Scientific capabilities of a high-tech industry:

Scientific capabilities of a high-tech industry:

Andrea Sánchez Licer

The case of the Spanish pharmaceutical sector

Advisor: Bruno Miguel Pinto Damásio, PhD.

Co-advisor: Vanda Vieira Vicente, PharmD, MSc.

November 2022

NOVA Information Management School

Instituto Superior de Estatística e Gestão de Informação Universidade Nova de Lisboa

SCIENTIFIC CAPABILITIES OF A HIGH-TECH INDUSTRY:

THE CASE OF THE SPANISH PHARMACEUTICAL SECTOR

by

Andrea Sánchez Licer

Dissertation presented as partial requirement for obtaining the master’s degree in Information Management, specialization in Knowledge Management and Business Intelligence

Advisor: Bruno Miguel Pinto Damásio, PhD.

Co-Advisor: Vanda Vieira Vicente, PharmD, MSc.

November 2022

ABSTRACT

The purpose of this thesis is to provide an exhaustive map of Spanish pharmaceutical companies publishing in terms of the proportion and growth of publishing over time, publications impact (citations), and companies’ collaboration with academic institutions (co-authorship). Using Web of Science (WoS) database, the scope of analysis was delimited to scientific publications by pharmaceutical companies headquartered in Spain without limiting a time range.

The premise that leads to this investigation is that the Spanish pharmaceutical industry is in the top 10 worldwide in terms of market share with 26.3 billion dollars in sales in 2020, ranking in eighth position.

The sector invests highly in R&D and almost 20% of the total industrial R&D in Spain is developed by the pharmaceutical industry.

We were able to define some patterns of publication among the 8 Spanish companies considered. Out of the 2,739 publications, PharmaMar is, by far, the company which has published the most (38%), followed by Almirall (35%). Most of the collaborations were with national universities and the majority of the most productive and influential authors were also affiliated to PharmaMar.

In what concerns to quantity and quality, the total publication growth between 1974-2012, the continued citation growth until 2021, the noticeable quantity of the publications by PharmaMar and the consequent of their citation impact should be highlighted.

KEYWORDS

Spanish Pharmaceutical Industry; Scientific Publications; Bibliometrics; R&D; Drug Development;

Scientific Capabilities; Innovation

INDEX

1. Introduction ... 1

1.1. Background and problem identification ... 1

1.2. Study objectives... 2

2. Literature review ... 3

2.1. R&D in the pharmaceutical field ... 3

2.2. Pharmaceutical industry: The case of Europe ... 6

2.2. Spanish pharmaceutical industry: Study relevance and importance ... 6

3. Object of Analysis ... 8

4. Methodology ... 13

4.1. Data Collection ... 13

4.2. Data Analysis Techniques ... 14

5. Data Analysis ... 16

5.1. Introduction ... 16

5.2. Selected Spanish Pharmaceutical Companies Publications ... 16

5.2.1. Scientific Publications Trend ... 16

5.2.2. Affiliation ... 18

5.2.3. Journals ... 18

5.2.4. Authors ... 21

5.2.5. Top Papers ... 22

5.2.6. Authors‘ Keyword Analysis ... 24

5.2.7. Content Mapping ... 26

5.2.8. Geography of Authorship ... 27

5.2.9. Collaboration Network ... 28

6. Conclusions and Limitations ... 30

7. Bibliography ... 32

8. Appendix ... 35

LIST OF FIGURES

Figure 1 - R&D intensity by industry ………..3

Figure 2 - Ranking of the 15 pharmaceutical laboratories with the best corporate reputation in Spain in 2020 ……… 11

Figure 3 - Venn Diagram with firm selection criteria ………. 12

Figure 4 - Data collection procedures in WoS ……….14

Figure 5 - Research items published ………. 17

Figure 6 - Average Citations of the publications by the selected Spanish pharmaceutical companies ……… 17

Figure 7 - Percentage of the total number of publications by each of the selected Spanish pharmaceutical companies ……….. 18

Figure 8 - Top 20 journals by number of total articles published ……… 19

Figure 9 - Top 20 journals local impact by H-index ………. 20

Figure 10 - Top 20 journals local impact by M-index ………. 21

Figure 11 - Author’s Words Co-occurrence Map ………..27

Figure 12 - Geography of authorship ……… 28

Figure 13 - Institutions Collaboration Network ………. 29

LIST OF TABLES

Table 1 - Spanish pharmaceutical companies’ sales data ………. 9

Table 2 - Spanish pharmaceutical companies’ R&D investment ………...10

Table 3 - Top 15 authors by articles and citations ………22

Table 4 - Details of the top 20 papers ………..23/24

Table 5 - Author’s Keywords Word Cloud ………. 25

Table 6 - Growth of Top 20 Author’s Words ……… 26

LIST OF ABBREVIATIONS AND ACRONYMS

AI Artificial Intelligence

FDA Food and Drug Administration IRR Internal Rate of Return

OECD Organization for Economic Co-operation and Development R&D Research and Development

RWE Real-world Evidence WoS Web of Science

1. INTRODUCTION

1.1. B

In recent years, scientific research has grown to the point where it becomes necessary to develop and implement several indicators to assess its importance for the scientific community. Considering the overwhelming volume of new information and data, bibliometric studies are becoming increasingly important in providing structured analysis to an extensive body of information and presenting the big picture of research.

In this regard, compared to other science-based industries, the pharmaceutical sector might have higher incentives to publish, due to the highly regulated nature of drug development and the importance of clinical evidence in influencing user acceptance of innovations, among other reasons that will be analyzed below. In a multi-sectoral paper (Camerani et al., 2018), it was stated that two of the top three most active firms in the world in terms of number of publications are two large pharmaceutical firms: Roche Holding AG and Pfizer Inc.

