Driving forces of technological change in medicine: Radical innovations induced by side effects and their impact on society and healthcare

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Driving forces of technological change in medicine: Radical innovationsinduced by side effects and their impact on society and healthcareq

Mario Coccia a,b,*

aCNR – National Research Council of Italy, ItalybGeorgia Institute of Technology, USA

a r t i c l e i n f o

Article history:Received 18 January 2012Received in revised form 26 June 2012Accepted 29 June 2012

JEL classification:I10O33

Keywords:Radical innovationIncremental innovationBreast cancerOral contraceptive pillSide effectsAdverse effectsMedicineHealthcareTechnological changeDrug discovery

a b s t r a c t

Technological change in medicine has complex interactions driven by demand- and supplyside determinants. The epistemological position of this paper is that scientific researchgenerates in medicine vital radical innovations (new drugs/therapies) that are associated,a posteriori, to moderate and/or severe side effects. These side effects spur feedbackmechanisms, which support a co-evolution of innovation in parallel technological path-ways: 1) incremental innovations with lower side effects and higher efficacy; 2) emer-gence of new radical innovations induced from severe side effects. Empiricist-positivistarguments support this stance and show the main role of society and healthcare in thepatterns of technological innovation in medicine. Critical evidences are the foundation tostate main inductive theoretical implications between observed facts.

� 2012 Elsevier Ltd. All rights reserved.

1. Epistemological position

The analysis of the underlying driving forces of techno-logical innovation in medicine is a complex task but

important, very important to understand and support drugdiscovery industry ([26]; p. 30ff; [2]; p. 188ff; cf. also [12,14]for efficient political economy of R&D across countries; [11]for the vital role of democratization to support economicand technological change; [8,9] for anaccurate descriptionoftechnometric approaches to evaluate the impact of techno-logical innovations on geo-economic systems). Dynamics oftechnological change in medicine are different from elec-tronics,mechanics, andother scientificfields, andwithin thebroad medical field, patterns of technological innovation inpharmaceuticals are different from biotechnologies andhealth technologies (cf. [67]; p.4ff). In addition, the linearmodel of technological innovation does not capture alldeterminants of technological innovations inmedicine sincetechnological change is driven by complex demand- andsupply-side factors that can act simultaneously in specific

q I thank the staff of the Ceris-CNR (Italy), Yale University and GeorgiaInstitute of Technology (USA) for main research support. Valuablesuggestions have been provided by Anees B. Chagpar from Yale Univer-sity, two referees and the Editor-in-Chief Charla Griffy-Brown of Tech-nology in Society. In addition, I gratefully acknowledge financial supportfrom the CNR - National Research Council of Italy for my visiting at YaleUniversity and Georgia Institute of Technology where this research hasbeen originated and developed. The usual disclaimer holds, however.* CERIS – Institute for Economic Research on Firm and Growth, Collegio

Carlo Alberto, via Real Collegio, n. 30, 10024 Moncalieri, Torino, Italy.Tel.: þ39 011 68 24 925; fax: þ39 011 68 24 966.

E-mail address: [email protected].

Contents lists available at SciVerse ScienceDirect

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0160-791X/$ – see front matter � 2012 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.techsoc.2012.06.002

Technology in Society 34 (2012) 271–283


spatial-temporal contexts. Several works have providedmany valuable insights into the origin and diffusion oftechnological innovation in medicine (e.g. [67]), howeversome driving forces of the technological change are notbeen accurately explored and/or are under-researched.

This paper, in order to analyze howmedical innovationsoccur, claims the following epistemological position:

Scientific research generates in medicine vital radicalinnovations (e.g. a new drug A) that are associated,a posteriori, to moderate and/or severe side effects.These side effects spur feedback mechanisms for tech-nological change that generates parallel pathways rep-resented, respectively by: a co-evolution of theinnovation A (incremental innovations with lower sideeffects and higher efficacy) and a possible new techno-logical paradigm (emergence of new radical innovationsto treat severe side effects, called adverse effect-inducedinnovations).

The studyhereprovidesempiricist-positivist arguments tosupport this stance. The analysis focuses on patterns of inno-vation in fertility control drugs in order to understand somedriving forces of technological innovation in medicine and toanalyze the effects on society andhealthcare.Mainfindings ofthis study can be generalized to understand driving forces ofpatterns of technological innovation in medicine.

