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CBS, Copenhagen, Denmark,
THE EMERGENCE OF A NEW TECHNOLOGY: A MULTI-PERSPECTIVE
ANALYSIS ON THE CASE OF HUMAN PAPILLOMA VIRUS (HPV)
MOLECULAR DIAGNOSTIC TESTSDaniele Rotolo
University of SussexSPRU-Science and Technology Policy Research
Michael HopkinsUniversity of Sussex
SPRU-Science and Technology Policy [email protected]
Ismael Rafols
University of SussexSPRU-Science and Technology Policy Research
AbstractEmerging technologies are sources of new industries and sub-sectors as well as they represent important drivers fortechnological change. Given the central role emerging technologies play, we aim to investigate the phenomenon ofemergence in order to reveal its complexity. To this end, by drawing on an institutional-evolutional framework, we use acase study approach that combines a multi-perspective investigation with mixed qualitative-quantitative analyses, i.e.
historical analysis, interviews, and advanced bibliometric techniques. Precisely, we investigate the process ofemergence for Human Papilloma Virus (HPV) molecular diagnostic tests since its conception in the 1980s. Thistechnology is one of the most promising technologies for the cervical cancer screening that accounts for an extremelylarge market of 100+ million tests performed annually. Preliminary analysis shows the emergence of HPV diagnosticsmainly driven by the intrinsic potential the technology has for the development of more reliable tests as well ascompanies seeking for new technological opportunities to compete with Pap test and profit from these. In addition, weshow that an emerging technology, rather than replacing, may co-exist with established ones especially in thoseinstitutional environments characterized by strong regulations and entrenched institutions.
Jelcodes:O33,O32
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THE EMERGENCE OF A NEW TECHNOLOGY:
A MULTI-PERSPECTIVE ANALYSIS ON THE CASE OF HUMAN PAPILLOMA
VIRUS (HPV) MOLECULAR DIAGNOSTIC TESTS
ABSTRACT
Emerging technologies are sources of new industries and sub-sectors as well as they represent
important drivers for technological change. Given the central role emerging technologies play,
we aim to investigate the phenomenon of emergence in order to reveal its complexity. To this
end, by drawing on an institutional-evolutional framework, we use a case study approach that
combines a multi-perspective investigation with mixed qualitative-quantitative analyses, i.e.
historical analysis, interviews, and advanced bibliometric techniques. Precisely, we investigate the
process of emergence for Human Papilloma Virus (HPV) molecular diagnostic tests since its
conception in the 1980s. This technology is one of the most promising technologies for the
cervical cancer screening that accounts for an extremely large market of 100+ million tests
performed annually. Preliminary analysis shows the emergence of HPV diagnostics mainly driven
by the intrinsic potential the technology has for the development of more reliable tests as well as
companies seeking for new technological opportunities to compete with Pap test and profit from
these. In addition, we show that an emerging technology, rather than replacing, may co-exist
with established ones especially in those institutional environments characterized by strong
regulations and entrenched institutions.
Keywords: emerging technology; institutional-evolutional framework; multi-perspective
approach; case study; mapping techniques.
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1. INTRODUCTION
Emerging technologies represent important opportunities for nations’ growth and wealth.
These technologies have potential to create new industries, and sub-sectors or change the
existing ones favouring then technological change (Adner and Levinthal 2002, Cozzens et al.
2010, Day and Schoemaker 2000). Yet, complexity and uncertainty characterize the process of
emergence. In fact, their development may undertake specific trajectories and reject others
according to the numerous visions, objectives, and expectations multiple actors involved have on
them (Blume 1992, Bijker 1995, A. H. Van de Ven et al. 1999, Robinson et al. 2011). Stakeholder
groups, or relevant actor groups generate a variety of options for change (Bijker 1995) that are
then subject to a “selection environment” that differentially favours particular options (Smith et
al. 2010). Change is therefore seen as strongly constrained by pre-existing socio-technical regimes
(Geels 2002). These are comprised of scientific/technical paradigms and routines that frame
researchers’ thinking (Dosi 1982), vested interests, the organisational capital of incumbents,
regulatory standards, sunk costs (Van de Ven and Garud 1989, Jacobsson and Johnson 2000,
Verbong and Geels 2007), practices subject to economies of scale and positive network
externalities (Arthur 1989); prevailing social practices (Shove 2003); dominant policies, legal
frameworks and professional lobbying (William 2000). This complexity means options can be
obscured and never properly considered, and processes influencing change are difficult to trace,
analyse, and manage. Network-incumbents also influence the selection environment, which
maintains the momentum of established options, and creates technological lock-in and
hegemonic stability (Stirling 2009, Verbong and Geels 2007). Authors suggest the resulting
innovation pathways may therefore be suboptimal or even socially undesirable (Arthur 1989,
Stirling 2008, 2009) which has lead to a body of research on Constructive Technology
Assessment (CTA) to address these problems. Yet these approaches are only as good as their
preparatory work, and this has been a limiting factor for CTA (Rip and Te Kulve 2008). In this
context we ask: (i) How can we find the selection mechanisms that occur during a technology’s
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emergence? (ii) What the possible trajectories that could be pursued and which actor groups are
supporting these? (iii) What role do epistemic communities play in the process of technological
emergence and how do they integrate or align when a new technology emerges?
