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. 2024 Nov 4;103(1):9–18. doi: 10.2471/BLT.23.291203

Disease foci of pharmaceutical research and development as reflected in applications for International Nonproprietary Names, 1953–2022

Maladies concernées par la recherche et le développement pharmaceutique d'après les demandes de Dénominations Communes Internationales, 1953–2022

Enfermedades objeto de investigación y desarrollo farmacéutico según las solicitudes de Denominaciones Comunes Internacionales, 1953-2022

البؤر المرضية في البحث والتطوير الدوائي كما تعكسها طلبات الحصول على الأسماء الدولية غير مسجلة الملكية، 1953 إلى 2022

1953-2022 年国际非专利名称申请中反映的药物研发相关疾病焦点

Очаги заболеваний, по которым велись фармацевтические исследования и разработки, отраженные в заявках на международные непатентованные наименования, 1953–2022 гг.

Sarel F Malan a,✉, Sophie AJ Lasseur a, Antonio Romeo a, Raffaella Balocco a
PMCID: PMC11704642  PMID: 39780999

Abstract

Objective

To evaluate trends in pharmaceutical research and development, and to correlate these trends with global medical need.

Methods

We obtained details of proposed pharmaceutical substances from 1953 to 2022 from the International Nonproprietary Names (INN) database. We used the DrugBank and Cortellis databases to obtain the INN included in approved medicines over the same period. To evaluate trends, we categorized INN into 12 therapeutic classes according to their stem classification, and compared these trends with actual global medical need by extracting the INN in medicines included in essential medicines lists.

Findings

Out of a total of 10 611 proposed INN within our 12 therapeutic groups, 2280 were included in approved or registered medicines. We observed a considerable decrease in the number of new INN for anti-infective and antiparasitic, central nervous system and cardiovascular system medicines over the study period. In contrast, the number of new substances in the fields of antineoplastic, immunomodulatory, blood and haemopoietic system, and cell and gene therapy medicines has been increasing. In terms of public health impact, only 17.3% (441/11 453) of all INN in approved medicines are included in the World Health Organization Model list of essential medicines, the highest proportion of which are anti-infective and antiparasitic medicines.

Conclusion

Despite a high demand from global health systems, medicine development for neglected tropical and other infectious diseases remains largely dependent on national policy, governmental and philanthropic funding, and partnerships. Better alignment of research and development strategy and investment in global medical needs is required.

Introduction

Neglected diseases, especially neglected tropical diseases, are prevalent in countries and communities that can least afford health care, leading to the restricted development and availability of medicines in these fields. Between 1975 and 2004, only 21 of 1556 approved medicines were for neglected tropical diseases, malaria or tuberculosis.1,2 From 2000 to 2011, 37 of the 850 new products to market targeted neglected diseases, comprising 25 products with a new indication or formulation, eight vaccines and only four new chemical entities. Of a total of 1 523 259 disability-adjusted life years counted during this period, neglected diseases accounted for 10.5% (159 976) (malaria and tuberculosis accounting for 33 976 and 34 217, respectively, or 2.2% each), with other infectious and parasitic diseases accounting for 11.9% (181 441).3 The limited development in this field is often attributed to the unfavourable cost-to-risk ratio in drug research and development, leading to the abandonment of potentially effective medicines for economic reasons.4 Oral eflornithine for sleeping sickness is an example of a drug that would currently be unavailable if not for specific initiatives and campaigns in the 1990s.5,6

Despite progress in treating the 20 neglected tropical diseases or disease groups listed by the World Health Organization (WHO), 1.65 billion people still required treatment for these diseases in 2021.7 The most prevalent of these diseases are soil-transmitted helminth infections, lymphatic filariasis, schistosomiasis, scabies, leishmaniasis, Chagas disease and dengue.8 Protozoan and helminthic parasites cause more than 50% of neglected tropical diseases, followed in number by bacterial, viral and fungal infections;9 however, the treatment of many of these diseases is based on medicines approved decades ago.10

Antimicrobial resistance is fast becoming a global challenge that could cause 2.4 million deaths by 2050.11,12 Fungal infections, responsible for an estimated 1.5 million deaths annually, remain neglected.13–15 Amphotericin B, a polyene that was developed in the 1950s, remains the preferred treatment for cryptococcal meningitis and mycosis.16