2. Scientific background and related works

Patterns of technological innovation in medicine are oftencharacterized by new technological paradigms. Dosi ([19]; p.152, original emphasis) states that a technological paradigm isa: “ ‘model’ and ‘pattern’ of solution of selected technologicalproblems, based on selected principles derived from thenatural science and on selected material technologies”. Thetechnological paradigm in a specific research field can spurseveral incremental and radical innovations that drive newtechnological and scientific trajectories. Sahal ([70]; p. 70,original emphasis) argues that: “the origin of revolutionaryinnovations lies in certain metaevolutionary processesinvolvingacombinationof twoormore symbiotic technologieswhereby the structure of the integrated system is drasticallysimplified”. In general, technological paradigms are generatedand driven by new scientific paradigms, although there can bean interval between scientific breakthrough, invention andinnovation that in some cases ismore than50 years (cf. [66]; p.198ff). New technological paradigms in medicine co-evolvewith the general process of technological change, leading toinnovative drugs for longer, better and healthier living (cf.[13,33]). According to Shine ([74]; p. 137): “Technology hasrevolutionized healthcare over the past 50 years” and someimportant medical innovations are proton pump inhibitors,serotonin reuptake inhibitors (SSRIs), etc. (p.138). Themedicalinnovations represent main technological advances but theyare also associated to adverse effects (see Refs. [75,48]).

Laubach ([46]; p. 212) argues that breakthroughs inbiomedical sciences are based on continuous small

scientific advances and interaction between clinicalresearch and clinical practice.1 Gelijns and Rosenberg ([27];pp. 8–9) describe the technological pathway of contracep-tive pill that, after the introduction in clinical practice(around 1960s), has been associated to an increased risk forthromboembolic disorders. The accumulation of clinicalexperience by feedback information of users and medicalstaff has played a key role for scientific research to find outthat high concentration of estrogen in contraceptive pillsmight be cause of these defects. Subsequent versions ofcontraceptive pills have decreased estrogen level with themain effect of a huge reduction of some serious pathologies(such as those linked to cardiovascular system). Currenttechnological change in medicine has a fast pace drivenmainly by scientific advances in molecular and cell biologythat focus on causes of diseases to produce innovativetreatments [13]. Perpich [60] shows the “astonishing”(p. 405) progress of genetics and human stem cells that hasbeen driving scientific advances in understanding thegenetic basis of diseases for supporting cancer therapiesand bio-regenerative medicine of hard and soft tissues (cf.also [50]; pp. xxx–xxxiii; [35]; pp.5–8). In particular, newdrugs have specificity for some diseases and target a singletype of receptor to reduce undesirable side effects incomparison to traditional agents that act in general way([72]; p. 71). The patterns of technological innovation inmedicine are complex and cannot be described with simplelinear models of R&D (cf. [69,67]). Radical innovations inmedicine are basic technological breakthroughs, oftenwithseveral shortcomings2; feedback mechanisms by users andmedical staff (in clinical practice) play a key role in R&D tospur the evolutionary change in new generations of drugswith incremental innovations in terms of higher efficacyand/or lower adverse effects and costs for healthcare ([26];p. 32ff). In fact, Gelijns and Rosenberg ([28]; p. 91ff) arguethat medical profession and clinicians have an active role inthe development of innovation in medicine that is often“user dominated”. There is a vast literature in theeconomics of innovation that analyzes these main topics,however some driving forces of technological change inmedicine are under-researched but they play a vital role inthe insurgence of new technological paradigms. In order toanalyze these critical determinants for the technologicalchange and progress in medicine, next section describesthe research strategy to support the epistemological posi-tion of radical innovations induced by adverse effects oforal contraceptive pill (e.g. breast cancer).

