KNOWLEDGE PORTAL
on innovation and access to medicines

SYNTHESIS OF THE LITERATURE

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DEFINITIONS

 

The literature uses various definitions for the term “small and medium-sized enterprise (SMEs)”, usually based on revenues and/or employee count. Some authors also further differentiate SMEs from what is referred to as “emerging” pharmaceutical or biotechnology biotech companies, but most papers include those in the definition of SMEs. For example, BIO used the term “emerging therapeutic companies” (ETCs) to refer to those that are “a) developing therapeutics with a lead drug in R&D, or b) have a drug on the market, but have less than $1 billion in sales at the time of the transaction” (Thomas 2019). Hay et al. used the term “emerging biotech” for those companies that have less than $0.1 billion in sales (Hay et al. 2014).

 

The following are examples of definitions based on:

 

Revenues

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• Below $1 billion in gross revenues (T. J. Hwang, Carpenter, and Kesselheim 2014; Thomas J. Hwang and Kesselheim 2016).

• Between $0.1-5 billion of sales (Hay et al. 2014).

• Below $100 million in sales for small biopharma companies and between $100 million and $1 billion for mid-sized biopharma companies (Geilinger and Leo 2019).

• Between $500 million to less than $5 billion in annual “global prescription sales” (IQVIA 2019b) for SMEs and less than $500 million in sales or with less than $200 million of research and development expenditures per year for “emerging biopharma companies” (EBCs) (IQVIA 2019b).

• Between $100 million and $3 billion in annual revenues for “emerging biopharma companies” (The Boston Consulting Group, cited by Brouwers, Garrison, and Barido 2011).

•  “Not more than €50 million in turnover or €43 million on the balance sheet” (European Union, Commission Recommendation 2003/361/EC, cited by Lincker et al. 2014).

 

Employee Count

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• Employee count of 100 or less as SMEs (Moran et al. 2007).

• Companies “[w]ith < 1,000 employees at time of drug discovery” (Kneller 2010)

• “Headcount [of] less than 250” (European Union, Commission Recommendation 2003/361/EC, cited by Lincker et al. 2014).

 

As may be gleaned from these examples, the literature does not adopt any standard definition for SMEs and vary widely in their criteria, whether based on revenue, employee count or both. It is also noted that SMEs and EBCs/ETCs sometimes have overlapping definitions.

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CHARACTERISTICS AND ADVANTAGES

 

SMEs are generally characterized as being externally funded, with a flexible structure and a higher degree of risk taking compared to large firms. Kaitin notes the changing trend within the pharmaceutical industry with respect to the R&D process - from the long-standing model of “a fully integrated pharmaceutical company model of R&D” wherein individual pharmaceutical companies are responsible for the entire drug R&D process to “a fully integrated pharmaceutical network” which utilizes the capabilities of all the relevant R&D actors, including the “small pharmaceutical and biotechnology companies” (Kaitin 2010). These small companies are described to be primarily reliant on external R&D funding, coming from sources such as venture capital or large companies, with substantial amounts of debt and limited numbers of products already on the market. However, these companies are seen by their larger counterparts to be more adaptable, able to take more risks and have a less rigid structure. These characteristics thus, allow them to “focus on emerging technologies and on developing highly innovative therapeutics” and has led to increasing collaborative projects with and takeovers by large companies (Kaitin 2010). Small biotech companies have also been observed to pursue drug targets deemed to be of higher risk and “less validated.” As compared to their larger counterparts, they are said to “more likely to have less experienced development teams and fewer resources” (Hay et al. 2014).

 

Gopalakrishnan and Bierly examined the “knowledge strategies” of 27 drug delivery-focused companies - 17 of which were categorized as small firms (having less than or equal to 500 employees) and 10 firms classified as large (having more than 500 employees). Among other observations made in the study, they found that the small firms’ ability to quickly adapt into their products or processes the latest available technologies (“learning speed”) was crucial for them to be able to obtain higher volumes of patents and citations (“technological strength”), as compared to their large counterparts, They noted that this observation is in line with results from prior studies that “speed and flexibility” are some of the main advantages that small companies have over large companies (Gopalakrishnan and Bierly 2006).

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R&D SHARE AND CONTRIBUTIONS

 

SMEs and EBCs are increasingly being recognized for their growing R&D contributions, especially in the U.S.