In addition to the above-mentioned diseases, noncommunicable diseases have surged in low- and middle-income countries. Noncommunicable diseases account for 17 million premature global deaths in those younger than 70 years; most of these deaths occur in low- and middle-income countries.17 However, these diseases have received minimal attention and only a small share of international health aid.18

Despite these challenges, several successes are evident as a result of the global drive to address unmet medical need.19 These include the development of the human papillomavirus vaccine, treatments for melanoma and hepatitis C, and the rapid deployment of messenger RNA technology for coronavirus disease vaccines.20

In this paper, we used the International Nonproprietary Name (INN) database, coordinated by WHO since 1953, as a proxy for drug research and development trends in specific therapeutic areas over the past seven decades. Because an INN is required by regulatory authorities before an application for registration of a drug can commence, INN applications for new pharmaceutical substances are typically submitted during phase I or early phase II clinical trials in the drug development pipeline (Fig. 1).21 Each INN is allocated following a systematic process and contains a stem (mostly a suffix) and a fantasy prefix. Stems are defined based on mechanism of action as submitted by the applicant or, in some cases, structural features, and each stem is included under a specific stem classification according to general pharmacological classes.22–24 In this paper, we aim to evaluate and correlate trends in pharmaceutical research and development with global medical need, as determined from essential medicines lists reflecting global and regional disease burden.

Fig. 1.

Drug development pipeline, depicting the various stages with approximate time and number of candidates involved

INN: International Nonproprietary Name.

Notes: the cumulative time from development to approval and possible inclusion in an essential medicines list is at least 12–15 years. New INN application typically occurs during phase I or early in phase II.

Fig. 1

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Methods

We obtained information on all proposed INN, from inception of the programme until the end of 2022 (up to and including WHO INN proposed list 128),25 from the INN integrated data management system database, including: list number and year; anatomical therapeutic classification (if available); WHO stem classification (e.g. S520 equates to antimycobacterials and H400 to antihyperlipidaemic drugs); and a mechanism of action and use statement.24 We combined the selected WHO stem classes into 12 groups for evaluation, namely: analgesic and anti-inflammatory; central nervous system (not classified as analgesic); anti-infective and antiparasitic; antineoplastic; immunomodulatory (not specifically indicated for cancer); cardiovascular; blood and haemopoietic system; respiratory and anti-allergy; gastrointestinal and urinary tract; metabolism, and water and mineral homeostasis; hormones; and cell and gene therapy (when not included in any of the previous groups).

We searched the DrugBank database and the Cortellis Partner Program on Clarivate Web of Science for products that have been registered, approved or launched (referred to throughout as approved) since 1953.26,27

We used the 22nd WHO Model list of essential medicines (2021)28 to obtain a primary list of INN in approved medicines that are included in essential medicines lists. We also obtained a combined list of approved medicines from the 2017 WHO model list and the essential medicines lists or national formularies of 137 countries (referred to throughout as the global list) from a published article,29 from which we derived information on global and country-specific essential medicines.

We conducted a technical check of all names obtained from external sources, and corrected INN for spelling, the addition or deletion of salt forms, and the use of national or common names instead of the appropriate INN; for example, we changed mesalamine to mesalazine and tifomycin to chloramphenicol. For the essential medicines list, we obtained the anatomical therapeutic chemical classification (of which there are 14 at the first level) from the 2023 index when included;30 when this classification code was not available, we deduced one according to the guidelines30 up to the second or third level to enable evaluation and comparisons in the essential medicines list data set.

We transferred all data to Access (Microsoft Corporation, Redmond, United States of America) and categorized them into our 12 main therapeutic groups of interest according to the INN stem classification.24,25 We sorted the essential medicines list and global list data according to the 14 anatomical therapeutic chemical classification main groups (where available) as well as the INN stem classification groups. In all data sets, we grouped the proposed INN within the seven decades from 1953 to 2022.