3. Sources and research method

The study here analyzes a main case study based on thedevelopment of the radical innovation of oral contraceptivepill that has driven an interesting technological change inmedicine. This case-study is the foundation of empiricist-positivist arguments to support the epistemological posi-tion. The starting point is a rational meta-analysis of thescientific literature to investigate the scientific chronicle of

1 An interesting example of fruitful technological development is theendoscope described by Refs. [26,28].

2 Cf. Ref. [10] for negative effects of other typologies of technologicalinnovations.

M. Coccia / Technology in Society 34 (2012) 271–283272


this main case study. An advanced search on Scopus-SciVerse [73] by Elsevier of combined keywords, repre-sented by radical innovation AND Adverse effect, such as“Contraceptive pill” AND “Breast cancer”, is carried out. Asgeneral rule, data mining has been performed including thekeywords into quotation marks: i.e. the search for the exactcombined keywords. The results are about 1200 articles ofjournals that indicate a proxy of scientific activities in thismain research field. After that, this vast scientific output hasbeen analyzed, considering Title-Abstract-Keywords, elimi-nating articles irrelevant to the subject of this scientificresearch. A restricted sample of about 100 articles con-cerning the research topic has been analyzed to pinpoint thecritical phases (chronicle) of technological change associ-ated to the radical innovation of oral contraceptive pill.

In addition, the study here carries out queries fromScopus-SciVerse [73] to detect the number of articles con-cerning innovations to treat breast cancer that is a strongindicator of trends in the scientific activity of this keyresearch field. In particular, two main advanced searches ofinnovative treatments for breast cancer are:

� Breast cancer and tamoxifen.� Breast cancer and trastuzumab.

The period of analysis is 1992 and earlier (first year)2011 (2012 is not considered because the scientific activityis in progress).

Data undergo a preliminary process of horizontal andvertical cleaning and by descriptive statistics (arithmeticmean, standard deviation, skewness, and kurtosis, usingthe SPSS statistics software) is checked the normal distri-bution of data to apply correctly the empirical analysis.

This vast sample of scientific articles is the basis to applysome models for analyzing the rate of scientific advances,which is an important indicator to assess the evolutionarygrowth of knowledge in breast cancer research. In partic-ular, as scientific advances in breast cancer research haveaccelerating, the exponentialmodel is a fruitful approach tomeasure potential technological pathways considering thefollowing assumptions (cf. [13] and references):

1. aP is the number of articles at 1993 (or first year).2. tP is the number of articles at 2011.3. t is the period analyzed.4. articles are a proxy of the scientific activity in this

research field.

The model is:

tP ¼ 0P$ert where e is the base of natural logarithm

(2.71828.).Hence ðtP=0PÞ ¼ ert; LogðtP=0PÞ ¼ rt;

r ¼Log

�tP

0P

�

t: (1)

r¼ rate of scientific advances in breast cancer research.

This method can offer an analytical framework for pin-pointing the evolution of technological and scientific

trajectories in breast cancer research based on innovativetreatments.

Data are also analyzed by models of linear regression. Inthis case, the logic relationship is:

Scientific output of radical innovation and=or research

field in medicine ðnumber of articlesÞ ¼ f ðtimeÞ:

The linearmodel of regression is applied on time series. Thegeneral specification is:

Radical innovation yi;t ¼ b0 þ b1Timei þ 3i;t (2)

where i subscript denotes the radical innovation, t subscriptdenotes time. The results can provide further informationto analyze technological change and to compare thepatterns of technological innovations in breast cancer withthe general development of breast cancer research associ-ated to contraceptive pills.

4. Empiricist–positivist evidence to support theepistemological stance: radical innovation for fertilitycontrol and its technology change

Dosi [20] states that an incremental innovation isa market-pull innovation, whereas radical innovation isgenerally originated by scientists and often incorporatesnew technologies or new combinations of existing tech-nologies. Thus, radical innovation is often classified asa technology-push innovation. In general, the driving forcesof technological change have diversity according to thesector, industry, institution, context and society in whichthe innovation has origin and is diffused. In particular, thetechnological innovation has heterogeneous and nothomogeneous patterns and determinants across andwithin industries. In medicine, technological innovationhas several and complex dimensions and technologicalchange in pharmaceuticals is different from the field ofmedical devices, as well as dynamics of innovations intherapeutics are different from diagnostics. In addition,innovation in medicine is not only a product or process, butalso a learning process between clinical research and clin-ical practice that supports the accumulation and advance-ment of technical knowledge (cf. [27]; p. 4ff).

First of all, I define a radical innovation A in medicine asa drastic drug and/or technology to treat and/or cure healthissues. This radical innovation can represent a new tech-nological paradigm and can generate twomain side effects:

- Moderate adverse effects are fixable disorders and/ordisorders that can be considerably reduced.