 

General R&D

 

In 2019, ETCs, on their own or with partners, were said to be responsible for 73% (5,067 out of 6,984) of the total global “industry” drug clinical-stage projects, with the remainder done by large companies. Disaggregated, ETCs would account for 71%, 76%, 68% and 62% of Phase I, II, III and new drug applications, respectively, as compared to those done by large companies. 45% of all ETC clinical-stage pipeline projects are conducted with other partner companies. Oncology is the top disease focus for these ETC clinical projects (Thomas 2019). In 2018, IQVIA identified that there are 74 small companies that have combined global sales of $159 billion and 446 drugs in their R&D pipeline, 9 mid-sized companies with $50 billion sales and 181 products, and 3,212 emerging biopharma companies with $139 billion sales and 8,752 products. In comparison, 25 large companies had combined annual sales of $637 billion and 1,845 products.  Comparing data between 2003 and 2018, EBCs were observed to have an increasing share of early-stage product pipelines (encompassing discovery until Phase I stages) from 68% to 84%. In 2003, there were 1,383 products identified globally in the late-stage phase (encompassing Phase II until registration stages) and this number increased to 2,891 in 2018. Again comparing data between 2003 and 2018, EBCs were also observed to have an increasing share of late-stage product pipelines from 52% to 73%, respectively. During the same period, small and mid-sized companies were observed to have a limited and decreasing share of late-stage product pipeline of 6% to 5% and 5% to 3%, respectively. The large companies also exhibited a similar decreasing trend for late-stage product pipeline from 36% to only 19%. The increased share of pipeline products from EBCs were attributed to their sizable involvement in oncology and orphan drug R&D activities (IQVIA 2019b).

 

According to the 2017 BIO Industry Analysis, small biotechnology companies are responsible for 70% of all biopharmaceutical clinical trials worldwide amounting to 6,679 programs, 43% of which were conducted in partnership with another company. The remaining 30% of these clinical trials were being conducted by large companies (Biotechnology Innovation Organization n.d.).

 

Using information contained in the BioMedTracker database, Hay et al. examined the success rates in clinical development of 4,451 investigational drugs in the U.S. belonging to 835 companies and involving 5,820 phase transitions during the period of 2003 to 2011. Looking closely at the composition of the drug developers, 4% were large pharmaceutical companies or biotechnology companies developing 47% of these investigational drugs, 11% were small to mid-sized pharmaceutical companies or biotechnology companies developing 16% of these drugs and 85% were emerging biotechnology companies developing 37% of these drugs. They found, among others, that only 10.4% of the 5,820 “indication development paths in phase 1 were approved by FDA.” In explaining their “lower success rates” results as compared to other studies, they noted as a contributing factor the sizable representation of small biotech companies. Funding limitations were also identified to have influenced the small companies’ drug development choices (Hay et al. 2014).

 

Disease and technology specific

 

Hwang and Kesselheim analyzed clinical trials for vaccine development from the Pharmaprojects database of Informa from 1990 to 2012. It was observed that 71% of new vaccine Phase I trials, globally, were initiated by SMEs as compared to 38% of Phase III vaccine trials, which had more involved of larger companies. Looking at disease specific vaccines, 69% of Phase I trials focusing on HIV, malaria, tuberculosis and tropical infectious diseases’ vaccines were attributed to SMEs (Thomas J. Hwang and Kesselheim 2016). In a 2007 study, Moran et al. found that SME-led vaccine clinical development for malaria comprised 13% of all clinical projects in 2006, with the rest conducted by public-private partnerships (PPPs) and public institutions, accounting for 25% and 62% respectively. This is different from 1995 when malaria clinical projects were undertaken only by PPPs, public institutions and multinational companies. In relation to malaria drugs, in 2006 SMEs had a 10% share of the global development portfolio and the remainder done by product development partnerships (47%), public institutions (24%) and multinational companies (19%) (Moran et al. 2007). For the Seventh EU Framework Programme on Human Vaccine Research, it was observed that the vaccine projects had private sector partners accounting for greater than 13% of the total number of project partners, specifically comprising of SMEs (39 partners) and large companies (5 partners). It was also noted that clinical trials for DNA vaccines are mainly sponsored by SMEs and not by large companies. Sautter et al. noted the importance of enticing pharmaceutical industry players, particularly SMEs, to “boost [vaccine] innovation and translational research” in the EU (Sautter et al. 2011). Similarly, for antibiotic R&D efforts, SME clinical trial efforts have increased from below 30% in 1990 to 60% in 2012 (T. J. Hwang, Carpenter, and Kesselheim 2014).