Drawing on an institutional-evolutional theoretical framework (Van de Ven and Garud 1989,
Blume 1992), the present paper aims to address these questions by investigating the process of
emergence shaping the Human Papilloma Virus1 (HPV) molecular diagnostic tests for cervical
cancer screening (Casper and Clarke 1998, Clarke et al. 2003, Hogarth et al. 2011). To capture
the complexity of the process of emergence, we conduct a multi-perspective analysis—including
scientific disciplines, technological areas, and actors and institutions involved in the process—
with a mixed qualitative-quantitative approach. In particular, this mixed approach allows
exploiting the broad view the bibliometric techniques provide on a phenomenon without losing
the intimate connection with the empirical reality required for the development of a valid theory
(Eisenhardt 1989, Glaser and Strauss 1967). Therefore, we believe our approach as able to
disentangle the complexity and uncertainty characterizing the process of emergence.
The remainder of this preliminary version of the paper is organized as follows. First, in
Section §2, we propose the theoretical framework. Section §3 presents the research methods
while Section §4 reports the preliminary results on our case study. Finally, Section §5 discusses
and concludes the study.
2. THEORETICAL BACKGROUND
New technologies emerge within established social systems constituting the institutional
environment that may facilitate or inhibit the process of emergence (Dosi 1982, Bijker 1995,
Smith et al. 2010). In fact, technological change involves also “changes in other elements such as
user practices, regulations, industrial networks, infrastructure, and symbolic meaning” (Geels
1 Human papilloma viruses are small DNA tumor viruses that belong to the family of Papovaviridae.
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2002 p.1257). Therefore, emerging technologies grow in pre-existing socio-technical regimes that
may speed as well as obstruct the process of emergence. Van de Ven and Garud (1989) proposed
a social system framework constituted by three interacting components: (i) institutional
arrangements, (ii) resource endowments, and (iii) proprietary functions. Institutional
arrangements serve as functions to govern, legitimate, regulate as well as standardize a new
technology (Powell and DiMaggio 1991). Therefore, they manifest in form of governmental
regulations (Nelson 1982, Teece 1986), firm’s legitimation (Maitland 1982), and establishment of
technology standards (Tushman and Rosenkopf 1992). According to this view, while firms
compete in the marketplace, they need also to compete in the institutional environment in which
they operate in order to legitimize and gain access to necessary resources (Pfeffer and Salancik
2003). The importance of resources for the development of new technologies leads to the
second components of the social system, i.e. the “resource endowments”. In particular, this
component encompasses all those public resources such as basic scientific or technological
knowledge, financing mechanisms, and pools of skilled labour available within the social system.
For instance, basic research is fundamental input firms transform into new technologies
(Freeman 1997, Mansfield 1985, 1995, Utterback and Abernathy 1975). However, this process of
transformation requires also other types of resources, such as financial and human resources,
firms need to gather within the social system. Finally, the component of “proprietary functions”
refers to all those functions a private firm leverages to commercialize the new technology for
profit such as R&D, manufacturing, marketing, and distribution functions. The transaction cost
theory (Teece 1986, Williamson 1989) helps to understand how firms perform these proprietary
functions such as the creation complementary assets in weak appropriability regimes.
Within this social system, emerging technologies follow evolutional trajectories while they
continuously interact with their institutional environment. Adopting the Blume's (1992) concept
of “career”, those technological patterns can be conceived as sequences of milestones and
phases that mark the evolution of a given technology following four main phases: exploration,
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development, adoption, and growth. The institutional environment influences, shapes, and
selects the technological trajectories in each one of these phases (Van de Ven and Garud 1989,
Blume 1992, Bijker 1995, Smith et al. 2010). In fact, within the social system, during the process
of emergence, networks of actors constitute and shape artefacts, techniques, and regimes
according to shared visions of future applications of a given emerging technology. Therefore, the
development of these trajectories may undertake and reject specific directions as they are
selected by the numerous visions, objectives, and expectations those actors have on them.