- Severe adverse effects are disorders and/or genetic damagesdifficult to repair that lead to diseases that put life at highrisk (e.g. cancer, stroke, myocardia infraction, etc.)

National Cancer Institute [57] describes the side effectas: “A problem that occurs when treatment affects healthytissues or organs”.

In general, the side effects are due to initial high uncer-tainty that a groundbreaking drugs has to treat a diseasewith efficacy. In other words, the initial high uncertainty of

M. Coccia / Technology in Society 34 (2012) 271–283 273


path-breaking drugs (radical innovations) is underpinnedin the interaction with complex mechanisms associated tothe evolution of the disease and/or carcinogenesis.

Hence, technological change of drug A can evolve withtwo parallel pathways that are important to set up thetheoretical framework of this research:

- Incremental innovation A0 is an improvement of thedrug A with lower adverse effects and/or lower risk ofmoderate and severe side effects; A0 acts with moreefficacy to treat and/or to cure diseases.

- Radical innovation B is a paradigm shift in the treatmentsof serious diseases for tissues and/or organs that can alsobe due to severe adverse effects generated by someinnovative drug A. It is a new technological paradigms.

These innovations can have a parallel development intwo different and simultaneous technological pathways.3

The epistemological position can be described in Fig. 1.The empiricist-positivist arguments to support the

epistemological position can be described in three mainsteps (as represented in Fig. 1) based on the analysis of theevolution of technological innovation in fertility controldrugs.

1. Step: Radical innovation A in Medicine (Oral ContraceptivePill: OC). Population acceleration since 1950s raises somesocio-economic problems and the “Club di Roma” arguesnegative scenarios for worldwide economic growth dueto high rate of population growth associated to limitednatural resources [55]. These problems and fears, asso-ciated to other dynamics, stimulate the scientificresearch in the direction of some innovations forcontrolling fertility ([5]; p. 184ff). In particular, a mainradical innovation in medicine is the oral contraceptivepills (OCs), based on synthetic estrogen and progestinhormones (highly active progestin norethindrone) syn-thetized by Carl Djerassi in 1951 and Frank B. Colton in1952 [61,62,65,25]. This discovery originates in US twoinnovative drugs: norethindrone by Syntex (Palo Alto,California), called Norlutin� and norethinodrel by Searle(Chicago, Illinois), commercial name Envoid� (cf.[64,81]). In 1957 these two drugs receive the approvalfor treatments of gynecologic disorders. In 1960 the USFood and Drug Administration also provides theapproval to use Envoid for contraception (cf. [43]). Later,these drugs are introduced in other countries. Since1960s, the use of OCs has had an exponential growth andthe estimation showed that the worldwide users ofcontraceptive pills were greater 12.5 million in 1967([78]; p. 12S) and about 200 million in 1996. In US, over40 years, the rate of adoption of OCs is between ¼ and 1/3 of women ([78]; p. 11S). Tyrer ([78]; p. 15S) also claimsthat: “by the end of reproductive years, >80% of United

States women have used the pill for an average of about5 years”. Nowadays OCs is widely diffused across allcountries. The introduction of the pill has also had a highimpact on American and worldwide society in terms ofsocial life, careers of woman, fertility control, laws andpolicy, religion, gender relations, feminist movement,sexual approaches, as well as health issues that will bedescribed in the next section.

2. Step: Adverse effects of contraceptive pills as background tospur technological change. The wealth, well-being andsocio-economic changes of richer countries are prone toa high demand of oral contraceptive pills (OCs) thatplays a vital role in birth control and demographictrends. Regan [63], studying Sweden context, shows thatthe effect of culture, historical factors, women’s level ofliteracy and religious composition are economicallysignificant determinants of the demand for oral contra-ceptive pills. Studies have showed that high concentra-tion of hormones, mainly in the previous versions of OCs,can be a main cause of several adverse effects such asheadache, dizziness, stroke, venous thromboembolism,myocardic infraction, cancer of the breast and liver, etc.[57]. In general, a high concentration of hormone in OCsmay generate adverse effects for women users and forthe next generation of daughter. In particular, breastcancer can be a severe adverse effect of high concen-tration of estrogen and other hormones present in OCsas well as in hormone therapy [3]. Breast cancer forms intissues of the breast, usually the ducts (tubes that carrymilk to the nipple) and lobules (glands that make milk).4

This cancer is the most frequent form of tumor affectingwomen in the world [31]. In fact, Table 1 shows theincidence and mortality of the most frequent cancers forwomen population, and confirms higher rates for thebreast cancer. Studies have estimated that approxi-mately 50% of breast cancer incidence can be due togenetic, physiologic, environmental, chemicals orbehavioral risk factors (alcohol consumption, smoking,etc.), with genetic risk factors accounting for 5–10% ofbreast cancer cases (cf. [21,51,29]).