 

As of December 2004, Moran et al. identified 29 out of 63 public-private partnership (“PPP”) projects focusing on drug R&D for neglected diseases that employed “small-scale commercial firms and academics/public groups working on a fully paid basis.” Of these 29 projects, 4 were identified to be done by “small companies focused on neglected diseases” and another 4 done by “small companies focused on Western diseases,” all of which are Western-based. The former group views neglected diseases as a “potential commercial niche market” and as such, they do not rely on PPP funding but rather expect to obtain monetary gains for actual sale of their products. The latter group, by specializing on Western markets, rely on financing from venture capitalists and are thus, pressured to produce profits which the neglected diseases market do not offer. For both groups, PPPs can offer financing and technical expertise, however these are said to be needed to a much greater extent by the latter considering that it still needs “catalyzing” agents to engage in neglected disease R&D activities (Moran et al. 2005).

 

Drug Approvals

 

Geilinger and Leo noted that, in 2018, 49% of U.S. drug approvals were owned or being licensed by smaller companies with sales amounting to $100 million or less as compared to the 25% share of the 10 pharmaceutical companies generating the topmost sales worldwide (Geilinger and Leo 2019). Kneller traced 252 U.S. Food and Drug Administration (FDA) approved-drugs between the period of 1998 to 2007 (this number reflects “almost all” the FDA-approved and Center for Drug Evaluation and Research-regulated drugs within the said period) and studied the involvement of different inventors during the drug discovery process. He concluded that the drug discovery levels by small companies are almost comparable to the large pharmaceutical companies. It was also noted that 18% of the 252 total drug base was discovered by biotechnology companies. (Kneller 2010).

 

Munos examined the origins of 1,222 FDA-approved new molecular entities (NMEs) between 1950 to 2008. He found, among others that: (i) 193 of these NMEs were developed by 103 small companies that were subsequently merged or acquired and thus, no longer exists; (ii) 25 were developed by 19 already-liquidated small companies; (iii) 79 were developed by 23 small companies that were active from 1950 to 2008; and (iv) 105 were developed by 66 small companies that existed by virtue of merger or acquisition agreements. He further observed that small companies were responsible for an increasing share of U.S. FDA-approved NMEs, from just approximately 23% in the 1980s to almost 70% in 2008. In contrast, the share of NMEs originating from large companies had decreased from 75% to 35% during the same period. It was observed that, beginning 2004, “small companies have consistently matched or outperformed their larger competitors.” This increased NME productivity from small companies had been attributed to the growing number of small companies with an NME and that small companies are increasing their “mean annual NME output.” Analyzing projects in the discovery stage between 1980 to 2004, small companies accounted for 47% of these which is a greater share as compared to only 38% from large companies. However, small and large companies were noted to have almost an equal share of projects in the development stage for the same period (Munos 2009).

 

For 59 “new active substances” submitted for approval with the U.S. FDA in 2018, IQVIA observed that 64% of these were invented by EBCs, another 5% each by small and mid-sized companies and 25% coming from large companies. For the submission of these 59 substances with the FDA, 47% were done by EBCs, and the large companies coming close at 44% and the remaining 5% and 3% made by mid-sized and small companies respectively (IQVIA 2019a). It was also observed that the active ingredient of approximately 22% of the 50 leading drugs in 2009 were discovered or created by EBCs (Brouwers, Garrison, and Barido 2011).

 

Further, Mullard noted the growing role of small “emerging sponsors” – referring to first-time recipients of U.S. FDA approvals - in drug development efforts. They were observed to be responsible for 41% of the drug approvals in 2012, and 37% in 2011. There were six emerging sponsors in 2012 and four in 2011 who independently obtained FDA approvals (Mullard 2013). Lincker et al. looked at 94 medicinal marketing authorization applications with a “new active substance” that received approval from the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use during the period of 2010 to 2012. They found that 27% of these approved applications and 61% of applications dealing with orphan drugs originated from SMEs. Also, 13% of these had SMEs as the “marketing authorization holder.” Looking at the transfer of products among developers, they observed that 18 applications originated from SMEs that were eventually transferred to large or “intermediate” companies, majority of which took place by virtue of out-licensing agreements (13 applications) and the rest (5 applications) resulted from a merger or acquisition agreement with a large company. SMEs were also the recipients of these transfers from “academic/public bodies/PPPs” at 5%, large or intermediate companies at 4% and other SMEs at 2%  (Lincker et al. 2014).