Building on this institutional-evolutional framework (Blume 1992, Van de Ven and Garud 1989)
we aim to shed light on the complexity of the process of emergence across all its dimensions.
3. METHODS: A MULTI-PERSPECTIVE APPROACH
To investigate the process of emergence, we conduct our analysis from a number of different
perspectives including scientific disciplines, technological areas, and involved actors and
institutions. In addition, we combine this multi-perspective approach with mixed qualitative-
quantitative analyses as historical analyses, interviews, and bibliometric techniques. We believe
the combination of a multi-perspective investigation with qualitative and quantitative analyses as
a key point to fully reveal the complexity that features the process of emergence. In particular,
while a multi-perspective analysis it is important to reach the triangulation of the data (Yin 2009),
it allows capturing the emergence of new technology in all its facets. In addition, this multi-
perspective analysis supported by a mixed qualitative-quantitative case study approach allows
exploiting powerful bibliometric techniques without losing the intimate connection with the
empirical reality required for the development of a valid theory (Eisenhardt 1989, Glaser and
Strauss 1967). Therefore, we expect our approach to be able to reveal other early developments
that have been lost in the histories that the comprehensive coverage by bibliometric mapping
provides.
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We first identify the key events in the process of emergence as captured by the historical
analysis and interviews, whereby a key event is defined as a critical incident occurred during the
development of each the institutional arrangements, resource endowments, and proprietary
function in the institutional framework (Van de Ven and Garud 1993, Van de Ven and Poole
1990). Then, we follow these key events through the lens of bibliometric tools, such as the
overlay mapping and collaborative networks. We use these tools to interpret the emergence
phenomenon in terms of how actors and technologies’ positions in networks evolve over time
within global maps of scientific disciplines and technological areas as well within the overall
collaborative network. We build our different perspectives by using multiple sources of data as
scientific articles (ISI Web of Science - WoS), patents (U.S. Patent and Trademark Office -
USPTO), companies’ alliances (Recombinant Capital - RECAP), historical analysis, and
interviews with experts in the field. We report in the following section the preliminary results of
our analysis.
4. THE CASE OF HPV MOLECULAR DIAGNOSTIC TESTS
We focus the attention on the process of emergence of HPV molecular diagnostics as one of
the most promising technologies for cervical cancer screening. About 500,000 new cervical
cancers occur and cause about 250,000 deaths each year. This led to the largest systematic
screening program with 100+ million tests performed annually. This program constitutes the
largest cancer screening market. In the 1980s, HPV emerged in this “socio-technical” landscape
where an alternative technology for cervical cancer screening, cytology-based testing using the
Pap Smear, already existed and was widely adopted (Casper and Clarke 1998). However, an HPV
diagnostics-based test was initially seen by some as a valid a alternative for more reliable and
sensitive tests (Hogarth et al. 2011) given the traditional Pap testing reporting a 15%-50% false-
negative rate. In fact, HPV diagnostics as gene-based diagnostics belong to broader field of
genomic molecularisation as a novel approach whereby actors aim “to understand diseases at the
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(sub)molecular level of proteins, individual genes, and genomes” (Clarke et al. 2003: 12) rather
than emphasising the role of germs, enzymes, and biomedical compounds.
By building on a recent case study (Hogarth et al. 2011), we conduct our analysis by
identifying the key events that shaped the emergence of HPV diagnostics. Then, with the aim of
attempting to check how newly developed hybrid-qualitative-quantitative approaches using
multiple perspectives match the picture constructed from interviewees and researcher-guided
retrospective analysis of historical sources, we will use these key events as guideline to
disentangle the process of emergence.
We report in Table 1 the chronological list of key events that marked the emergence of HPV
diagnostics since the early 1980s. We defined the key events as transpired from the historical
analysis and interviews. Specifically, we rely on 12 interviews selected based on their involvement
within the development of HPV diagnostics. Then, following the evolutional perspective (Blume
1992, Hogarth et al. 2011), we clustered the key events according to four main phases of the
process of emergence: (i) exploration, (ii) development, (iii) adoption, and (iv) growth.
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Insert Table 1 about here.