Consequently, pharmaceutical companies use publications as a means of information dissemination that must be carefully designed to achieve a greater impact on the community and stakeholders, such as prescribers, investors, or regulatory agencies. The quality of the journal where the studies are published is decisive in the impression the doctors will have of the quality of the drug (Smith, 2005).

They use scientific publications to support two critical aspects of the commercialization process of drugs and related products. On one hand, scientific publications could be helpful in obtaining approval from regulatory agencies. A close link exists between the use of publications to support the approval and commercialization of pharmaceutical products (Camerani et al., 2018). Evidence has shown that publishing is part of the drug lifecycle, between 1999 and 2004, according to Sternitzke (Sternitzke, 2010), each new molecular entity approved by the Food and Drug Administration (FDA) was accompanied by an average of 19 publications and 23 patents, and pharmaceutical firms used these strategies to obtain drug approval, boost commercialization, and influence pricing. Regarding the latter, price regulation of new drugs is lax. Some of the factors besides the development costs that companies take into consideration when pricing their drugs are a combination of the novelty of the drug, its effectiveness, its impact on patients’ lives and the competition from other companies (Hawley, 2022). The objective is to influence reimbursement once a drug has been approved (not including Generics). In Spain, at that stage, drugs go through a health and technology assessment process where reimbursement of the drug by Spain´s Autonomous Regions is discussed and only those

meeting certain criteria are reimbursed (Faus et al., 2022). This process will be explained in more detail in the next section.

On the other hand, advertising the effectiveness and safety of a drug to doctors and hospitals could stimulate the diffusion of that drug as well as increase the company´s reputation. It works particularly well if a company submits articles to prestigious journals: these journals are more likely to be considered credible by physicians than the firm's marketing and promotional materials (Camerani et al., 2018). The prestige these companies obtain can be relevant to increase the market value of the public traded companies; to attract new business opportunities, as the higher visibility might facilitate new collaborations; or to attract talent.

1.2. S

The main objective of this dissertation is to investigate the scientific capabilities of the Spanish pharmaceutical industry in terms of number of publications, citations, and co-authorships. The empirical material will allow us to address several questions, like: How has the volume of scientific publications by Spanish pharmaceutical companies evolved? Which players are leading and what is their impact? As a means of achieving this objective, we will appeal Web of Science database for the purposes of surveying the data without a delimited time range.

The reminder of this article is structured as follows. Section 2 focus on the theoretical review of R&D investments within the sector, the Spanish pharmaceutical industry evolution, and the particular relevance of publishing within this field. Section 3 explains the criteria selection to determine the object of analysis. Section 4 articulates the bibliometrics approach and the methodology used with Web of Science database to identify and analyze the scientific publications by pharmaceutical companies headquartered in Spain. Section 5 presents the analysis and discussion of the bibliometric data together with the findings. Finally, Section 6 concludes, presenting also some limitations.

2. LITERATURE REVIEW 2.1. R&D

The pharmaceutical sector invests highly on R&D. Looking at the eighteen Organization for Economic Co-operation and Development (OECD) countries, the pharmaceutical industry expenditure on R&D increased by 14% between 2010 and 2016. On average this sector spent almost 12% of its gross value added on R&D in the OECD countries, being the third sector after electronic and optical products, and air and spacecraft with the highest R&D intensity (Figure 1) (OECD, 2019).

Figure 1- R&D intensity by industry Source: OECD, 2019 Belgium

Japan United States

16.6 14.6 OECD

Average 11.6

4.7

0.9 0.8 0.4 0.3 0.2

0 10 20 30 40 50

Electronic & optical products Air & spacecraft Pharmaceuticals Total manufacturing Mining & quarrying Total services Utilities Agriculture, forestry & fishing Construction

% BERD / GVA

Industry

R&D intensity by industry

Country Australia Austria Belgium Canada Chile Czech Republic Denmark Estonia Finland France Germany Greece Hungary Italy Iceland Ireland Israel Japan Korea Lithuania Mexico Netherlands New Zealand Norway Poland Portugal Slovak Republic Slovenia Spain Sweden Switzerland Turkey United Kingdom United States OECD Average Note: R&D intensity measured by the Business Enterprise R&D Expenditure (BERD) as a proportion of

Gross Value Added (GVA) for 2014 or the nearest year.

Pharmaceutical companies R&D expenditure is influenced by three principal factors: the expected return on investment, i.e., the projected revenues from commercially exploiting the new drug; the costs of developing that drug; and prescription drug policies and programs that impact its supply and demand (CBO, 2021).

Estimating a drug's revenue stream is a forecasting exercise. Companies consider factors such as the likely sell price of the drug in different markets around the world, and the expected market penetration, meaning the number of people that might use the drug. On the other hand, developing new drugs is uncertain, expensive, and lengthy. Additionally, many potential new drugs are never approved or commercialized. Approximately 12% of drugs that enter clinical trials are eventually approved for marketing by the FDA. In Europe, in 2021, the European Committee for Medicinal Products for Human Use (CHMP) issued five negative opinions on new medicines and recommended ninety-one medicines for approval (European Medicines Agency, 2021). The estimated R&D cost per new drug ranges from near $1 billion to more than $2 billion. During the course of drug development, which can take 10 years or more, companies do not perceive a financial return on the investment.

Additionally, R&D costs are expected to keep rising due to the increasing complexity of development and longer cycle times (Deloitte, 2021). Lastly, federal policies have the capacity to affect supply and demand of drugs, for instance, with recommendations for specific treatment or subsidizing the purchase of a prescription drug (reimbursement) (CBO, 2021).

It is worth making a distinction between three different product types commercialized by pharmaceutical companies, as they all will be considered in this paper: the ones that are the innovative and original drugs (the reference medicine), generic products which are manufactured to be bioequivalents to the reference medicine, and biosimilar products which are developed to be highly similar to the reference product (Medicines for Europe, 2016b, 2016a).

Generics and biosimilars are both advertised as more affordable equivalents of pricey name-brand medications. When the drug industry's exclusive patents expire, both can be accessible in the market.