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R&D COSTS AND EFFICIENCY

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There is limited research on the actual R&D costs incurred by SMEs. From the existing studies, it is unclear whether their costs are higher or lower than their larger counterparts. Myers and Shyam-Sunder estimated the risk values and capital costs as of December 1988 for seven “‘small’ pharmaceutical firms” and compared them to the corresponding values for large pharmaceutical firms. They observed that the small firms had higher risk values and capital costs than their larger counterparts (Myers and Shyam-Sunder 1996). Figures from 2005 from DiMasi and Grabowski showed the costs for research and development of seventeen biopharmaceuticals developed by four biotech firms (the definition of which was not provided in the study). Among others, they found that: (i) each approved biopharmaceutical will involve the following “out of pocket” estimated expenditures, USD 198 million for preclinical, USD 361 million for clinical and a total of USD 559 million, and (ii) using data adjusted for time period differences, total biotech R&D “out of pocket” cost for each approved biopharmaceutical at USD 559 million is less costly than “traditional pharmaceutical firms” at USD 672 million [monetary figures are expressed in 2005 USD values] (DiMasi and Grabowski 2007).

 

Ardal et al. surveyed 25 SMEs (majority of which deal with “human health” but 28% of which also work on “animal health and/or environmental issues”) in Europe as to the costs and time frames of antibiotic research and development (R&D), from lead compound identification to phase II clinical trials. They identified the following estimate costs and time frames: (i) during the identification phase for lead compounds, SMEs may incur costs between € 100,001 to greater than € 1,000,000 taking between 6 months to 4 years; (ii) during the optimization phase of lead compounds, many of the SMEs incurred or project to incur costs of € 1 – 5 million again within 6 months to 4 years; (iii) during preclinical trials, many of the SMEs incurred or project to incur costs of € 1 – 5 million within 1 to 2 years; (iv) during clinical – Phase I trials, many of the SMEs incurred or project to incur costs of € 1 – 10 million within 6 months to 2 years; and (v) during clinical – Phase II trials, many of the SMEs incurred or project to incur costs of € 1 – 20 million within 1 to 4 years. Their results were interpreted to indicate that SMEs anticipate to incur less R&D costs than their larger counterparts (Årdal et al. 2018).

 

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R&D CHALLENGES

 

Clinical development programs, especially in terms of their design and implementation, pose significant challenges for small biopharmaceutical companies. These are mainly attributable to constraints in finances, resources and limited experience. Moscicki and Tandon discussed four rare disease-drug development cases conducted by small biopharmaceutical companies and the approaches they used to overcome specific clinical program difficulties. They also provided a sample list of small biopharmaceutical companies who obtained drug approvals between 2014 and 2015 after conducting phase III clinical trials and the institutional strategies used by these companies to overcome drug development challenges, i.e. targeting only certain diseases, focusing on drug-repurposing or reliance on licensing agreements (Moscicki and Tandon 2017). Particularly for vaccine research and development efforts in the EU, the main challenges to SME participation as determined during the stakeholder discussions conducted by the Innovation Partnership for a Roadmap on Vaccines in Europe, are: skills and expertise acquisition, and funding availability (Medaglini et al. 2018). ten Ham et al. surveyed 271 for-profit companies involved in the European market (as of January 2017) on their development efforts for advanced therapy medicinal products on the challenges they faced in their clinical development efforts. Out of their 68 respondents, 65% were identified to be SMEs (having an employee count of between 1 to 249 individuals) and the remaining respondents were large companies. The authors noted greater SME involvement in advance therapy medicinal products than in “small-molecule and biotechnology industry.” Challenges confronting SMEs working in this area include those related to preclinical translation and clinical development financing (ten Ham et al. 2018).

 

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STRATEGIES

 

Innovation

 

Several researchers have examined the innovation strategies of SMEs and ETCs. Wikhamn et al. surveyed 104 Swedish biopharmaceutical SMEs to determine the extent of industry awareness and employment of “open innovation activities.” Their study revealed that, among others, while open innovation is not a widely-known concept among the Chief Executive Officer - survey respondents, the majority of the SMEs were engaging in business practices that are aligned to this concept, for example “external networking” attributable to “standard [industry] practices.” Further, they observed that the use of open innovation practices by SMEs within their own research and development departments was not intended to scale down these departments. Lastly, they noted that SMEs that employ open innovation strategies are deemed to be more innovative than their peers (Wikhamn et al. 2016). Prokop and Stejskal examined and identified the variables that affect “product and process innovations” of German SMEs. With respect to the “473 Chemical and Pharmaceutical” organizations included in the study, they found, among others, that for small firms (those that have an employee count of less than 50), the most influential variables for “innovation activities” are “in-house and external R&D activities and expenditures” (Prokop and Stejskal 2019).