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The exploration phase begins with the important scientific discovery, by Harald zur Hausen
(German Cancer Research Centre) in 1983, on the association between cervical cancer and
human papilloma virus. However, it is worth noting that the first clue on the possible viral
origins of the cancer of the uterus can be traced in 1842 when an Italian physician, Domenico
Rigoni-Stern, in his mortality statistics of women dying of cancer in the city of Verona, pointed
out how the cancer of uterus was much more common in married women and widows than in
virgins and nuns. (Rigoni-Stern 1842). Only around the 1960s-1970s cytologists started to
recognize the presence of “koilocytes”—cells characterized by large nuclei and large, clear
perinuclear spaces—as a manifestation of a viral infection of genital “condylomas” as a sexually
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transmitted disease. The link between “koilocytes” and “condylomas”, hence the viral origin of
cervical cancer, attracted the interest of virologists such as Harald zur Hausen (Reynolds and
Tansey 2009). In 1972, zur Hausen commenced to conduct research for evidence supporting the
basic idea that certain viruses infecting the cell are able to change the cell’s properties turning it
into a cancer cell (Figure 1). Lastly, in 1983, he discovered that the HPV type “16” was
associated with cervical cancer. Even though the high scepticism of the scientific community on
the zur Hausen’s results, his discovery established the pillars for a new emerging filed of research
on the viral origins of cervical cancer—zur Hausen won the Nobel Prize in “Physiology or
Medicine” in 2008.
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Insert Figure 1 about here.
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To highlight how zur Hausen’s discovery changed the existing fields of research on cervical
cancer and opened a new one, we report in Figure 2 the scientific activity around the HPV and
cervical cancer as measured by number of published scientific articles. Specifically, we measured
this activity in four areas: (i) cervical cancer, (ii) HPV as well as (iii) a combination of these two
fields (iv) with further specification on the diagnostics area. We retrieved publication data by
queering, with different search strings (see Appendix A1 for technical details), the WoS database
contained in ISI Web of Knowledge. The search was performed in articles’ titles, abstracts, and
keywords. However, given that WoS includes abstracts only for articles published after 1990, to
avoid bias in the interpretation of the scientific activity’s trends, we performed two main
searches: one based keyword-search in articles' titles (Figure 2a) and the other one based on
keyword-search in articles' titles-abstracts-keywords for those article published since 1991
(Figure 2b). The initial low growing rates of “HPV+Cervical Cancer” and “HPV+Cervical
Cancer+Diagnostics” research areas, compared to the growing rates of the broader fields of
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“HPV” and “Cervical Cancer”, confirm the initial high scepticism of the scientific community on
zur Hausen’s discovery.
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Insert Figure 2 about here.
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In addition, Figure 3 confirms our ex-ante qualitative analysis on the rise of new research
areas on HPV and the cervical cancer as well as the growing interest around it. In particular,
building on Rafols, Porter, and Leydesdorff’s map of science and overlay techniques (2010),
Figure 3 shows the evolution of the cervical cancer area across the scientific areas for the 1975-
2011 period adopting a 5-year time window and by overlaying 36,521 publications (see Appendix
A1 for technical details). Each node represents an ISI subject category while a node’s size is
proportional to the scientific activity in the given subject category the node represents.2 In
addition, the set of subject categories were clustered according to 19 macro-disciplines having
different colours as reported in Figure 3 (see Rafols et al. 2010). It is worth noting that, while the
research on cervical cancer grows around its traditional scientific areas—“Biomed Science”,
“Clinical Medicine”, and “Health & Social Issues”—there is an increasing involvement of
“Infectious Diseases” area (starting from 1985-1989 period) after the zur Hausen’s discovery
thus confirming the involvement of virology in cervical cancer research.
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Insert Figure 3 about here.
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The private sector sought zur Hausen’s discovery as new technological opportunity for the
development of diagnostic tests able to compete with Pap test—in this period cytology-based
2 The node’s size follow a logarithmic function as a logarithmic function Area = ln(1+1000· pi), where pi is the
number of publications in the given i subject category. This choice facilitates the visualization of small nodes.
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testing using the Pap Smear already existed and was widely adopted (Casper and Clarke 1998). In
the mid-1980s, BRL-Life Technologies (BLT) was one of the first companies that attempted the
development of a commercial HPV test. To this end, BLT established a strong collaboration
with Georgetown University that, at that period, was providing grade cervical cancer samples.
