Background
Access to affordable, safe, quality medicines is a key to achieving the Sustainable Development Goal (SDG) 3, namely, to ensure healthy lives and promote well-being for all at all ages. Indicators for SDG 3 include tracking the incidence of major infectious diseases, such as malaria and HIV [
1]. To assure that active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs) for these and other priority diseases are safe, appropriate and meet stringent quality standards, the World Health Organization (WHO) established the Prequalification of Medicines (PQM) programme.
WHO prequalification (PQ) aims to provide qualified, safe and efficacious medicines for United Nations’ (UN) procurement agencies and to countries for bulk purchasing and distributing medicines in resource-limited countries [
2]. In addition to UN agencies, other donors and agencies, such as the global fund to fight AIDS, tuberculosis and malaria (GF), have followed the UN’s example and also require WHO PQ for bulk purchasing of medicines. Since these large purchasers require WHO PQ, this designation can be a significant advantage for a company to receive WHO prequalified status for its FPP [
3]. Currently, over 500 medicines have achieved WHO PQ status [
4]. Approximately 70% of WHO PQ medicines are generic drug products [
5].
China has been engaged in global health since the 1950s, having transformed from an aid-recipient country to an aid-donor country [
6]. China’s foreign assistance to low-income countries includes dispatching medical teams, constructing health care delivery facilities, training health care personnel, and donation of drugs and medical equipment [
7]. China is also a major manufacturer of the anti-malarial artemisinin (qinghaosu) and its derivatives, with an integrated industry encompassing
Artemisia annua planting, exaction, research and development (R&D), drug production, and commercialization [
8]. However, China is not the top sales country in terms of total export value of FPPs of anti-malarial drugs. The top ten countries of total export value of anti-malarial drugs are located in Asia (India, Pakistan), North America (USA), Africa (Sudan, Uganda, Ivory Coast, Nigeria), and Europe (Italy, The Netherlands, Switzerland) [
9]. Certain European and Asian countries, including Switzerland, France and India, are major importers of China’s anti-malarial drugs. Since the burden of malaria is not endemic in Switzerland and France and is in the control phase in India, anti-malarial drugs exported to these countries are usually transported or processed for further sale in other countries where malaria is endemic.
The sale of anti-malarial drugs through PQ pharmaceutical companies in a third country not only limits profit for Chinese pharmaceutical companies, but also raises procurement cost and elapsed time from manufacturer to end users [
9]. In order to provide affordable anti-malarial drugs to malaria-endemic countries, China could increase the amount of direct exportation of anti-malarial drugs. However, Chinese companies primarily rely on providing APIs for foreign companies to produce final anti-malarial drugs, while the direct exportation of anti-malarial drugs from China still faces the challenge of indirect sale due to the lack of having obtained WHO PQ certification [
9]. While WHO and the Chinese Government have been engaged in WHO PQ procedures for over a decade, only 11 anti-malarial drugs produced by one pharmaceutical factory in China have achieved WHO PQ to date [
4]. This study aims to examine the reason for the slow progress of WHO PQ in China, and discusses possible approaches to improve the situation of the dearth of WHO PQ anti-malarial drugs in China.
Discussion
Although WHO PQ has provided access for anti-malarial drugs to enter the global market, few Chinese pharmaceutical companies have achieved WHO PQ for anti-malarial drugs. This study used qualitative methods to understand the underlying reason behind this situation, with the intent to offer suggestions on how to accelerate progress not only for anti-malarial drugs, but potentially for other Chinese medical products to enter into global public sector market.
This study included all of the KIs that were identified as involved with R&D of anti-malarial drugs in central government agencies, pharmaceutical companies, as well as universities and research institutes. According to the interviews, most respondents recognized that the lack of WHO PQ has become a huge barrier for Chinese anti-malarial products to enter global public sector market. According to previous research, the total export value of artemisinin-derived FPPs has been increasing and has roughly equaled that of artemisinin-derived APIs from 2012 to 2014 [
9]. This indicates that China is moving away from exporting raw APIs to FPPs, which are more technologically advanced and profitable. However, without WHO PQ certification, most of Chinese anti-malarial drugs are destined for the private retail market in Africa or sold through intermediaries that are exporting FPPs to a third country. Entering the African market through a third country reduces the profit for Chinese pharmaceutical manufacturers, likely limits the affordability of Chinese anti-malarial drugs in Africa, and potentially stunts R&D of Chinese medical products. Anti-malarial drugs are mostly provided through the African public sector market. Since WHO PQ is the fundamental prerequisite for most international public sector purchasers and for entering the public sector market, WHO PQ could expand the global production of Chinese anti-malarial drugs.
While the merits of achieving WHO PQ are well accepted in China, existing barriers, such as high upfront costs, unpredictable benefit, as well as limited information and technical support have slowed application for WHO PQ. Every country has its own standard for pharmaceutical production. Due to the differences between Chinese GMP, GCP, GLP and WHO requirements, few enterprises could likely pass WHO PQ without high upfront costs, such as purchase of new equipment or even building a new factory. This may be the main reason why few Chinese pharmaceutical companies start the WHO PQ process, especially when investment may not lead to predictable sales and profits.