Additionally, both are intended to work clinically in a similar way to their reference medicines.

However, generic medications are equal to the original in terms of chemical composition, whereas biosimilar medications are very similar, but sufficiently comparable to the original to provide the same therapeutic and clinical result as they contain significant amounts of living organisms that involve large and complex molecules (CTCA, 2018). Companies that produce generics are also relevant to this study as they need to invest in R&D as well, as the full recipe of the reference medicine is not fully disclose, thus, they still need scientists to develop this new product or try to build up another drugs around

existing patents to be able to commercialize the product before the reference medicine’s patent expires.

In terms of R&D growth, biomedical innovation ability to develop and gain regulatory approval for new drugs has increased doubling the number of products launched globally in 2021 compared to 5 years earlier with 84 new therapies (IQVIA Institute, 2022). The total number of products which are in development world-wide overpasses 6,000, 68% higher than in 2016, and although the COVID-19 pandemic disrupted the life sciences sector, innovations in therapeutics and vaccines continue to be developed.

On the contrary, in a study from 1995-2009 (Rafols et al., 2014), showed that the number of publications per annum was decreasing by a 0.8% rate, which contrasted with the increase in R&D expenditure, with an annual growth rate of 1.1.%. Notwithstanding, the study differentiated publications by “core firms”, i.e., publications by R&D laboratories of the main firm before the merger, and “acquired firms”, i.e., publications by acquired firms. It was observed that publications by core firms were increasing, unlike publications by the acquired companies. This differentiation took place due to the trend of large pharmaceutical companies to increasingly leapfrog R&D to external organizations by acquiring smaller firms’ technology. The results proved to increase efficiency, but the internal rate of return (IRR) has been decreasing until 2020, when it experienced an uptick of 0.9%

compared to 2019 (Deloitte, 2021). However, the 2.5% IRR from 2020 is still lower than in 2013 (3.9%).

The analysis also confirmed that the trend towards longer clinical cycle times (from the start of Phase I to fulfillment of Phase III) still prevails. The reason for this has been the increasing complexity of drug development; a growing level of competition to enroll participants for clinical trials and a difficulty in retaining them; and the complication of data capture, collection, and management to comply with regulations.

Over the last three years, partly driven by the COVID-19 pandemic, we observed the accelerated adoption of innovative drug development technologies by companies, such as digital tools; and the adoption of exceptional policies by regulatory bodies for shortening drug approval time. While the latter is unknown whether it will prevail in time, the former certainly will. Digital transformation is a big focus of companies nowadays, and pharmaceutical companies are starting to integrate artificial intelligence (AI) and digital technologies into drug discovery and development to streamline clinical trial processes. The use of transformative approaches to drug development such as master protocols, adaptive trial designs, enhanced segmentation of patients and diseases, and real-world evidence (RWE) is gaining momentum; however, scaling them up will be imperative to reduce development cycle times and bring new medicines to the shelves of pharmacies and hospitals faster.

Consequently, the prediction is that these new technologies and methodologies will overturn the IRR decline and foster a new future for R&D.

2.2.P

: T

E

Europe is the second largest pharmaceutical market after the US in terms of sales of new drugs launched between 2015 and 2020, with 17.4% of world-wide sales (EFPIA, 2021). This industry is the sector that invests the most in research and development in Europe. This is according to the report

"The pharmaceutical industry in figures", published by the European industry's employers' association (EFPIA, 2021). As the publication indicates, the European industry invested 39 billion euros in R&D in 2020. In fact, the sector contributes to 15.4% of the R&D investments made to the region, followed only by the IT and software sector, which accounts for 11.8% of investments across Europe.

In this regard, the report recalls that it takes an average of 12 to 13 years for a drug to reach the market, with an estimated cost per molecule of 1,926 million euros. In addition, they point out that on average only one or two molecules out of every 10,000 successfully pass all the development stages required to become a marketable drug. Nevertheless, the pharmaceutical industry is also a benchmark sector in terms of employment, providing 830,000 direct jobs throughout the EU, 125,000 of which are in R&D. In terms of production, the European pharmaceutical industry generates 310 billion euros.

Meanwhile, exports account for 515 billion euros.

However, the report also points out that Europe is facing higher competition as emerging economies are experiencing an accelerated growth and a higher investment in R&D activities, leading to a shift towards non-European markets of the R&D base.

2.2. S

: S

The health crisis caused by COVID-19 has illustrated the relevance of having sectors able to adapt rapidly and with the productive capacity to react to a health emergency. This situation has highlighted how closely economy, and health are intertwined and how this sector in general and the pharmaceutical sector have become strategic for the economic recovery that Spain is facing. The latter is a major driver of a country's economy, thanks to the high added value it produces, the generation of highly qualified jobs and the high level of investment in research and development made by

companies to offer increasingly effective treatments that improve patients' life expectancy and quality of life (elEconomista, 2021).

Spain is in the top 10 pharmaceutical markets worldwide in terms of market share with 26.3 billion dollars in sales in 2020, ranking in eighth position (Mikulic, 2022). Regarding jobs and sales, this industry in Spain is the fourth largest in Europe, preceded by Germany, France, Italy, and Switzerland (EFPIA, 2021). It generates approximately 40,000 direct jobs in Spain, 59% of them being university- educated professionals. It is the sector with the highest number of jobs in high technology (58% of the total) (Farmaindustria, 2020b).

A significant portion of Spanish industry's total investment in R&D is attributed to this sector: “Almost 20% of the total industrial R&D in our country is developed by the pharmaceutical industry. One of every five euros that are invested in research in Spain come from this sector. This represents almost 8% of all R&D investment considering public and private research.” said the deputy director of Farmaindustria, Javier Urzay (Farmaindustria, 2020b).