However, while BLT was focusing its efforts on the development of a test for the detection of
two high-risk types of human papilloma virus (HPV-16 and HPV-18) two scientists, Attila Tibor
Lorincz (one of the zur Hausen’s collaborators) and George Roth (Institute Pasteur), discovered
and patented many novel types of human papilloma viruses.3 Due to these discoveries, their
scientific reputation as leading international scientists in the research on HPV and cervical cancer
began to grow.
In 1988, BLT gained the FDA (Food and Drug Administration) approval for its first HPV
test kit called “Virapap kit”—this can be considered as the beginning of development phase for
the emerging HPV diagnostics (Hogarth et al. 2011). Nonetheless, the BLT’s Virapap kit
presented two main issues: it was able to detect a limited number of high-risk HPV types (i.e.
HPV-16 and HPV-18) as well as it was radioactive and then, potentially hazardous to lab staff.
This reinforced the pathologists and cytologists’ scepticism on using HPV tests for detecting
cervical cancer. Therefore, given the commercial failure of Virapap kit, in 1990, BLT decided to
sell its molecular diagnostics division to Digene Corporation. While many other types of HPV
were still discovered, in 1992, Digene was able to develop and patent a new non-radioactive
detection technique called “Hybrid Capture” (HC). This novel technique presented a crucial
technical advantage that was an improved sensitivity on HPV strains—it was able to detect 14
HPV types. Specifically, by hybridised HPV DNA from clinical samples with complementary
RNA sequences, the HC captured the DNA-RNA hybrids created from an HPV infected sample
3 More than 100 types of HPV have been identified and more than 40 types can infect the genital area (“Sexually
Transmitted Diseases Treatment Guidelines, 2010”, Centre for Disease Control and Prevention).
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through antibodies (Lorincz et al. 1992). The HC test outperformed Digene’s competitors in this
emerging area.
Afterwards, during the 1990s, Digene was involved in a large number of head-to-head clinical
studies against the Pap test as well as to build a widespread collaboration network with different
institutions such as charities, government departments, universities, and research institutes.
Finally, in 1999, Digene was able to gain the FDA approval for the adoption of its second kit
(HC2) for the use in ASC-US triage protocol in 1999.4 The crucial collaboration on two studies
with Kaiser Permanente and National Cancer Institute (NCI) played an important role for the
FDA approval since Digene’s strategy it was clearly oriented to promote its HPV test as
supporting the gold standard of Pap test rather than as substitute test.
With the FDA approval of HC2 the development phase ends and an adoption phase of the
emerging HPV diagnostics commences. In particular, in this phase the consensus on the HPV
test as a better way of triaging woman with ASC-US grows. For instance, data from NCI-funded
ALTS trials (for which Digene provided supplies free of charge) create the consensus for the
inclusion of HPV testing in clinical guidelines issued by the American Society for Colposcopy
and Cervical Pathology (ASCCP). These guidelines recommended the HPV testing as an added
tool to the existing cytology-based screening process. In 2002, further support on the use of
HPV screening arrived from the American Cancer Society (ACS) that recommended, in its
guidelines, HPV testing as an adjunctive screen in women over 30. This indication gained the
FDA approval in 2003. Given the increasing consensus, the FDA approval, and the
endorsement in clinical guidelines were creating on the use of HPV screening, Digene made
massive investment in sales and marketing to speed the adoption of its test. Specifically, Digene
dedicated ad hoc sales force for targeting physicians as potential users of the test. All this activity
4 HPV testing could compete for three possible protocols in the cervical cancer screening namely: “ASC-US triage”,
“Adjunctive screen with pap”, and “Sole primary screening test”.
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around the HPV testing led Digene to become the primary sponsor and shaper of HPV clinical
trials given the numerous international collaborations with key actors in the field it established
and the adoption of the HC2 test in U.S. cervical screening.
One of key elements in Digene’s strategy was to build a broad collaboration network with the
organisations in its institutional environment as highlighted in Figure 4. Specifically, by building
on the sample of 5,873 publications on HPV Diagnostics (see Appendix A1), we use
bibliographic data in scientific articles (co-authorship) (Melin and Persson 1996, Newman 2001a,
b) at organisational level to construct the collaboration networks in HPV diagnostics area for the
1990-2011 period.5 Then, we highlighted the ego-network of the top-four private organisations
as measured by number of published scientific articles related to HPV diagnostics (see Table 2
for the top-10 list of private organisations).6 These private organisations are: “Digene Corp.”,
“DDL Diagnostic Laboratory”, “Merck & Co. Inc.”, and “GlaxoSmithKline Biologicals”. In
particular, yellow nodes represent each one of the top-four private organisations, while red
nodes represent the direct connections (co-authorships) these four organisations had with other
actors in the network (the remaining grey nodes). The size of each node is proportional to the
normalized degree centrality of the given actor in the overall collaboration network (Freeman
1979, Wassermann and Faust 1994).7 By comparing these four private organisations’ ego-
5 “The Vantage Point” software was used to clean the WoS data on affiliations (organizations) reported in
publications bibliographic information.