Recent medical literature shows an association betweenbreast cancer and OCs either overall or especially insubgroups of women. For instance, Travis and Key [77]discuss about the epidemiological and experimentalevidence of estrogen in the etiology of breast cancer (p.239). Women currently using OCs and/or who had usedthem in the past 10 years have a slightly higher risk of breastcancer. “Experimental data suggest that conventionalestrogen treatment regimens, both as oral contraceptives(OCs) and hormone therapy (HT)., upset the normalestrogen/androgen balance and promote ‘unopposed’estrogenic stimulation of mammary epithelial proliferationand, hence, potentially breast cancer risk” ([17]; originalemphasis). Other research shows different results (OCs arenot associated to an increased risk of breast cancer, cf. [68];p. 32). Klassen and Smith ([45]; p. 219) argue that exoge-nous exposures to estrogen and other hormones, presents in

3 A referee of this paper argues that when scientists find side effects ofmedicines, they could choose to: 1) develop a completely new drugwhich then bypass the side effects; 2) incrementally improve the drug sothat there are less side effects; or 3) develop new drug/remedies forcuring the side effects. 4 As defined by Ref. [57].



OCs, increase the breast cancer risk. Gaffield et al. [24]evidence that women taking OCs in the period before the1975 may be at greater risk for breast cancer (p. 372). Anempirical research carried out by Chagpar and Coccia [7]shows that the breast cancer tends to be higher acrossricher countries that are prone to a greater demand of OCs.In particular, the relationship between incidence of breastcancer and GDP per capita analyzed by partial correlation,controlling -ceteris paribus- the number of computedtomography (CT) scanners across countries, shows a highcoefficient equal to 60.3% (sign.0.00). In addition, the esti-mated relationship shows an expected breast cancer inci-dence increase of approximately 0.05% for a GDP increase of1% and an expected breast cancer incidence increase ofapproximately 3.23% for a CT scanner increase of 1% [7]. DeRoo et al. ([16]; p. 497ff) find that Geneva women (inSwitzerland) had a greater prevalence of oral contraceptiveand hormone replacement therapy use that is associated toan increased risk of breast cancer in comparison withShanghai women that had different habits (e.g. Shanghaiwomen have a longer duration of breastfeeding thanGeneva women). It is also important to note that richercountries have routine mammographic screening as anaccepted practice for the early detection of breast cancer.Mammographic screening national plans and other medicalequipment increase the incidence of cancers but also playa vital role to reduce the mortality from breast and othercancers [7]. It is important to note that although severalchanges in doses and biochemical structures have takenplace over time for OCs, there is a hot scientific debate aboutthe possibility that oral contraceptives (OCs) may increasethe risk of breast cancer [6,53,52].

3. Step. Parallel technological pathways: incremental inno-vations (co-evolution) and new radical innovations fromadverse effects of previous innovations.

The adverse effects of OCs and HT (Hormone Therapy)for breast and other organs have been playing a criticalrole to spur an intensive scientific activity in order todrive the co-evolution of incremental innovations to reducemoderate adverse effects and the insurgence of vital radicalinnovations to treat severe adverse effects (e.g. anticancertreatments for breast).

- As far as the first technological pathway is concerned, theadverse effects of OCs have supported a continuous streamof incremental innovations represented by new genera-tions of OC pills. The evolution of this technologicalpathway, after the introduction of first-generation inno-vation, is driven by feedback mechanisms based oninformative flows from users (patients) and medical staffthat spur improved generations of this technologicalinnovation in medicine. In general, users in medicine(patients, clinicians, healthcare, etc.) affect the direction ofthe patterns of technological innovation by selectionmechanisms for improving innovations and/or reducingcosts ([26]; p. 32). A main feedback of OC users hasgenerated the reduction of the high concentration ofestrogen and progestin presents in OCs with the criticaleffect of a huge decrease of several pathologies and sideeffects (e.g. venous thromboembolis, etc.). In particular, atthe beginning Envoid (the first OC) contained 150 mg5

estrogen and 9.85 mg progestin, in 1965 the dose was100 mg estrogen and 2.5 mg progestin ([78]; p. 13S). Since1983 the majority of OCs has a dose of about 50 mg (orlower). In addition, Envoid is dismissed in 1988, alongwithother first-generation of high-estrogen OCs ([78]; p. 15S).Hence, the side effects act as demand drivers for incre-mental innovations of previous pioneering innovations.

