In this study, we investigated the relationship between the leading pharmaceutical companies’ global innovation activities, focusing on recent R&D activities, and DALYs by income level and region. In addition, the associations between country-specific innovation activities and DALYs in certain countries were further explored.
It was previously demonstrated that there has been a misalignment between big pharmaceutical companies’ research publications and the global burden of diseases [29]. The study indicated that the focus of the companies’ research did not match well with global health concerns. Our study investigated the research efforts of multinational pharmaceutical companies more in terms of practical productization than academic output, by analyzing the innovation activities performed in the drug development pipeline.
The results from our study identifying the disparity of innovations by income level and region are consistent with findings in previous studies that pharmaceutical innovations are biased toward developed countries [11, 12, 16]. We demonstrated this pattern with stronger evidence, by comparing the associations between innovations and DALYs, with the income levels of the countries divided into four groups and the regions of the world divided into six groups, with the most up-to-date dataset on reported R&D cases of the pharmaceutical companies. This disparity was observed not only in the case of the top 20 companies, but for all pharmaceutical companies that had R&D activities in the last three years, as shown in Table S2 in the Supplementary Material. This can be attributed to the fact that the top 20 companies’ innovation activities comprise a substantial proportion of total pharmaceutical innovation and other companies that are not included in the top 20 companies also prioritize the pursuit of business profit.
In regard to discrepancies by disease categories, this study confirmed that in high income countries, the innovation activities on neoplasms, diabetes, urogenital, blood, and endocrine diseases have continued to be excessive compared with their DALYs values until recently (Fig. 1(a)) [12, 16]. In low income countries, we found a severe scarcity of innovation activities for treating Communicable Diseases (CDs) such as diarrhea, lower respiratory diseases, other common infectious diseases, and neglected tropical diseases and malaria which have the highest burden values in low income countries (Fig. 1(b)).
Since most of the top 20 companies are located in the US or European countries, it is somewhat understandable that they may be more responsive to the disease burdens in these countries. However, in a world that is increasingly more globalized and closely connected, it may not be wise to focus R&D activities only on specific regions or countries. As in the cases of Middle East Respiratory Syndrome (MERS), Severe Acute Respiratory Syndrome (SARS), and Coronavirus disease 2019 (COVID-19), the outbreak of pandemics which began in developing countries can spread at any time to developed countries and pose a grave threat worldwide. In this regard, taking proactive innovation efforts that take into account diseases prevalent in underdeveloped countries can be beneficial not only to public health but also to corporations’ potential returns.
In the case of COVID-19, hundreds of thousands of people are losing their lives due to the unprecedented worldwide pandemic. To date (as of June 21, 2020), Europe and North America accounted for 61.6% of total confirmed cases and 80.1% of total deaths in the world [30]. Numerous pharmaceutical companies are making tremendous efforts to develop vaccines and treatments to combat COVID-19 and therefore 240 drugs are currently under development [24]. Since clinical trials on a single drug often proceed in several countries simultaneously, multiple counting by country was allowed, to investigate the drug development activities on COVID-19 by region. It was observed that drug development activities have been predominantly conducted in Europe (40.4%) and North America (29.5%) (Fig. 2). It is reasonable that R&D activities are biased toward these regions where developed countries are located, because the number of the confirmed cases and deaths due to COVID-19 are also predominantly high in these regions. On the other hand, it can be seen that the regions where low income countries are located such as Africa, Oceania, and South America are significantly marginalized in COVID-19 R&D activities.
However, the progression and prognosis of the virus can be influenced by race/ethnicity (e.g. immunological differences), climate, sociodemographic factors (e.g. population density and poverty rate), etc., which vary from region to region [31,32,33,34,35,36]. In addition, mutations of the virus, SARS-Cov-2, are continuously being reported as the spread of COVID-19 accelerates throughout the world [37, 38]. In this regard, targeting only specific countries or demographics would not be the most effective way to develop more potent vaccines and therapies. Moreover, in countries where healthcare resources are limited, timely and large-scale diagnosis, treatment, control, and prevention are all huge challenges that cannot be established in the near future, leading to national catastrophes. From this perspective, there is a strong need to consider marginalized regions and people together in both private and public sectors.
Several policy implications were derived from our study for both the private and public sectors. First, in the private sector, globally leading companies should further expand the development of drugs contributing to reducing the burden of marginalized diseases and/or countries, even if these types of drugs are less profitable. Of course, it should be acknowledged that the discrepancy between the innovation activities of the leading companies and DALYs is not particularly worse than the discrepancy found when we include the innovation activities of all other companies (Table S2 in Supplementary Information); furthermore, these leading companies should be given some credit for having contributed significantly to the development of orphan drugs. The top 20 companies accounted for 33% of the total innovation activities for orphan drugs during the period included in our analysis (Table 1). Over the past twelve years, multinational pharmaceutical companies’ investment in neglected tropical diseases (NTDs) has continuously grown, increasing fivefold since 2007, and they accounted for the vast majority (86%) of total industry sector investments in NTDs in 2018 [39]. However, despite these remarkable efforts and contributions, they accounted for only 16% of all funding for NTDs R&D in 2018 [39]. In other words, the investment in NTDs still depends heavily on the public sector. From this perspective, the leading companies which can better afford to manage their product portfolios taking into account both societal values and business returns, compared to small companies or startups where pursuit of profit is a top priority for survival, still have room for making meaningful progress in areas that have not fully benefited from support and investment for NTDs. Moreover, the public is increasingly demanding Corporate Social Responsibility (CSR) from large pharmaceutical companies [23]. It has been found that one of most preferred CSR activities by general public expected from pharmaceutical companies is the “promotion of public health” through activities such as the development of innovative drugs in untreated areas [40].