Spain also maintains a leading position in high-tech production and exports, accounting for almost 23%

of the total of Spanish high-tech exports and produces 15,000 million euros and exports 12,100 million euros, a historic figure reached in 2019 (elEconomista, 2021).

Companies spent more than 1.2 billion euros on R&D in Spain in 2019, a historical record, according to data published by Farmaindustria in its survey on R&D activities (Farmaindustria, 2020a). This figure represents an increase of 5.2% over the one recorded in 2018. In addition, in the last decade the weight of research projects developed in partnership with hospitals and public and private entities has grown 3.6%, equaling 43.6% of total investment, putting up to 528 million euros in 2019, compared to 683 million euros devoted to internal research (Farmaindustria, 2020b).

3. OBJECT OF ANALYSIS

In order to define the object of analysis, criteria have been applied. Spanish pharmaceutical companies have been scrutinized and selected according to their sales, growth rate, whether they are publicly listed, their R&D investment and corporate reputation. Each criterion is analyzed separately, and then combined to obtain the final list of companies’ objects of analysis.

Firstly, the list of pharmaceutical companies operating in Spain was obtained from combining the list of Farmaindustria sales data and IQVIA own research, a databased recognized globally with highly reliable sales data, to identify the pharmaceutical companies headquartered in Spain and publicly listed. The list includes sales data for Moving Annual Total (MAT) Q1, that is between March 2020 and March 2021. Besides Spanish laboratories, this list also includes the markets of Italy, France, UK and Germany. For this reason, an analysis of all the companies was performed to select the laboratories headquartered in Spain. Companies operating in Spain but headquartered in a different country will not be considered in this analysis. For the purposes of this study, the list of the top 25 Spanish companies ordered by sales from higher to lower can be observed in the following table.

SALES IN SPAIN (M€) SALES GROWTH SALES WEIGHT PUBLICLY LISTED

NORMON 392.1€ 7.6% 1.7%

INFARCO 385.6€ 4.5% 1.7%

KERN PHARMA 374.7€ 0.8% 1.6%

ROVI 296.4€ 3.4% 1.3% Yes

GRIFOLS 256.0€ -2.4% 1.1% Yes

ALMIRALL 247.2€ -4.7% 1.1% Yes

ESTEVE 211.8€ -5.1% 0.9%

FERRER 179.8€ -4.1% 0.8%

FAES FARMA 142.3€ 3.3% 0.6% Yes

REIG JOFRE 75.5€ -7.6% 0.3% Yes

LABORATORIO ALDO- UNIÓN

53.1€ - 21.4% 0.2%

SALES IN SPAIN (M€) SALES GROWTH SALES WEIGHT PUBLICLY LISTED

LABORATORIOS RUBIÓ

51.9€ 0.2% 0.2%

INSUD PHARMA 23.4€ 13.9% 0.1%

CANTABRIA LABS 22.9€ 9.4% 0.1%

GRUPO URIACH 20.8€ -19.5% 0.1%

PHARMA MAR 18.1€ -1.7% 0.1% Yes

MABO FARMA 15.7€ -3.4% 0.1%

ISDIN 12.8€ -6.5% 0.1%

GP PHARM 12.7€ 7.3% 0.1%

LABORATORIOS VIÑAS

12.6€ -6.4% 0.1%

LAINCO 8.5€ -5.4% 0.0%

FARMASIERRA 8.2€ -10.9% 0.0%

SEID LAB 7.7€ -3.5% 0.0%

UXAFARMA 6.7€ -54.1% 0.0%

MELYFARMA 4.2€ 118.7% 0.0%

Table 1– Spanish pharmaceutical companies’ sales data Source: Farmaindustria and IQVIA

The companies marked in bold were selected due to their sales, growth rate or the fact that they are publicly listed to study their R&D investment. From the top 15 in terms of sales, the ones that have not been selected are due to a decrease in their growth rate of more than 15%.

The next step involved evaluating the R&D investment. The first quarter of 2020 was compared to the one of 2021 to study R&D investment growth as well as the total percentage spent on R&D over

Note: In bold, the selection of the companies based on sales data in the Spanish market. In red, the reason why some of the companies were rejected despite high sales and/or sales growth. In green, the reason why some companies were selected despite not having a high sale and/or sales growth in comparison to other rejected firms.

revenues by each company. This quarter was chosen after studying the different reports published by each company, as it is the most recent period for which we have more information for most of the previously selected companies. Information regarding R&D investment was found for the following companies (see Table 2). This information has been obtained from the companies own financial reports in their respective websites.

2021 R&D expenses (descending)

Growth Net Revenue 2021 Revenue Growth vs 2020

Rate of R&D spending over Revenues in 2021

GRIFOLS 354.8€ million 20.6% 4,933€ million (7.6%) 7.2%

ALMIRALL 73.6€ million (6.7%) 836.5€ million 2.7% 8.8%

PHARMA MAR 72.2€ million 34% 92.8€ million (32.3%) 77.8%

FAES FARMA 27€ million 73% 83.2€ million 14.6% 32.4%

ROVI 24.7€ million 15% 650€ million 54% 3.8%

REIG JOFRE 3.6€ million (7.7%) 5.1€ million (9.9%) 70%

TOTAL 555.9€ million Average 33.3%

Table 2 – Spanish pharmaceutical companies’ R&D investment Source: companies own financial reports for 2021

Even though two companies lowered their R&D investment for the analyzed period, Reig Jofre and Almirall, the former has one of the highest percentages of R&D expenses over revenues in absolute numbers. In relative numbers, Grifols has the highest R&D expenses. Reig Jofre will be excluded because of its relative low investment in R&D and decrease in growth and revenue year over year. Rovi will be excluded due to its low rate of R&D spending over revenues. Therefore, we will select Grifols, Almirall, PharmaMar and Faes Farma due to their relative high R&D expenses, and particularly

Note: The revenues reported by the companies in their reports is not matching the IQVIA sales data in previous table. This is expected, as the revenues reported by the companies are worldwide revenues, while data from IQVIA is only for Spain.