6 For clarity of visualization, we highlighted the ego-network of the top-four publishing private organisations only in
the largest component of the overall collaboration network.
7 The degree centrality measure counts a given node’s pk number of adjacencies. Considering a network of N nodes,
degree centrality adjusted for the network size, namely the normalized degree centrality, is measured as in the
followings:
1
),(
1)()(' 1
−=
−=
∑=
N
ppa
NpCpC
N
iki
kDkD
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network in Figure 4, it is worth noting how Digene spanned more broadly its network across the
overall network of collaborations in HPV diagnostic by establishing connection with the most
central public organisations (e.g. institutions, universities, research centres, governmental
organisations, etc.). This supports our historical analysis that highlighted how Digene’ was able
to shape its institutional environment by the creation of an intimate connection with the
entrenched institutions and organisations in the field. It is worth noting that the involvement of
large pharmaceutical companies, as Merck & Co and GlaxoSmithKline Biologicals, in the
diagnostic area was mainly due to the fact that at this time these companies commenced to
develop vaccines for the HPV. Therefore, they needed to be increasingly involved in the
diagnostic area being the diagnostic a fundamental component for the development of vaccines.
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Insert Table 2 about here.
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Insert Figure 4 about here.
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After the adoption phase, a period of growth characterized the emergence of HPV
diagnostics with an increasing consensus on the use of molecular diagnostic for cervical cancer
screening starting from 2003. Digene decided to rename its HC2 test in “DNAwithPap” to
reinforce its vision on a strong link between the molecular and cytological test for cervical
cancer. However, while Digene was focused on the larger primary screening market (ASC-US),
other companies entered in this market and commenced to report growing sales. In fact, not all
HPV testing was done by using Digene’s products as reported in a survey in 2006 (Moriarty et al.
where a(pi, pk) = 1 if and only if nodes pi and pk are connected by a line 0 otherwise. Then, the normalized degree
centrality ranges from 0 to 1.
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2008). Therefore, Digene started to build a strategy based on its status as the only company with
an FDA-approved test and the intellectual property rights to raise market entry barriers. This
involved Digene in a patent litigation, between 2001 and 2009, with important rivals such as
Gen-Probe, Roche, Beckman Coulter, and Third Wave. In addition, Digene redesigned its test to
make it self-contained and independent from the reagents other rival companies were selling.
Digene finally succeeded and its test became a “golden standard” for HPV diagnostics. This
successful strategy attracted the interest of another company, Qiagen, which bought Digene for
$1.6 billion in 2007 confirming then, the perceived value of the HPV testing market. However,
despite Digene’s success in building a monopoly position in cervical cancer screening market, the
HPV testing did not replace the traditional Pap test. On the contrary, the two technologies still
co-exist.
PRELIMINARY DISCUSSION AND COCLUSION
Given, the importance of emerging technologies for favouring technological change (Adner
and Levinthal 2002, Cozzens et al. 2010, Day and Schoemaker 2000), there is a growing pressure
to speed the process of understanding of the complexity and uncertainty that characterize the
process of emergence. With this preliminary version of the paper, we aim to shed light on this
complexity by a multi-perspective investigation of this phenomenon. To this end, we used an
institutional-evolutional theoretical framework (Van de Ven and Garud 1989, Blume 1992) to
analyse the emergence of HPV molecular diagnostic test (Casper and Clarke 1998, Clarke et al.