Results

Proposed INN and INN in approved medicines

We obtained 11 453 unique proposed INN, with anatomical therapeutic chemical classification available for 2897.24 The number of pharmaceutical substances proposed per decade ranged from 968 in 1953–1962 to 2642 in 2013–2022 (Fig. 2). The total data set for the 12 selected therapeutic groups included 10 611 proposed INN, with the other 842 INN comprising miscellaneous compounds such as excipients, detergents, diagnostic aids, sunscreens, chelating agents and detoxicants. Central nervous system (16.9%; 1790), antineoplastic (16.7%; 1773), anti-infective and antiparasitic (15.0%; 1592) and cardiovascular (12.4%; 1312) compounds comprised 60.9% (6467) of the 10 611 INN included.

Fig. 2.

The number of INN proposed between 1953 and 2022

INN: International Nonproprietary Name.

Fig. 2

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Clear trends in drug development and discovery are evident (Fig. 3). In the first three decades, central nervous system, anti-infective and antiparasitic, cardiovascular, and analgesic and anti-inflammatory substances featured prominently, comprising 71.8% (3032/4223) of all proposed INN. Central nervous system (29.8%; 288/968) and anti-infective and antiparasitic (23.5%; 227/968) substances represented the highest proportions in the first decade of the INN Programme, while cardiovascular substances grew in prominence to a high of 22.0% (685/3116) during 1973–1992. However, this picture changed substantially in the decades that followed: of the total number of INN proposed during 2013–2022, these four groups comprised only 23.5% (620/2642) while antineoplastic and immunomodulatory substances comprised 56.3% (1485/2640).

Fig. 3.

The changing composition of proposed INN as obtained from its integrated database, in 12 categories based on the INN stem classification, 1953–2022

INN: International Nonproprietary Name.

Fig. 3

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INN proposed for substances affecting metabolism and water and mineral homeostasis remained relatively constant throughout the study period; 34.8% (230/660) of the substances in this group were indicated for carbohydrate metabolism.

In the last decade of study (2013–2022), monoclonal antibodies (mAbs) and kinase inhibitors comprised at least 62.3% (650/1044) of INN proposed in the field of antineoplastic drug development, comprising 292 naked mAbs, 83 mAb-conjugates and 275 kinase inhibitor new INN.

From the DrugBank and Cortellis databases, we found 2343 and 1235 unique INN in approved medicines, respectively.26,27 We combined these results and eliminated duplicates to yield 2549 unique INN, 2280 of which were included in our selected therapeutic groups over the study period (Fig. 4).26,27 Amongst others, we observed a reduction in the numbers of INN for central nervous system and cardiovascular medicines during the past decades.

Fig. 4.

The changing composition of INN of pharmaceutical substances included in registered or approved medicinal products, in 12 categories based on the INN stem classification, 1953–2022

INN: International Nonproprietary Name.

Fig. 4

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Essential medicines

The 22nd WHO model list28 contained 555 individual items, with 441 of these having a unique INN. Vaccines and other immunological agents (31) are included among the 114 medicinal substances on the list for which there was no INN. The global list contained 2060 individual items, 1590 of which had a unique INN; 1483 of these 1590 are included within our 12 selected therapeutic groups.29

Fig. 5, depicting the number of INN in approved medicines that are included in the WHO model list and global list for each of the 14 anatomical therapeutic chemical classes, demonstrates a public health need for anti-infective (class J) and antiparasitic (class P) substances. These two classes comprise 30.8% (136/441) of all INN included in the 2021 WHO model list. The inclusion of anti-infective and antiparasitic substances from other classes such as alimentary tract and metabolism (class A), dermatologicals (class D), genito-urinary system and sex hormones (class G) and sensory organs (class S), increases this percentage to 34.2% (151/441). Antineoplastic and immunomodulating agents (class L) included 68 INN (15.4%), of which 45 (10.2%) are included as antineoplastic substances (class L01).

Fig. 5.

Number of INN in approved medicines categorized according to their anatomical therapeutic chemical codes, 1953–2021

INN: International Nonproprietary Name; WHO: World Health Organization.