The last criterion involves analyzing the corporate reputation. Only three pharmaceutical companies headquartered in Spain appear among the top 15 pharmaceutical laboratories with the highest corporate reputation: Almirall, Rovi and Esteve (Statista, 2021).

Figure 2 - Ranking of the 15 pharmaceutical laboratories with the best corporate reputation in Spain in 2020 Source: Statista, 2021. Data collected in an online survey in Spain in 2020.

After evaluating each criterion separately, a Venn diagram was designed to better visualize and select the final firm sample (Figure 3). Almirall is the only pharmaceutical company that complies with all four criteria. In order to select the top ten companies for this study’s sample, the companies that meet two or more criteria have also been selected (PharmaMar, Grifols, Faes Farma, Reig Jofre, Rovi, and Esteve).

To complete the set of 10 companies, the last three companies to be chosen are the ones with the highest sales revenue (Normon, Infarco and Kern Pharma).

Figure 3 – Venn Diagram with firm selection criteria Source: Own Compilation

Finally, the selection of the ten Spanish pharmaceutical firms is achieved: Almirall, Esteve, Rovi, PharmaMar, Grifols, Reig Jofre, Faes Farma, Normon, Infarco, and Kern Pharma.

Note: after analyzing the four different criteria in the previous figures and tables, the companies that meet at least two criteria were chosen. Only seven companies met at least two criteria, so to complete the final selection of ten firms, the three companies with highest sales and sales growth were also chosen (Normon, Infarco and Kern Pharma). Sales and Sales Growth data is for Spain only.

4. METHODOLOGY 4.1.D

C

In this chapter, we will address the process to identify the scientific publications authored by researchers based at the firms in the above-mentioned sample. This empirical strategy involves several steps described below.

Nowadays, the most frequently used sources for bibliometric data are Web of Science (WoS) and Scopus (Pranckutė, 2021). Each platform provides a web interface with basic and advanced search options and analytical tools. Using 2006 data, a study (Gavel & Iselid, 2008) analyzed the overlap between Scopus and WoS journal coverage and found that 54% of titles in Scopus were also in WoS, while 84% of titles in WoS were also indexed in Scopus. In another study (Archambault et al., 2009), a wide correlation between country citations and papers analyzed with WoS and Scopus was proved, suggesting both databases are important for scientometric analyses. Both databases are internationally recognized, but for this study WoS will be the primarily data source due to its coverage and large amount of data.

For data collection, scientific publications have been collected, filtering the search in WoS by affiliation with the names of the companies in the sample. The extraction and tabulation are done without a delimited time range to ensure thoroughness. Different name combinations were written for each firm with Boolean operators in order to retrieve the maximum number of publications to ensure higher data reliability. For example: OG= (Laboratorios Almirall OR Almirall S.a. OR Almirall Prodesfarma OR Almirall OR Laboratorios Almirall, S.a. OR Almirall Prodesfarma S.a. OR Laboratorios Almirall S.a. OR Almirall Sa OR Almirall Prodesfarma Sa OR Almirall Research Center)

As seen in Figure 4, results were obtained for eight companies of our sample: Almirall, Esteve, Grifols, Faes Farma, Reig Jofre, PharmaMar, Infarco and Kern Pharma. The data was filtered out from publications due in 2022, an incomplete year, and only for the country Spain. Therefore, the databank includes 2,739 documents from 1974 to 2021. These records were authored by 8,138 individuals in 673 sources.

N= Included in the sample size E= Excluded from the sample size

Figure 4 – Data collection procedures in WoS

4.2. D

A

T

After finalising the data collection, the data analysis will be performed in the next section using an open-source tool, bibliometrix R Package. It is written in R language, a preferred language for scientific computation due to the effective statistical algorithms and integrated data visualization tools (Aria &

Cuccurullo, 2017).

Data analysis involves a descriptive analysis and network extraction. A descriptive analysis will allow to study the temporal evolution of the number of publications and the most important patterns, like identifying the most cited references or authors, calculating the authors’ dominance ranking or the most relevant keywords. For that, several metrics are used like averages, growth rates and proportions. This, combined with another different types of analysis such as co-citation and collaboration analysis, will allow to provide a structured analysis of the large amount of data.

Co-citation analysis uses citation counts to determine how similar documents, authors, and journals are. It involves tracking cited papers that appear in the same source article and clusters of research

are (Aria & Cuccurullo, 2017) formed when the same papers are cited by many authors (Surwase et al., 2011).

Co-author analysis interprets multiple-authors papers as a measure of collaboration within a field. The authors and their affiliations are examined to determine the structure of cooperation and social interaction among them (Aria & Cuccurullo, 2017). In co-author networks, nodes represent authors or countries, and links represent co-authorship (Surwase et al., 2011).

This chapter presents the methodology that will be implemented to analyze the publications in question. It explained the process for data collection as well as the techniques for the data analysis that will be implemented. In the next section, these data will be analyzed to characterize the pharmaceutical publishing in Spain.

5. DATA ANALYSIS 5.1. I

This chapter summarizes the data collected using Web of Science in several analyses. In terms of scientific production, it will be analyzed the number of scientific publications by each one of the selected companies and their respective number of citations to determine their influence in terms of authorship and impact; who were the authors and their affiliations to analyze the most productive and impactful ones; as well as the publications main subjects to gain insights of the trending topics, the main purposes for publishing, and how the conversation is evolving within the field.

5.2. S

S

P

C

P

5.2.1. S

P

T

This section covers the number of publications and average of citations per year and the evolution of each company from 1974 to 2021.

The total number of entries by Spanish pharmaceutical companies are shown in Figure 5 with an Annual Growth Rate of 7.65% The first publications were in 1974, but it is from 1991 onwards when production rose, until 2012. From that year, however, the number of entries started to decrease. In absolute numbers, 2012 is the year with more scientific publications (169), while 2019 is the year with the highest average number of citations (2.45) as shown in Figure 6.