2003, Hogarth et al. 2011). Specifically, by combining the multi-perspective analysis with a mixed
qualitative-quantitative approach, we showed that the emergence of HPV diagnostics was mainly
driven by potential the technology had for the development of more reliable tests as well as by
companies seeking for new technological opportunities to compete with Pap test and profit from
these. However, as revealed by prior interviews and scientific and technological activity in the
field, only with the action of key actors, HPV diagnostics emerged as a new field of research and
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entered in the market for cervical cancer screening. Among these actors, Digene played an
important role and it was able to establish a monopoly position in the use of HPV test for
cervical cancer screening. In particular, Digene succeeded in its action by building on acquisition
of knowledge and competences and strong IPR strategies. Yet, most importantly, Digene was
able to challenge the existing standard (i.e. Pap test) by focusing its efforts in the establishment
of inter-organizational relationships with key institutions as charities, government departments,
universities, and research institutes. Accordingly, Digene started be increasingly engaged and
embedded in the social system surroundings the cervical cancer screening. This position in the
social system allowed Digene manipulating the institutional environment to legitimize and
influence the process of regulating and standardizing a new technology (Van de Ven and Garud
1989, 1993). Despite the Digene’s success in taking the lead of this emerging technology, HPV
diagnostics did not replace the existing standard, but it started to co-exist with Pap test. This is
consistent with the strong regulations and entrenched institutions that characterize this domain,
which spans several communities of practices such as cytologists and
obstetricians/gynaecologists.
Our work is on going, but our preliminary findings may suggest how key actors’ can be
motivated to support an emerging technology and give clues as to the effectiveness of policy
levers to stimulate and push the given technology towards development. For instance, this may
be crucial to coordinate visions (i.e. roadmaps), and supports the interaction among the different
actors in the social system across multiple institutional levels. Finally, we stress the importance to
combine qualitative analysis with comprehensive quantitative approaches to capture the process
of emergence in all its facets.
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Arthur, W. B. 1989. Competing technologies, increasing returns, and lock-in by historical events.
The Economic Journal 99(394) p.116-131.
Bijker, W. E. 1995. Of Bicycles, Bakelites, and Bulbs: Toward a Theory of Sociotechnical Change.
Cambridge, MA: MIT Press.
Blume, S. 1992. Insight and Industry: on the Dynamics of Technological Change in Medicine. Cambridge,
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FIGURES
Figure 1. Harald zur Hausen’s schematic representation of the data on the association
between HPV and cervical cancer (zur Hausen, 1987).
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(a)
(b)
Figure 2. Number of publications overt time: keyword search based on articles’ (a) titles and
(b) titles-abstract-keywords.
0
200
400
600
800
1000
1200
1400
1600
1800N
um
ber
of P
ub
licat
ion
s
HPV Cervical Cancer HPV+Cervical Cancer HPV+Cervical Cancer+Diagnostics
0
500
1000
1500
2000
2500
3000
Nu
mb
er o
f Pu
blic
atio
ns
HPV Cervical Cancer HPV+Cervical Cancer HPV+Cervical Cancer+Diagnostics
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Figure 3. The emerging of infection disease area in the cervical cancer research domain.
2007-2011 2005-2009
2000-2004 1995-1999 1990-1994
1985-1989 1980-1984 1975-1979
Agriculture Science Geosciences Biomedical Science Health & Social Issues
Business & Management Infectious Diseases Chemistry Materials Science
Clinical Medicine Mathematical Methods Cognitive Science Mechanical Engineering Computer Science Physics Ecology Science Psychology
Social Studies Economics Politics & Geography
Environmental Science & Technology
Infection Diseases starts to be
increasingly involved in cervical cancer
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Figure 4. Top-four companies’ ego-network overlaid on the overall collaboration network in HPV diagnostics area (1990-2011 period).
Merck & Co. Inc. GlaxoSmithKline Biologicals
Digene Corp. DDL Diagnostic Laboratory
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TABLES
Table 1. Key events in the emergence of the HPV molecular diagnostic test.
Phase Period Event
Exp
lorat
ion
1972-1983 Harald zur Hausen (Nobel Laureate in 2008) and his research team hypothesize and find support on the association between the HPV infections and cervical cancers.
mid-1980s
BRL-Life Technologies (BLT), in collaboration with the Georgetown University that providing graded cervical cancer samples, starts to work on the development of a commercial HPV test (initial focus on high-risk HPV types, i.e. HPV-16 and HPV-18).
Attila Lorincz and George Roth (Institut Pasteur) become leading international scientists in the research on HPV and cervical cancer due their important discoveries on novel HPV types.
Attila Lorincz and George Roth patent their discoveries.
Deve
lopme
nt
1988 BLT is the first company to gain the FDA approval for an HPV test. The first kit is called the “Virapap kit” and it is composed primarily of synthetic nucleic acid probes.
1990 Given the radioactivity issue and the profound scepticism of pathologists and cytologists on the Virapap kit, BLT decides to sell its molecular diagnostic division to Digene (a company co-founded by Attila Lorincz).
1992 While other actors continue to discover new HPV types, Digene develops and patents a non-radioactive detection technique called Hybrid Capture (HC). At the same time Digene starts to invest in a large number of head-to-head clinical studies against the Pap test as well as to collaborate with charities, government departments, universities, and research institutes.