Notes: for definition of anatomical therapeutic chemical classifications, see Norwegian Institute of Public Health.30 The WHO list is the 2021 WHO Model list of essential medicines, 1953–202128 and the global list is a combined list of national essential medicines lists, 1953–2017.29

Fig. 5

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In terms of public health impact, only 17.3% (441/2549) of all INN included in approved medicines (or 3.9% [441/11 453] of all INN) were included in the 22nd WHO Model list of essential medicines. Based on the INN stem classification, the highest proportion of 34.5% (148/429) is observed for anti-infective and antiparasitic substances, while that for antineoplastic and immunomodulatory substances are 16.7% (47/282) and 11.5% (16/139), respectively (Fig. 6). The proportion of INN in approved medicines included in global lists was 58.2% (1483/2549), with the highest proportions observed for gastrointestinal and urinary tract (88.4%; 61/69), respiratory and anti-allergy (83.3%; 40/48), and anti-infective and antiparasitic substances (78.6%; 337/429). The WHO and global lists included 9 and 27 mAbs, respectively, but it is reasonable to assume that the composition of essential medicines lists will also change in the future to reflect more technologies and pharmaceutical substances developed in recent years.

Fig. 6.

Number of INN included in the 2021 WHO model list of essential medicines and the global list, 1953–2021

INN: International Nonproprietary Name; WHO: World Health Organization.

Notes: the WHO list is the 2021 WHO Model list of essential medicines, 1953–202128 and the global list is a combined list of national essential medicines lists, 1953–2017.29 The curves and right-hand axis provide an indication of the percentages of INN in approved medicines that are included in the respective lists. Numbers and groupings are based on INN stem classification. Only 11 out of 12 of our analysed therapeutic groups are shown because no essential medicines lists included any cell and gene therapy medicines.

Fig. 6

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Discussion

From the late 1960s, applications for new INN were generally published in two separate lists annually, containing between 50 and 482 INN per year. The decrease in annual INN proposed observed in the 1990s and early 2000s could be the result of changes in the research and development environment, including investment and return on investment being linked to the advent of managed care, changes in brand name protection and more rigorous regulatory requirements, market strategies, policy amendments, and global events and politics.31–33 The last decade of study (2013–2022) coincided with a substantial increase in new INN and thus pharmaceutical substances beginning, or progressing through, clinical trials. The benefits of technological developments, especially in the development of biological and biotechnological substances,34,35 as well as the increase in INN application numbers from countries such as China, contributed to this increase.36

The global burden of disease data demonstrate that in 2024 cardiovascular disease and cancers are the main contributors to burden of disease in higher-income countries, and that neonatal disorders, neglected tropical diseases, malaria, tuberculosis and other infectious diseases are the major contributors in lower-income countries.37 Based on the numbers of INN included in the selected therapeutic groups, trends in research and development are not currently aligned with unmet medical need, especially that of lower-income countries.

The decline in new medicines for infectious and neglected tropical diseases is worrying;2–16 the reduction in the development of novel substances in the fields of central nervous system, cardiovascular and respiratory fields is also of concern. Substances acting on the blood and haemopoietic system peaked during the 1990s, while interest in substances acting on metabolism and water and mineral homeostasis increased in the two decades between 2003 and 2022. The first trend can be attributed to developments in the heparin, platelet aggregation and thrombin inhibitor fields. The second trend can be linked to significant development and interest in peroxisome proliferator-activated receptor and glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase IV and sodium glucose co-transporter inhibitors, all of which address carbohydrate metabolism and diabetes.

The research and development trends affect the number of novel substances being registered or approved. Although the proportion of anti-infective and parasitic substances reaching the market seems to have stabilized at 13.6% (92/676) of the total INN during 2003–2022, this was the result of increased numbers of antiviral substances (66). The last antiprotozoal agent approved or registered was pyronaridine (named in 2007) and, before that, tafenoquine and artenimol (named in 1998 and 1999, respectively). No new anthelmintic or antinematode agents have reached the market since moxidectin (INN proposed in 1990), initially indicated for veterinary use and approved for human use and treatment of onchocerciasis (river blindness) in 2018.38

With the time to progress from phase I/II clinical trials to approval reported to be 7–8 years (although eight out of the 24 INN proposed for severe acute respiratory syndrome coronavirus 2 immunization during 2020–2022 reached market by the end of 2022),21,35 the bulk of pharmaceutical substances with INN proposed in the last decade of the study are currently still in the drug development pipeline. A substantial increase in antineoplastic, immunomodulatory and other biological or biotechnological medicines can therefore be expected in the next few years.

In terms of public health impact, less than one fifth of INN were included in the 22nd WHO Model list of essential medicines. The largest group of medicines included is for infective diseases. Comparing lists, the WHO list contained between one tenth (analgesic and anti-inflammatory, and respiratory and anti-allergy) and one half (antineoplastic) of the approved medicines in the global list. Other disease areas where large variations are observed between the lists are the gastrointestinal and urinary tract, cardiovascular, central nervous system (not analgesic) and hormone groups.