When looking at the average of citations it has been slightly increasing but fairly stable, with a decrease in 2021 from 2.27 average citations to 1.52. There is an increase in production from 2011 to 2012, where the number of publications increased by 55. However, there is a sign of slowing down. This decrease has been stated in another paper that analyzed the scientific production of the top 15 pharmaceutical firms in Europe (Rafols et al., 2014). The paper concluded that there is more external collaboration, suggesting a tendency to outsource.

Figure 5 – Research items published by the selected Spanish pharmaceutical companies, by year, 1974-2021 Source: this paper, the same for all graphs and tables henceforth

Figure 6 – Average Citations of the publications by the selected Spanish pharmaceutical companies, by year, 1974-2021 3 3 9 4 3 2 8 5 8 7115 7129117131921

19 41

28 32 53

66 5261

53 97

83 95105

92 119

143135

114 169157

148145

97 113

85 90

80 96

0 20 40 60 80 100 120 140 160 180

1971 1976 1981 1986 1991 1996 2001 2006 2011 2016 2021

Number of Articles Published

Years

Annual Scientific Production

0.06 0.150.27

0.42

0.05 0.37

0.19 0.11 0.86

0.4 0.19

0.43 0.36

0.32 0.33

0.320.27 1.22

0.43 0.95

2.05

0.44 1.4

1.22 0.85

0.78 1.37

0.95 1.39

1.34 1.611.63

1.5

1.24 1.2 1.82

1.91

1.571.6 1.951.87

1.68 2.04

1.92 2.412.45

2.27

1.52

0 0.5 1 1.5 2 2.5 3

1971 1976 1981 1986 1991 1996 2001 2006 2011 2016 2021

Average Citations

Years

Average Citations per Year

5.2.2. A

According to Figure 7, 38% of the publications from 1974 to 2021 are affiliated to PharmaMar. Almirall is the second company with the highest percentage of publications, 35%, followed by Esteve with 13%

of the total publications. Grifols has 11% and Faes Farma 3% and the rest of the companies have about 0.49%.

Figure 7 – Percentage of the total number of publications by each of the selected Spanish pharmaceutical companies from the highest to the lowest

Analyzing these values, 86% of the publications found belong to the same three companies:

PharmaMar, Almirall, and Esteve. When analyzing the previous figure, it is notorious that PharmaMar and Almirall have the biggest number of publications.

5.2.3. J

Figure 8 illustrates the major journals where the research has been published, being the top four journals specialized in oncology. The first two publications in 1974 came out in the international peer-

review journal: Arzneimittel-Forschung/Drug Research. However, this journal is not part of the top 20 journals nowadays.

Figure 8 - Top 20 journals by number of total articles published

Overall, the number of journals publishing research by Spanish pharmaceutical companies has been significantly rising, from just 7 in 1980 and 32 in 2020 to 73 in 2021.

In order to analyze each sources impact and see in which areas of study focus the most influential ones, Figure 9 shows the top 20 journals with the highest H-index. The H-index is a metric to measure the cumulative impact of research contributions. It compares publications to citations to evaluate how much impact their publications have had, combining an assessment of both quantity (number of publications) as well as quality (citations). The journal with the highest impact based on this index is Journal of Medicinal Chemistry, however it ranked fifth in terms of number of publications. The journal Annals of Oncology is the only one of the top five sources with the highest number of publications to rank also on the top five sources with a highest impact.

Figure 9 - Top 20 journals local impact by H-index

A correction of the H-index for time is the M-index and can be used to compare journals of different seniority. Figure 10 presents the top 20 journals with the highest M-index. As it can be observed, the rank changes from the previous index, as it overcomes its inconsistency with measurement. Whereas the latest initial year of the top five journals by H-index was 1998 (Annals of Oncology), now with the M-index is 2020 (Cancers).

Figure 10 - Top 20 journals local impact by M-index

Analyzing these top journals, we can observe the importance and impact of the oncological arena, with five oncology journals among the top 20 (Annals of Oncology, Cancers, Cancer Chemotherapy and Pharmacology, Clinical Cancer Research, and British Journal of Cancer). Another area of high interest and impact is related to respiratory medicine research (Respiratory Medicine, European Respiratory Journal, and Pulmonary Pharmacology & Therapeutics).

5.2.4. A

In Table 3, the Top 15 most productive authors (left-hand side) can be compared with the Top 15 most impactful authors (right-hand side). As authors may have changed affiliation over the course of their career, they were assigned to the institution of their last paper in the database.

On one hand, productive authors latest affiliation is mainly PharmaMar (6 out of 15), followed by Almirall (5 out of 15). On the other hand, the most influential authors are also mostly affiliated to PharmaMar (5 out of 15), but it is worth noticing that the 6^th and 7^th most influential authors have Esteve as their latest affiliation, but they do not make up the Top 15 authors with more publications.

Authors affiliated to Almirall lose influential power compared to their productivity.

Therefore, the most productive and impactful authors are affiliated to PharmaMar, which would make the company more visible and trustworthy to the scientific community.

