes version be provided.

One issue for me is that “Lowest Priced Generic” was not clearly defined. Does this mean that the authors identified a lowest priced generic brand overall (how?) in the province, and searched for that at the pharmacies? If so, that isn’t that interesting if there are other fairly low-priced generics which are available instead. and it is understandable that that particular brand was not always available. Or in each pharmacy, did they identify the lowest priced generic carried by that particular pharmacy, which wasn’t always available? What is there was another fairly low priced generic available instead? There is a big different in policy implications between no generic alternative being available at all, or another one being available at a slightly higher price.

Abstract: I was puzzled as to why Methods, Findings and Conclusions were repeated twice. Perhaps one was original, one was revised? In any case, under Findings, line 4 (both versions): suggest refer to “innovator brands” instead as “OBs” – confusing to the reader to call the same thing by two different names.

Introduction, para 2: don’t mention the “three in one” policy without a brief explanation – readers will not all be familiar with this. Readers will also not understand what the significance of the “province’s unification” is without explanation.

In many places a space is missing: I will list the words and suggest the authors do a “search and replace”: “anadditional” “mainurban” “theprice” “andcollected” forms.No” “Taizhou,Jiaxing” “Zhejian:one” “ratios(MPRs)” “brands(OBs)” “generics(LPGs)” “work .For” “expenses, [15]and” “studywas”

Table 2: this is a continuation of Table 1, and should have the title “Table 1 (continued)” or similar, and subsequent tables should accordingly be renumbered.

Table 3: suggest add “n=50” to the title for clarity

Table 7: in the column titles, clarify in a footnote perhaps that “Duration” means “duration of treatment course over a one-month period” or similar.

Discussion: second full paragraph discusses “the government’s inadequate subsidies for essential medicines..” – is what is meant that the government does not permit any handling fee for medicines by pharmacies? (That is indeed a problem regarding incentives).

Same paragraph: “.Although hospitals have charged for pharmaceutical services..” (insert underlined word). Also “…pharmaceutical services in Zhejiang or China are in their infancy..” (not “is”)

Paragraph beginning: “The essence of "4 + 7" is to exchange price by quantity.” I don’t understand what the authors mean here. Is what they are saying “The essence of “4+7” is to use larger volumes of purchase to drive down prices”.

“but also has its own policies among various provinces” – not clear what is meant here. Are the authors trying to say “but each province has its own policies”. “The policies of Zhejiang Province encourage public and private pharmacies to increase the availability of medicines and

reduce the affordability of medicines.”. How?

Our research is based on the actual situation of Zhejiang Province, China, and is different from other countries. Other countries do not have the same policies as China, so the research results are also different.” This may be true but is too vague to be useful.

Next page: “Due to confidentiality reasons, some data have errors and missing” – what confidentiality reasons? Please explain

Conclusion: “the government should increase investment” – in what? People don’t usually consider providing a pharmacy service fee for medicines, as investment.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Dear Authors,

Thank you for the effort towards improving the ms. However, it is very difficult to know if changes were clearly made or points were inserted in the revised version of the ms. Changes were neither highlighted nor indicated by track changes.

Conclusions - Authors are supposed to conclude based on the objectives and main findings. But, the last paragraph, the authors have included a ref i.e. Minghuan Jiang et al, and it looks like a discussion section.

Figure 1 - cetirizine - small letter 'c'. The authors mentioned that this typo had been corrected.

I doubt that proper actions have been taken and please highlighted the corrections and improvements in the revised ms.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Mohamed Izham Mohamed Ibrahim

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While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

20 Aug 2020

Dear Susan Horton

Thanks you very much for your comments and suggestions.

As suggested, We have made amendments to the academic papers, in accordance with the requirements of the academic editors, and responded to the comments made by the reviewers. The details are attached below. Some of our basic research data is written in Chinese, which may be difficult to understand. Our research data has been uploaded to the submission system. Because it is the most primitive data, it is all in Chinese。

We have revised the manuscript, according to the comments and suggestions of reviewers and editor, and responded, point by point to, the comments as listed below. Some of the references we cited are published in domestic academic journals in China and may not be found in foreign databases.

I would like to re-submit this revised manuscript to PLOS ONE, and hope it is acceptable for publication in the journal.

Looking forward to hearing from you soon.

With kindest regards.

Yours Sincerely

Guojun Sun

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

27 Aug 2020

PONE-D-19-30034R2

Availability, prices and affordability of essential medicines in Zhejiang Province,

China

PLOS ONE

Dear Dr. Sun,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Oct 11 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Susan Horton

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Thank you for responding to the previous comments. There is one outstanding issue. "Lowest priced generic" is still not well-defined. Is this one particular brand which is deemed the lowest-priced in the province? (this is what it seems to be)? If not, please define out of which subset it is "lowest priced".

Thank you for explaining the policy in the conclusions more fully. Unfortunately the language of the draft is unacceptable at the moment. At this point you need to pay someone for whom English is their first language and who has some understanding of the subject matter to edit the draft. This will be the third revision of this article. I strongly recommend that you perfect the language this time since I do not know if the journal will accept further revisions (this is up to the editor).

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[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

6 Oct 2020

Dear Susan Horton

Thanks you very much for your comments and suggestions.

As suggested, We have made amendments to the academic papers, in accordance with the requirements of the academic editors, and responded to the comments made by the reviewers. The details are attached below. We have asked editge to help us polish the language and correct the previous language problem.

We have revised the manuscript, according to the comments and suggestions of reviewers and editor, and responded, point by point to, the comments as listed below. Some of the references we cited are published in domestic academic journals in China and may not be found in foreign databases.

I would like to re-submit this revised manuscript to PLOS ONE, and hope it is acceptable for publication in the journal.

Looking forward to hearing from you soon.