- As far as the second technological pathway is concerned(grey area in fig. 1), I also consider in the epistemologicalposition that severe adverse effects of medical innova-tions, such as breast cancer in the case of OCs, can spura technological change with main technological

Table 1Most frequent cancers for women (World data).

Cancer Incidence Mortality

Number ASR (W) Number ASR (W)

Breast 1384155 39.0 458503 12.5Cervix uteri 530232 15.3 275008 7.8Colorectum 571204 14.7 288654 7.0Lung 515999 13.6 427586 11.0Stomach 348571 9.1 273489 6.9Corpus uteri 288387 8.2 73854 2.0Ovary 224747 6.3 140163 3.8

Note: Age-standardized rate ASR (W). Source: Ref. [31] (IARC) Section ofCancer Information (5th January 2012).

T T+1 T+2

1. Radical innovation Ain Medicine:OCs

2. Some side effects (Sef) of innovation A

3. Technological change/ Co-evolution

Incremental Innovation A’ to reduce Sef of A

New radical induced Innovation B to treat Severe Sef of A

INFER

Scientific Research

Scientific Research

Fig. 1. Parallel pathways of technological change in medicine and adverse effect-induced innovations (grey area).

5 A microgram (mg) is a unit of mass equal to one millionth (1/1,000,000) of a gram.



breakthroughs to treat these diseases/disorders. Thistypology of technological change in medicine is under-researched and I would like to provide arguments tosupport my stance. The studies by Lilienfeld, McMahonand Feinleib [49,54] and others scholars, between femalereproduction and breast cancer considered the hypoth-esis that estrogen was a carcinogen factor. The subse-quent scientific research, also stimulated by higherincidence of breast cancer across population, has gener-ated a critical breakthrough that has revolutionized thisfield: the discovery and analysis of the estrogen receptor(ER) on human breast cancer [38,39]. In fact, severalscholars found that patients affected by breast cancer,associated to high level of ER expression, were moreresponsive to hormone-ablative therapy. These mainresults around the role of the ER in breast cancer raisedthe possibility of developing innovative anticancer drugsbased on anti-estrogenic compounds. A vital radicalinnovation in this setting is tamoxifen, which is a non-steroidal anti-estrogen [32]. In particular, in 1970s theearly research about triphenylethylenes (Tamoxifen)focused on birth control, but cancer researchers realizedthat these drugs might also be useful as estrogen antag-onists to inhibit the growth of cancer cells, specificallybreast cancer cells. However, at the beginning the leadingpharmaceutical firms were focusing on anti-estrogeniccompounds as contraceptives and they were not inter-ested in developing innovative anti-cancer drugs. Whenthe development of these medical compounds ascontraceptives achieved the maturity phase, some phar-maceutical companies accepted to commercializeTamoxifen in the treatment of breast cancer [41,42]. Thiscan be seen as an extension of the use of drugs fordifferent diseases that can contribute to increase thecosts for healthcare. Trials show that treatment withtamoxifen after surgery interventions reduced the inci-dence of recurring breast cancer such that it is consideredits vital role in the chemoprevention (cf. [22]). Somestudies also discuss whether tamoxifen is effective toreduce the mortality from breast cancer [23,79,80].Tamoxifen is the first step in the research field ofhormone anticancer treatments [40]. Another mainscientific breakthrough is the discovery, in 1970s, thatgenetic damages caused by radiation, chemicals and/orenvironmental toxins can generate cancers. Subsequentadvances in molecular biology have created the back-ground to support innovative treatment for geneticdisorders and diseases (cf. [72]; p. 73ff.). In particular, thecontinuous research on breast cancer (underpinned inprevious scientific advances), converging with othermain scientific discoveries, has focused on moleculartargets, which are the cellular receptor for the female sexhormone estrogen that is the pathway signals for breastcancer growth. “When estrogen binds to the estrogenreceptor (ER) inside cells, the resulting hormone-receptorcomplex activates the expression of specific genes,including genes involved in cell growth and proliferation.Research has shown that interfering with estrogen’sability to stimulate the growth of breast cancer cells thathave these receptors (ER-positive breast cancer cells) isan effective treatment approach. Several drugs that