Secondly, the roles and responsibilities of the public sector remain crucial. The voluntary participation of private companies alone cannot sufficiently alleviate the disease burdens around the world. It has already been demonstrated that pharmaceutical innovation is significantly affected by market size [41, 42]. Our empirical analysis of several high income countries also proved that innovations are more closely related to market size than disease burden. In this context, it is natural that innovations are more concentrated in high income countries with large market sizes. Of course, diseases with high burden values are becoming more similar across both high and low income countries as non-communicable diseases (NCDs) have increased in low income countries in recent years [43]. Therefore, the drugs already developed for such diseases in high income countries can be delivered to low income countries to reduce the disease burdens in those countries. In particular, global leading companies have made striking contributions to ensure that these drugs are more widely available, accessible, and affordable in these countries, by utilizing diverse strategies such as equitable pricing, licensing, and product donations [9]. Their efforts and contributions should not be overlooked. However, even though the burden rankings of certain CDs such as HIV/AIDS, tuberculosis, diarrhea, malaria, and neonatal disorders have already been lowered in high income countries, they still rank high in low income countries (Table S1 in Supplementary Information). In addition, while major CDs such as HIV/AIDS, tuberculosis, and malaria are receiving high levels of R&D funding, other kinds of NTDs (WHO NTDs) have received very low levels of R&D funding, and what is worse, the funding levels have stagnated in place over the past decade [39]. There are still unresolved areas that require careful attention and further actions. In this regard, international non-profit institutions and non-governmental organizations (NGO) need to more extensively strengthen support and investment for these marginalized diseases and countries by accurately identifying the areas where drug development by the private sector itself has been scarce.
In addition, national governments should lead and foster basic research especially in areas where technological development is challenging due to the difficulties of mechanism identification or the lack of scientific knowledge. Such governmental initiatives should embrace a wide range of fundamental and original research conducted in various fields including academic, clinical, and industrial fields, which can contribute to population health in the long-term [44].
Finally, public and private sectors should cooperate strategically by utilizing collaborative programs such as Product Development Partnerships (PDPs) to develop products that are societally valuable but provide uncertain potential return, such as the vaccine for Acquired Immune Deficiency Syndrome (AIDS) [18, 45]. Specifically, the public sector should provide attractive incentives and benefits (e.g. assistance for clinical trials, ease of regulatory control, intellectual property protection, guaranteed profits, and so on) to the companies engaged in the programs. Since companies are fundamentally pursuing their own profit, it obviously to be expected that private firms will follow market forces. In this regard, the public sector can lead to increasing the market size of the disease areas where improvement is urgently required for the sake of public health. That is, governments can provide market incentives to induce the private sector to be more energetic in conducting innovation activities for diseases whose burden should be lowered more preferentially [46]. This can be accomplished by implementing policy strategies such as allowing companies to increase their drugs prices, expanding the coverage of national healthcare insurance, and compensating for the development costs and ensuring the profitability of the drugs. Several relevant policies have been implemented in many countries, but it is necessary to strengthen these policies for diseases with the highest burden globally.
The limitations of our study are as follows. First, when analyzing R&D activities by country, this study did not include cases where drugs that had already been developed elsewhere by leading pharmaceutical companies were delivered to marginalized countries through donation programs or free supplies, since we focused more on R&D activities than currently available drugs in a particular country. It should be recognized that billions of drugs and treatments are donated by the pharmaceutical industry partners. For instance, medicines for over 1.8 billion treatments were provided to impoverished and hardest-to-reach communities by donation programs in 2016 [47]. If further studies that broaden the scope beyond this study were to incorporate other types of innovations such as product donations, building/strengthening healthcare systems, education/training of clinicians and scientists, improving awareness of diseases, etc. in addition to the R&D pipeline analysis, such studies can be expected to yield richer and broader implications from diverse viewpoints. Secondly, there were some data losses in the process of data transformation. The innovation activities aggregated based on AC were sequentially converted to data based on ICD, followed by GBD causes. In the process, since the AC code was linked only to the top ICD code, the one that was the most prescribed, other diseases for which the drug was also prescribed were excluded from our analysis. Thirdly, other variables besides disease burden and market size that can affect pharmaceutical innovation could not be fully covered in this study due to the difficulties of acquiring relevant data. For example, by considering market concentration and/or degree of competition as other explanatory variables [48], the effects of each variable on pharmaceutical innovation could be investigated in more detail.