Most productive Most impactful

Authors Affiliation Articles Author Affiliation Citations

CUEVAS C PharmaMar 191 JIMENO J PharmaMar 1113

JIMENO J PharmaMar 143 D'INCALCI M

Mario Negri Institute for Pharmacological

Research 469

PALACIOS JM Almirall 89 CUEVAS C PharmaMar 322

GALMARINI

CM PharmaMar 81

GALMARINI

CM PharmaMar 313

MIRALPEIX M Almirall 79 FAIRCLOTH G PharmaMar 477

D'INCALCI M

Mario Negri Institute for Pharmacological

Research 73 GUZMAN C Esteve 276

MARTINEZ A Grifols 73 ZAMANILLO D Esteve 251

AVILES P PharmaMar 72 VELA JM Almirall 241

JORQUERA JI Grifols 64

LOPEZ-

LAZARO L PharmaMar 240

NIETO A PharmaMar 61 BEIJNEN JH

Slotervaart Hospital &

Utrecht University 230

GIL EG Almirall 60 ERBA E

Istituto Mario

Negri 220

VELA JM Almirall 60 BLAY JY

Centre Leon

Berard 182

SOTO-MATOS

A PharmaMar 59 BAEYENS JM

University of

Granada 179

GAVALDA A Almirall 57 ROSING H

The Netherlands Cancer Institute 176

TEJEDOR D Grifols 57 DEMETRI GD

Ludwig Center at Dana-Farber Cancer Institute and Harvard Cancer and

Sarcoma Center 175

Table 3 - Top 15 authors by articles and citations

5.2.5. T

P

Table 4 shows the Top 20 most cited contributions locally. The affiliation is not heterogeneous, as all but one paper are affiliated to PharmaMar, the other being affiliated to Esteve. A majority of eight contributions were published in Journal of Clinical Oncology. Only three publications were written

clinical trials of an anti-cancer product by PharmaMar, Trabectidin, also referred as ecteinascidin-743 or ET-743, and four papers are about another product by the same company known as Aplidin or Aplidine. This demonstrates PharmaMar's great efforts to demonstrate the efficacy and obtain approval for its drugs.

Title Document Affiliation Local

Citations

Global Citations

LC/GC Ratio (%)

Normalized Local Citations

Normalized Global Citations Phase I and pharmacokinetic study of

ecteinascidin-743, a new marine compound, administered as a 24-hour continuous infusion in patients with solid tumors

TAAMMA A, 2001, J CLIN ONCOL

PharmaMar

S.A. 45 134 33.58 14.15 6.75

In vitro antitumor activity of the novel marine agent, ecteinascidin-743 (ET-743, NSC- 648766) against human tumors explanted from patients

IZBICKA E, 1998, ANN ONCOL

PharmaMar

S.A. 39 135 28.89 11.30 6.64

In vitro activity of aplidine, a new marine- derived anti-cancer compound, on freshly explanted clonogenic human tumour cells and haematopoietic precursor cells

DEPENBRO CK H, 1998, BRIT J CANCER

PharmaMar

S.A. 37 84 44.05 10.72 4.13

Ecteinascidin-743, a new marine natural product with potent antitumor activity on human ovarian carcinoma xenografts

VALOTI G, 1998, CLIN CANCER RES

PharmaMar

S.A. 35 136 25.74 10.14 6.69

Phase II and pharmacokinetic study of ecteinascidin 743 in patients with progressive sarcomas of soft tissues refractory to chemotherapy

GARCIA- CARBONE RO R, 2004, J CLIN ONCOL

PharmaMar

S.A. 35 221 15.84 13.45 7.60

Phase II study of ecteinascidin-743 in advanced pretreated soft tissue sarcoma patients

YOVINE A, 2004, J CLIN ONCOL

PharmaMar

S.A. 35 241 14.52 13.45 8.29

A review of trabectedin (ET-743): a unique mechanism of action

D'INCALCI M, 2010, MOL CANCER THER

PharmaMar

S.A. 35 291 12.03 18.75 12.68

Pharmacological properties of S1RA, a new sigma-1 receptor antagonist that inhibits neuropathic pain and activity-induced spinal sensitization

ROMERO L, 2012, BRIT J PHARMAC OL

Esteve 35 126 27.78 20.83 7.90

Trabectedin for Women With Ovarian Carcinoma After Treatment With Platinum and Taxanes Fails

SESSA C, 2005, J CLIN ONCOL

PharmaMar

S.A. 34 144 23.61 9.56 5.19

High antitumour activity of ET743 against human tumour xenografts from melanoma, non-small-cell lung and ovarian cancer

HENDRIKS HR, 1999, ANN ONCOL

PharmaMar

S.A. 33 100 33 16.38 5.57

Aplidin™ induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase C δ

GARCIA- FERNANDE Z LF, 2002, ONCOGEN E

PharmaMar

S.A. 33 121 27.27 8.33 4.36

Phase II Study of ET-743 in Advanced Soft Tissue Sarcomas: A European Organisation for the Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group Trial

LE CESNE A, 2005, J CLIN ONCOL

PharmaMar

S.A. 33 315 10.48 9.28 11.34

Efficacy and Safety of Trabectedin in Patients With Advanced or Metastatic Liposarcoma or Leiomyosarcoma After Failure of Prior Anthracyclines and Ifosfamide: Results of a Randomized Phase II Study of Two Different Schedules

DEMETRI GD, 2009, J CLIN ONCOL

PharmaMar

S.A. 32 358 8.94 11.11 15.16

Title Document Affiliation Local Citations

Global Citations

LC/GC Ratio (%)

Normalized Local Citations

Normalized Global Citations Ecteinascidin-743: A Marine-Derived

Compound in Advanced, Pretreated Sarcoma Patients—Preliminary Evidence of Activity

DELALOGE S, 2001, J CLIN ONCOL

PharmaMar

S.A. 31 138 22.46 9.75 6.95

Aplidin induces apoptosis in human cancer cells via glutathione depletion and sustained activation of the epidermal growth factor receptor, Src, JNK, and p38 MAPK

CUADRAD O A, 2003, J BIOL CHEM

PharmaMar

S.A. 31 134 23.13 10.66 5.27

Aplidine, a new anticancer agent of marine origin, inhibits vascular endothelial growth factor (VEGF) secretion and blocks VEGF- VEGFR-1 (flt-1) autocrine loop in human leukemia cells MOLT-4