With kindest regards.

Yours Sincerely

Guojun Sun

Submitted filename: Response to Reviewers(2020.9).docx

Click here for additional data file.

12 Oct 2020

PONE-D-19-30034R3

Availability, prices and affordability of essential medicines in Zhejiang Province,

China

PLOS ONE

Dear Dr. Sun,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Nov 26 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Susan Horton

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Thank you for getting help with the English. Now that I can understand better what you are trying to say, I can now offer the following edits so that the readers of the journal will also understand. I recommend the following edits. Since there do not seem to be page or line numbers, I have numbered according to the page number in the proof which overall has 53 pages.

P13 of 53: “LPGs are the cheapest generic drugs found in the research institute” Do you mean “LPGs are the cheapest generic drugs found by the University research institute”?

p13 pf 53 “Data collection included six cities in Zhejiang Province. Hangzhou was identified as the major urban center of Zhejiang, and an additional five cities were chosen randomly. As a result, six cities were selected: Hangzhou, Ningbo, Shaoxing, Huzhou, Taizhou, and Jiaxing”. Delete this sentence – duplicates statement previously. In following sentence say “area surveyed” not “surveyed area”

In several places the authors say “We refer to Table X”. This is unnecessary, as long as the table is cited in the text.

P17 of 53, last 2 lines (last 2 lines of Table 2). These should be deleted.

P19 of 53. Restate the following sentence: ,”The results in Table 5 show that the patient price in the public sector is 13.41 lower than that in the private sector for OBs, while it is 5.21 higher for LPGs.” As “,The results in Table 5 show that the patient price in the public sector is 13.41 for OBs, lower than that in the private sector while for LPGs it is 5.21, higher than that in the private sector “.

P20 of 53: “treating peptic ulcer with omeprazole required 5.2 days’ wages.” Treating for how long (the recommended course is 4-8 weeks).

P21, last line. “the mean availability of OBs and LPGs was 12.9% and 29.5%, respectively.[11].” Is this in private pharmacies? If so, state that.

P22 of 53, last line. Does “social” pharmacies mean “public”? If so, make this change from here onwards (used several times).

P23 of 53: I think instead of “4+7 belt quantity purchasing policy” what is means is “4+7” bulk purchasing policy. State that.

P23 of 53, last line. If the average price of medicines was reduced by more than 60%, what exactly was reduced by 92%?

P24 of 53, line 4: instead of “burden of patients” say “burden on patients”.

P24. Delete entire paragraph (duplicates material elsewhere “The essence of “4+7” policy is to use larger purchase volumes to drive down prices. Successful bidders who pass the conformity evaluation of generic drugs will

greatly reduce the price of drugs. The government will give the winning bidder a

certain market share. The coverage of high-quality and low-price generic drugs will

expand; the pressure to make drugs affordable will be reduced; and patients will have

better drug choice.[19Some pharmaceutical industry associations apply for

implementation of the policy to be suspended, but the decision of the health insurance

department to implement the policy is very resolute. Because of their own interests,

pharmaceutical enterprises will strictly control the quantity of drugs produced,

resulting in a rapid reduction in the availability of drugs.[20]”

p24. Also delete sentence “In China, each province has its own policies, and

the provincial government will respond to the official documents of the Chinese

government and issue relevant policies based on the development of its own province.” Since this simply restates what was said in the previous sentence.

P25: delete “This reflects the examination of the self-procurement system of public

medical institutions. In this study, we adopted a systematic research method to study related issues, combined with the actual situation and policies to study the availability and

affordability of drugs in public and private pharmacies in Zhejiang”. This simply restates what has been previously said.

P26: delete “The availability and affordability of medicines is a complex systemic problem.

The question first needs to clarify the essential causes of the shortage of drugs; on this

basis, grasp the key factors; and propose solutions in regard to drug prices, market

environment, policy systems, and legislation. The smooth implementation of these

solutions also requires the coordination and cooperation of various government

departments and stakeholders of the drug supply. Only when the main bodies of the

drug supply chain work together can the current issues of great concern be solved to

the greatest extent.” Also repetitious.

P26: Delete “In terms of the development trend,” (repetitious)

P26: what is meant by “the income of the basic medical insurance fund”? Does this mean aggregate income of the fund in the province, or does it mean “each worker’s basic medical insurance allotment”

P26: “Second, the government should further play the role of social

pharmacies in improving the availability and affordability of essential medicines”. Suggest restate as “Second, the government should improve the availability and affordability of essential medicines in public pharmacies”.

P27. Delete “with diagnosis and treatment of behavior belonging to shall, through the

proper way to manifest the value of their labor”: sentence is clearer without this.

[Note: HTML markup is below. Please do not edit.]

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

20 Oct 2020

Dear Susan Horton

Thanks you very much for your comments and suggestions.

As suggested, We have made amendments to the academic papers, in accordance with the requirements of the academic editors, and responded to the comments made by the reviewers. We have made changes based on the previous manuscript.The details are attached below. We have asked editge to help us polish the language and correct the previous language problem.

We have revised the manuscript, according to the comments and suggestions of reviewers and editor, and responded, point by point to, the comments as listed below.

I would like to re-submit this revised manuscript to PLOS ONE, and hope it is acceptable for publication in the journal.

Looking forward to hearing from you soon.

With kindest regards.

Yours Sincerely

Guojun Sun

Submitted filename: Response to Reviewers(2020.10).docx

Click here for additional data file.

21 Oct 2020

Availability, prices and affordability of essential medicines in Zhejiang Province,

China

PONE-D-19-30034R4

Dear Dr. Sun,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

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Reviewers' comments:

5 Nov 2020

PONE-D-19-30034R4

Availability, prices and affordability of essential medicines in Zhejiang Province, China

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