interfere with estrogen binding to the ER have beenapproved by the FDA for the treatment of ER-positivebreast cancer. Drugs called selective estrogen receptormodulators (SERMs), including tamoxifen and tor-emifene (Fareston�), bind to the ER and prevent estrogenbinding” [57]. This intensive activity on breast cancerresearch, also driven by severe side effects of OCs mainlyin richer countries, is the background that has beensupporting innovative anticancer drugs, called targetedtherapies (cf. [13]). They represent a technological para-digm in cancer therapies. These medical (radical) inno-vations offer the possibility of creating new therapies tostop an uncontrollably growth of cancer cells in breastand/or other organs/tissues. In fact, the first of these vitalmolecular-targeted treatments is the monoclonal anti-body called “Trastuzumab” (US brand name isHerceptin�). This anticancer drug, called signal trans-duction inhibitors,6 was discovered by scientists A. Ull-rich and H. M. Shepard at the University of California LosAngles (UCLA) and jointly developed between UCLA andthe biotech company Genetic Engineering Technology,Inc. It is approved for the commercialization in 1998 totreat some typologies of breast cancers. Trastuzumab isa recombinant humanized monoclonal antibody7 tar-geted against the human epidermal growth factorreceptor 2 (HER2)8 that is overproduced in manyadenocarcinomas. HER2-positive cancers are moreaggressive and women with this form of breast cancerhave a higher risk of disease recurrence and death. Sla-mon et al. [76], that have had a main role in developingthis medical radical innovation, find that women withadvanced breast cancer, treated with this new anticancerdrug, have a higher survival rate as well as quality of life,in comparison with patients who received standardchemotherapy and/or treatments. In short, this targetedtherapy blocks specific enzymes and growth factorreceptors involved in breast cancer cell proliferation.Trastuzumab, though has several side effects, increasesthe survival of womenwithmetastatic breast cancer, andnew trials are assessing the benefit of this treatment asfirst-line approach, i.e. in the early-stage of the cancer[57]. Trastuzumab shows that molecular-targeted treat-ments can effectively treat cancers, generating a revolu-tion in clinical practice by new anticancer treatments for

6 “The process by which a cell responds to substances in its environ-ment. The binding of a substance to a molecule on the surface of a cellcauses signals to be passed from one molecule to another inside the cell.These signals can affect many functions of the cell, including cell divisionand cell death. Cells that have permanent changes in signal transductionmolecules may develop into cancer.” [57].

7 “A type of protein made in the laboratory that can bind to substancesin the body, including tumor cells. There are many kinds of monoclonalantibodies. Each monoclonal antibody is made to find one substance.Monoclonal antibodies are being used to treat some types of cancer andare being studied in the treatment of other types. They can be used aloneor to carry drugs, toxins, or radioactive materials directly to a tumor” [57].

8 “A protein involved in normal cell growth. It is found on some types ofcancer cells, including breast and ovarian. Cancer cells removed from the bodymay be tested for the presence of HER2/neu to help decide the best type oftreatment.HER2/neu is a typeof receptor tyrosinekinase. Also called c-erbB-2,human EGF receptor 2, and human epidermal growth factor receptor 2” [57].



breast and other organs/tissues. In fact, Trastuzumab isalso applied for gastric or gastro esophageal junctionadenocarcinoma. In addition, this radical innovation hasopened the innovation avenue to several innovative tar-geted therapies such as Gefitinib and Erlotinib applied totreat non-small cell lung cancer [13].

Hence the dynamics of technological change in medi-cine is driven by a synergic system of demand- and supply-side forces that simultaneously act to support fruitfultechnological trajectories and new technological para-digms. The chronicle timeline of technological change inbreast cancer research that induces incremental and radicalinnovations from moderate and severe adverse effects isrepresented in Fig. 2.