This study indicated that some incentives might accelerate the WHO PQ progress in China, including supportive policies related to tax and the drug approval process. Since WHO PQ requires a drug production license of the local country, the slow process in China of applying for national license sometimes stops pharmaceutical factories from applying for WHO PQ. Many other countries have used similar incentives to accelerate R&D for certain medical products, such as the ‘Fast Track’ or ‘Accelerated Approval’. Also, tax relief could be a great incentive for pharmaceutical companies. This means that if a pharmaceutical company has been involved in anti-malarial production, it could have a percentage of tax relief. Such accelerating processes could be incentives for pharmaceutical companies to focus on products that mainly affect developing countries. However, government support is the foundation for making these incentives possible.
In order to facilitate the development of WHO PQ in China, more incentive policies and financial support from government should be provided. Initial funds for R&D could be provided by the Chinese Government. A successful example of collaborating with government in China is the WHO PQ-intravenous artesunate achieved by Guilin Pharmaceutical, a process that involved technical assistance from the non-profit organization Medicines for Malaria Venture. It shows that when government provides a favourable environment and necessary services for enterprise development, it is possible to take industry to the next level [
13].
In addition to supporting the development of equipment and standard production process in pharmaceutical factories, human resource training related to WHO PQ is needed. To be specific, training administrators from Chinese pharmaceutical companies to understand the requirements and assessment process of WHO PQ will help them be well prepared to meet the requirements. WHO conducted multiple training on WHO PQ of medicines and vaccines in China between 2006 and 2010, and offered targeted training and consultation services to help over 400 pharmaceutical companies apply for WHO PQ between 2010 and 2012, with financial support from GF and the Bill & Melinda Gates Foundation [
14]. WHO conducted PQ training workshops in 2013 and 2014 during the China Pharma Holdings Inc (CPhi) exhibition, and attended the CPhi exhibition to answer questions regarding FPP and API prequalification procedures in 2016 and 2017. With the consultation and human resource training provided by Medicines for Malaria Venture, Guilin Pharmaceutical became the first WHO PQ pharmaceutical company worldwide to produce intravenous artesunate in 2011 [
13]. According to the KIs, training content might need to be more specific, such as targeting deficiencies in Chinese pharmaceutical companies, apart from a general introduction to PQ process and standard.
Governments could also facilitate progress by bilateral or multilateral collaboration and negotiation with African countries and international organizations. India is a good example, illustrating the importance of government participation. The collaboration established between the national regulatory agencies of India and the user country and WHO has facilitated prequalification of medical products by WHO in India [
15]. The Indian Government has been collaborating with WHO to strengthen pharmaceuticals in India through the provision of technical support for the development of a Comprehensive Institutional Development Plan [
16]. India has 12 major manufacturing facilities producing vaccines that are sold in the national and international market in 150 countries, making India a major global vaccine supplier. Nearly one-third of the prequalified vaccines, and over two-thirds of the medicines purchased through international organizations were produced in India [
4]. Moreover, although India is one of the major importers of China’s anti-malarial drugs, it might be also a strong competitor for Chinese anti-malarial markets in Africa. At May 2017, 17 types of WHO-PQ reviewed medicines/FPPs are manufactured in China, including 11 types of anti-malarials, while 368 types of WHO-PQ reviewed medicine/FPPs are manufactured in India, including 21 types of anti-malarial drugs. Due to the high percentage of PQ products from India, Indian medical products have become a major brand in African countries, bringing the companies profit and the country a better international reputation.
The Chinese Government has prioritized supporting African local production of medicines, and has donated many medical products to African countries. Many Chinese pharmaceutical companies have gained certification from a certain country or a region to sale their medical products. However, while these methods could bring Chinese drugs to other countries and might seem to be a bypass for WHO PQ, in the long run, they may benefit only a few countries or regions. As mentioned by the KIs, if the Chinese Government could help Chinese anti-malarial drugs to be included in the procurement list of international buyers through multilateral or bilateral negotiation, and in some way guarantee the potential market for Chinese anti-malarial drugs, it could be an incentive for pharmaceutical companies to start the PQ process.
Strengthening collaboration with sub-Saharan African countries, and others, could be a mechanism for developing the WHO PQ process in China, such as the public–private partnership (PPP) of Chinese enterprises collaborating with scientific institutions and non-governmental organizations to obtain WHO PQ for the live-attenuated Japanese encephalitis vaccine in 2013 [
17]. PPPs can share the risk and develop innovative, long-term relationships between public and private sectors [
18]. However, PPPs have been somewhat controversial, in that private investors may seek to acquire a higher rate of return than the Chinese Government’s bond rate, while much of the income risk associated with a project may be borne by the public sector [
19]. Contract management is a vital factor in the success of PPP collaboration.
While this study interviewed KIs from multiple representative backgrounds, it has some limitations. First, since the study was designed to understand the underlying reason for limited PQ application in China, only Chinese KIs relevant to anti-malarial R&D and WHO PQ were included. KIs from WHO or donor institutions who might have provided useful suggestions from different perspectives were not included. Second, since the KIs were located in various geographical locations, it was not possible to use focus group discussions for this study. However, conducting the KI interviews in their workplaces allowed for considerable insight into the perceived barriers and their suggestions.
Authors’ contributions
YH conceived the study, designed and coordinated the interviews, carried out data collection and analysis, and prepared the first draft of the manuscript. KP, AS and DP participated in writing, reviewing and editing the manuscript. All authors read and approved the final manuscript.