BROGGINI M, 2003, LEUKEMIA

PharmaMar

S.A. 31 114 27.19 10.66 4.48

Trabectedin Plus Pegylated Liposomal Doxorubicin in Recurrent Ovarian Cancer

MONK BJ, 2010, J CLIN ONCOL

PharmaMar

S.A. 30 275 10.91 16.07 11.98

A phase I and pharmacokinetic study of ecteinascidin-743 on a daily x 5 schedule in patients with solid malignancies

VILLALON A-CALERO MA, 2002, CLIN CANCER RES

PharmaMar

S.A. 29 70 41.43 7.32 2.52

Pharmacokinetics and Pharmacodynamics of the Novel Marine-derived Anticancer Agent Ecteinascidin 743 in a Phase I Dose-finding Study1

VAN KESTEREN C, 2000, CLIN CANCER RES

PharmaMar

S.A. 28 75 37.33 8.13 2.49

PM01183, a new DNA minor groove covalent binder with potent in vitro and in vivo anti- tumour activity

LEAL JFM, 2010, BRIT J PHARMAC OL

PharmaMar

S.A. 28 74 37.84 15 3.22

Table 4 – Details of the top 20 papers

5.2.6. A

K

A

Author’s keywords are freely selected by the authors, encapsulating the whole text of a document in succinct fashion. As stated by Jones and Jackson (1970), “Keywords are a list of words or phrases that are provided by the author and signify the meaning or main ideas presented in the paper".

Table 5 shows the frequency of keywords from the papers in the dataset. Trabectedin is the keyword with the highest frequency, 60, followed by Pharmacokinetics with a frequency of 46. Trabectedin, also referred to as ecteinascidin 743 and ET-743, is a chemical compound used as a drug for ovarian cancer commercialized by PharmaMar under the name Yondelis. This is no surprise as most of the top 20 contributions were related to this drug.

The third keyword is COPD which stands for Chronic Obstructive Pulmonary Disease. This result is aligned with the one obtained in the analysis of the journals where a high interest in respiratory

The fourth author’s keyword with a higher frequency (28) is Lurbinectedin, sold under the brand Zepzelca, it is a drug used to treat small cell lung cancer. This brand is a registered trademark of PharmaMar used by Jazz Pharmaceuticals under license. The fact that several of the most frequent keywords refer to drugs belonging to the same pharmaceutical company indicates the successful results of the firm to impact the scientific community and gain recognition.

ZEPZELCA is a registered trademark of S.A. used by Jazz Pharmaceuticals under license

Terms Frequency

trabectedin 60

pharmacokinetics 46

copd 30

lurbinectedin 28

migraine 26

almotriptan 25

plitidepsin 24

safety 23

chemotherapy 21

chronic obstructive pulmonary disease 20

phase i 20

bilastine 19

copd - management 19

cytotoxicity 19

multiple sclerosis 19

pain 19

apoptosis 18

asthma 18

et-743 18

alzheimer's disease 17

Table 5 – Author’s Keywords Word Cloud

A survival time analysis was also conducted for these words. Table 6 shows the former author’s keywords with their frequency of occurrence by year: the darker the orange shade, the higher the relative frequency of appearance of a word in a year. The X-axis shows the terms with the highest growth rates (year-on-year) in descending order (from left to right). As it can be observed, the first of the top 20 author’s words appeared for the first time on a paper in 1992, Pharmacokinetics, and it has been gaining importance ever since. Trabectedin started rising in 2006 and 2007, being the latter the year when the European Commission approved the marketing of this drug (European Medicines

Agency, 2015) and it gained more importance from 2011 onwards, obtaining the authorization of the FDA in 2015 (Yondelis (Trabectedin) FDA Approval History, 2015).

The most recent growing concept to appear was Lurbinectedin in 2013, which was approved for medical use in the United States in 2020.

Table 6 – Growth of Top 20 Author’s Words

5.2.7. C

M

The constellation of themes can be interesting to see how author’s keywords are connected and, thus, providing more meaning and details to the keywords analysis. In Figure 11, author’s keywords appearing in the total population of papers are connected, showing the coexistence of key concepts.

In this image, Pharmacokinetics and Trabectedin are the most central concepts; around them we see large (frequency) and close-by (co-presence) terms that illustrate underlying concepts: both broad

(response, stability, pain, ...) and specific concepts (biomarkers, aclidinium, almotriptan, ...), which are organized in particular topic dimensions (shades of colors).

Aside from Trabectedin, the prevalence of Pharmacokinetics indicates that publications are centered around evidencing the clinical performance of new drugs under development.

Figure 11 – Author’s Words Co-occurrence Map

5.2.8.G

A

Authorship information can be used to trace the international distribution of knowledge production.

Data was filtered to the country of interest, Spain, but it can be insightful to see with which countries there is more collaboration. As it can be observed in Figure 12, the top three countries with more inter- country collaboration with Spain are USA, France and United Kingdom. However, a big number of publications come from intra-country collaboration (880 articles). In the following section, we will analyze which players of these countries have a higher connection with our subset of firms.

Figure 12 – Geography of authorship

5.2.9. C

N

In order to analyze the research collaboration environment, Figure 13 shows the different institution networks. There are a few major players that have the most influence: universities, hospitals and research institutes.

On one hand, the most influential players are university institutions mainly from Spain, but also from France, the UK, the US, and the Netherlands. The most central university players are Universitat de Barcelona (Spain) and Gustave Roussy Institut (France). The former has strong relationships with Grifols, Esteve and Almirall and constitutes the largest community (green) with the largest average citations and constituted mainly by academic institutions and pharmaceutical companies. University of Granada and University Pompeu Fabra also have a tight collaboration with Esteve. Within the overall network, other players are discernible: hospitals. The most central ones are Hospital Ramon and Cajal (Spain), Hospital Santa Creu and Sant Pau (Spain), and Hospital Clinic de Barcelona (Spain).

Again, this pattern contributes with another layer of understanding since networks with universities are the most common within the research collaboration environment.

Figure 13 – Institutions Collaboration Network