 

Licensing Arrangements

 

Thomas showed that in 2018 ETCs out-licensed projects and received “upfront” fees totaling $9.1 billion from large companies. This reflects a 107% increase from the licensing activities in 2017, which only amounted to $4.4 billion. Between the years 2009 to 2018, the global average of acquisition deals involving ETCs, whether R&D or market-oriented, is 41 deals. The number of acquisitions in 2018 was slightly lower than the average at 32 deals, of which 66% involved U.S.-based ETCs and had a total value of $26.4 billion. 88% of these 2018 deals involved R&D-oriented ETCs with a total acquisition value of $32.5 billion and the remainder involved market-oriented ETCs with a total acquisition value of $2.2 billion (Thomas 2019). Song and Leker analyzed the licensing agreements of pharmaceutical companies in Korea in order to determine their use “to differentiate distinct innovation strategies.” Among other things, the study examined “firm size” as one of the variables and noted that this has a positive influence on whether companies would enter into licensing arrangements. Further, they noted that the small Korean pharmaceutical companies included in the study only had a few licensing arrangements (Song and Leker 2019).

 

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INCENTIVES

 

Incentives for SME R&D efforts may include direct grants, tax credits and priority review vouchers.

 

Actual Incentives

 

A few papers analysed the financial incentives currently available for SMEs. The 50% tax credit for clinical trial costs, which was available to entities conducting drug R&D for rare diseases under the 1983 U.S. Orphan Drug Act, is said to have a positive effect on SMEs’ survival and growth (T. J. Hwang, Carpenter, and Kesselheim 2014). To assist diagnostics-focused SMEs in the EU, the European Commission through its Horizon 2020 program made available € 130 million of funds for “clinical research for the validation of biomarkers and/or diagnostic medical devices.” It was observed that this call received quality proposals from 1194 respondents (Sanne 2018).

 

Ekins and Wood discussed their experiences in setting up 2 U.S.-based small companies for “early stage” research efforts on rare and neglected diseases. Their companies sought federal funding from the Small Business Technology Transfer and Small Business Innovation Research programs of the U.S. National Institutes of Health. They opined that the potential issuance of a FDA priority review voucher[1] for drugs on rare pediatric diseases may help their companies attract private investors such as venture capitalists “in the absence of a sizable patient population” for their target diseases (Ekins and Wood 2016).

 

With respect to financing, Thomas found that in 2018, global venture capital financing directed towards ETCs increased to $17.5 billion from only $4.4 billion in 2009. Particularly, U.S. based ETCs received venture investments amounting to $12.3 billion in 2018, 95% of which were intended for new R&D projects while the rest were allocated for drug improvement R&D efforts. These U.S. based companies received a significantly higher amount of venture funding compared to their non-U.S. counterparts, which received a total of $5.2 billion. U.S. and non-U.S ETCs focusing on R&D activities for oncology receive the most funding from venture capitalists (Thomas 2019).

 

Suggested Incentives

 

Another set of papers discussed incentives that could be made available for SMEs health product development. Noting their significant share in the conduct of Phase I vaccine trials as compared to large pharmaceutical companies, Hwang and Kesselheim suggested the enactment of policies – i.e. public-private partnerships and prize incentives - to assist the R&D efforts of SMEs in this area (Thomas J. Hwang and Kesselheim 2016). Similarly, Hwang, Carpenter and Kesselheim suggested that policy measures should target SMEs conducting antibiotics R&D to help them in their activities, i.e. through tax credit schemes, public-private partnerships and direct research funding (T. J. Hwang, Carpenter, and Kesselheim 2014).

 

Useful resources

 

• Since 2015, BIO has published an annual report on global trends concerning ETCs, from funding to drug pipeline portfolio shares. The reports are accessible from this link: https://www.bio.org/bio-industry-analysis-reports.

• The EMA’s SME Register (found in this link: https://fmapps.emea.europa.eu/SME/search_advanced2.php) provides a searchable database of SMEs registered as such in the European Economic Area. Among others, the results can be filtered based on R&D stages in relation to (bio)pharmaceutical and medical device and technology sectors as well as by type of products, substances and therapeutic areas.

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RESEARCH GAPS

 

• Analysis on R&D contributions of non U.S.-based SMEs

• Analysis on R&D costs and efficiency incurred by SMEs

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NOTES

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[1] There is a separate research synthesis on priority review vouchers, available at https://www.knowledgeportalia.org/priority-review-vouchers

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CITED PAPERS WITH ABSTRACTS