The falling numbers of novel anti-infective and antiparasitic substances, especially antifungals, do not address neglected tropical diseases or the growing dilemma of antimicrobial resistance. The outlook for new drugs for noncommunicable diseases is equally poor, as demonstrated by the decline in research and development interest in these fields, the exploitation of well-known therapeutic targets, and the fact that any new developments are focusing on fewer indications for use in the treatment of relatively small populations.39 The relatively successful low-cost treatment of chronic noncommunicable diseases might also have led to a demand for medicines offering only incremental benefits.40

Unmet medical needs and neglected diseases have undoubtedly benefitted from new drug development technology, but novel chemical entities and additional technology remain critical. Partnerships, incentives and innovative initiatives remain of utmost importance as, with the exception of dengue and other viral neglected tropical diseases, no significant developments in this field are evident among the major pharmaceutical companies.8 The environment for development of medicines for neglected diseases remains dependent on product development partnerships such as the Drugs for Neglected Diseases initiative (DNDi),41 Medicines for Malaria, academic laboratories, and investments such as the Bio Ventures for Global Health accelerator. Regulatory incentives such as the priority review voucher and orphan products grant programmes of the United States Food and Drug Administration (FDA) have seen limited success in this field, with only 4.4% (37/850) of new registered products approved (comprising 25 products with new formulations or indications, and 8 vaccine or biological products). Only 1.2% (4/336%) of new medicines approved for neglected diseases between 2000 and 2011 contained new chemical entities.42 Initiatives such as Generating Antibiotic Incentives Now have also been ineffective in meeting the need for new chemical entities with antimicrobial actvity.43

However, although limited on the macroscale, studies indicate that 2.4 billion people have benefitted from more than 60 new health technologies introduced by product development partnerships.44 Two examples of successful neglected tropical disease initiatives are (i) the 2018 FDA approval of moxidectin for onchocerciasis (river blindness) via a collaboration between Medicines Development for Global Health (who received a priority review voucher), WHO Special Programme for Research and Training in Tropical Diseases, Medicines for Malaria Venture and GlaxoSmithKline;45 and (ii) the development of tafenoquine for Plasmodium vivax by GlaxoSmithKline (who received a priority review voucher) in collaboration with Medicines for Malaria Venture.38 Although INN for these substances date from 1989 and 1998, respectively, the collaborations and priority review vouchers contributed to getting these medicines to market. Another example is fexinidazole, the INN of which was proposed in 1977. Although initially developed as a broad-spectrum antimicrobial, fexinidazole is now approved for African trypanosomiasis and included on the WHO Model list of essential medicines as a result of the DNDi and Sanofi collaboration.46

The repurposing of existing substances has also been shown to be an effective approach to treating neglected tropical diseases. Pertinent examples include: miltefosine, an antineoplastic substance from the 1980s, now approved for the treatment of visceral leishmaniasis;47 amphotericin B, used for treating fungal infections since the 1960s and now also in the treatment of leishmaniasis;48 and eflornithine, developed as an antineoplastic and approved in 1990 for the treatment of African trypanosomiasis.49

A limitation of our study is that the INN stem classification is based on the mechanism or mode of action as submitted by the applicant for an INN; in some instances, the final therapeutic application, or even the proposed mode of action, could change during the development process or as a result of the substance being repurposed at a later stage. Classification by anatomical therapeutic chemical code is only available for medicines marketed in regions where this is a requirement. It would therefore be beneficial if a method of harmonizing the INN Programme and anatomic therapeutic classification could be realized.

Our study has highlighted that, despite various initiatives to address neglected diseases and multiple programmes focusing on antimicrobial resistance and stewardship, there has been no significant growth in drug discovery and development in these fields over the past few decades. This absence of important new medicines, combined with a decrease in novel therapies for high-incidence noncommunicable diseases, indicates that current and probable future global needs are not being met. We conclude that research and development strategies and investments require better alignment with global medical needs.

Acknowledgements

SM is also affiliated with University of the Western Cape, Cape Town, South Africa.

Competing interests:

None declared.

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