1999 Digene gains the FDA approval for the adoption of its second kit called “HC2” in ASC-US triage testing protocol as results of a close collaboration with Kaiser Permanente and National Cancer Institute (NCI).
Ado
ption
2000 Data from NCI-funded ALTS trials (for which Digene provided supplies free of charge) demonstrates and creates the consensus that HPV test was a better way of triaging woman with AS-CUS.
The American Society for Colposcopy and Cervical Pathology (ASCCP) includes the HPV testing in its clinical guidelines.
2001 Digene is involved in a patent litigation against Gen-Probe, Roche, Beckman Coulter, and Third Wave (the litigation ends in 2009).
2002 The HPV test is included in the guidelines issued by the American Cancer Society (ACS) as an adjunctive screen in women over 30 (FDA-approved in 2003).
Digene speeds the adoption process of its test by massive investments in sales and marketing.
2003 Digene becomes the primary sponsor and shaper of HPV clinical trials given the numerous international collaborations with key actors in the field it established and the adoption of the HC2 test in cervical screening in the USA.
Grow
th
2003 New companies entered in the market of cervical cancer screening based on molecular approach reporting growing sales in this area, while Digene’s renames its HC2 kit in “DNAwithPap”.
2006 Digene’s test is now recognized as a “golden standard” as further supported by American Society for Colposcopy and Cervical Pathology’s (ACSSP) guidelines.
2007 Qiagen acquires Digene for $1.6 billion.
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Table 2. Top-10 publishing private organisations in HPV diagnostic area.
Private organisation
Number of publications in HPV diagnostics area
(1985-2011) 1) Digene Corp. 78
2) DDL Diagnostic Laboratory 63
3) Merck & Co. Inc. 60
4) GlaxoSmithKline Biologicals 50
5) Roche Molecular Diagnostic 30
6) Information Management Service Inc. 30
7) Abbott Molecular Inc. 15
8) Norchip A.S. 10
9) Cytyc Corp. 9
10) CETUS Corp. 8
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APPENDIX-A1
We queried the WoS database between January and February 2012. In particular, we used the
advanced search interface of the database to retrieve scientific articles in the research fields of: (i)
cervical cancer, (ii) HPV, (iii) HPV and cervical cancer, and (iv) HPV, cervical cancer and
diagnostics. Specifically, since WoS includes the abstracts of scientific articles starting from 1991,
we performed the keyword-search in articles' titles, abstracts, and keywords—named topics in
WoS and coded "TS"—only for those articles published after 1990. While we performed
keyword-searched in articles' titles—coded "TI" in WoS—for the whole period. Table A1
reports the WoS search strings.
Table A1. Search strings used in WoS and relative number of publications retrieved.
Area WoS search string Number of
publications (up to the year 2011)
Cervical cancer TS="Cervical Cancer*" OR TS="Cervical Tumor*" OR TS="Cervical Carcinoma*" OR TS="Cervical Neoplasm*" OR TS="Cervical Neoplasia*" OR TS="Cervix Cancer" OR TS="Cervix tumor" OR TS="Cervix Cercinoma" OR TS="Cervix Neoplasm" OR TS="Cervix Neoplasia*" OR TS="Cancer of the Cervix" OR TS="Tumor of the Cervix" OR TS="Carcinoma of the Cervix" OR TS="Neoplasm of the Cervix" OR TS="Neoplasia of the Cervix"
36,525
HPV TS="HPV*" OR TS="Human Papilloma Virus*" OR TS="Human Papillomavirus*" OR TS="Human Papilloma*virus*" OR TS="Human*Papilloma*Virus*”
31,573
HPV and cervical cancer
(TS="HPV*" OR TS="Human Papilloma Virus*" OR TS="Human Papillomavirus*" OR TS="Human Papilloma*virus*" OR TS="Human*Papilloma*Virus*”) AND (TS="Cervical" OR TS="Cervix")
15,818
HPV, cervical cancer, and diagnostic
(TS="HPV*" OR TS="Human Papilloma Virus*" OR TS="Human Papillomavirus*" OR TS="Human Papilloma*virus*" OR TS="Human*Papilloma*Virus*”) AND (TS="Cervical" OR TS="Cervix") AND (TS="diagnose" OR TS="diagnostic" OR TS="test" OR TS="assay" OR TS="detect" OR TS="screen" OR TS="screening")
5,873