In short, in addition to incremental innovation on OCs,the combination of several factors, such as scientificresearch on control fertility, side effects of oral contracep-tive pills (e.g. breast cancer), scientific breakthrough inmolecular and cell biology, and also luck, has underpinnedthe pathway of the technological change in anticancertreatments by radical innovations (targeted therapies)induced from severe side effects (e.g. breast cancer) ofprevious innovations (i.e. OCs). This co-evolutionaryprocess has been paving the innovation avenue to

a branch of several technological paradigms that havegenerating a revolution in clinical practice, represented by:

a) Gene therapy involves the introduction of geneticmaterial into a person’s cells to fight disease;

b) Biological therapies use the body’s immune system tofight cancer;

c) Targeted cancer therapies: “are drugs or other substancesthat block the growth and spread of cancer by inter-feringwith specificmolecules involved in tumor growthand progression” (as defined by [57]).

4.1. Empirical analysis

The evolutionary growth of knowledge in breast cancerresearch analyzed by the rate of scientific growth (Eq. (1)) ispresented in Table 2, whereas Table 3 shows the estimatedrelationships of scientific output (Eq. (2)) in key researchfields and innovative drugs for breast cancer.

The rate of scientific growth shows the considerablefigure in the research field of oral contraceptive pill andbreast cancer research (7.05%) that has driving the techno-logical change. The rate of scientific growth on Tamoxifen islow because the scientific research on this drug is ina maturity phase (it was launched in 1970s). Instead, the

Highly active progestin

norethindrone synthetized

Djerassi (1951) and

Colton (1952)

Norlutine and Envoid

receive the approval for treatment of gynecologic disorders.

Approval to use Envoid for contraception

[150µg estrogen and

9.85µg progestin]

1965 Incremental innovation: lower dose,

[100µg estrogen and

2.5µg progestin]

Since 1983 the majority of pills have a dose of about 50µg. In

addition, Envoid is dismissed in

1988.

Discovery and analysis of the

estrogen receptor (ER)

on human breast cancer (Jensen et al.,

1971)

1970s the early research aboutTamoxifen focused on birth control, but cancer researchers realized that these drugs might also be useful as estrogen antagonists to inhibit the growth of cancer cells, specifically breast cancer cells. Tamoxifen, originally described as an anti-oestrogen and antifertility agent, is now a pioneering medicine for the treatment and prevention of breast cancer. Laboratory and clinical research defined the concept of selective oestrogen receptor modulation in the 1980s.

Research in biomedicine has focused on a molecular target, which is the cellular receptor for the female sex hormone estrogen that is the pathway signals for breast cancer growth. The first of these vital molecular-targeted treatments is the monoclonal antibody called “Trastuzumab” (brand name is Herceptin®). Trastuzumab is approved for the commercialization in 1998 for the treatment of certain types of breast cancer.

2. Scientific breakthrough and incremental innovationsinduce from adverse effects of 1st generations of OC pills

1. Radical innovation of contraceptive pill

3. Radical innovations induced also by severe adverse effects of OCs: Targeted therapies for breast cancer

Fig. 2. Chronicle timeline based on radical innovation with adverse effects (1st period) that spur incremental innovations (2nd period) & radical innovationsinduced by adverse effects (3rd period).



innovative drug Trastuzumabhas thehigher rate of scientificgrowth because this new targeted therapy has generatinga revolution in clinical practice as anticancer treatment forbreast and other typologies of tumors (Table 2).

Table 3 shows the estimated relationship. The modelsprovide robust estimates by fairly high t-ratios (larger than 2)for all coefficients and F test significant at the level of 0.00. Thegoodness of fit measured by R2 adjusted (the coefficient ofdetermination adjusted) shows high values. Durbin–Watsontest, after correction with the Prais–Winsten estimationmethod shows low serial correlation (5% significance level).Coefficient of regression confirms the high magnitude for theinnovative drug Trastuzumab, Tamoxifen and in general forbreast cancer research (sign. 0.001). This empirical evidenceconfirms the high intensity of breast cancer research associ-ated to oral contraceptive pill and innovative drugs for breastcancer that have been laying the foundation to pave theinsurgence of further new technological paradigms andtechnological trajectories in not-too-distant future.

5. Discussion and inductive theoretical implications

Exponential growth in medical knowledge and theintroduction of innovative drugs over the past fifty yearsare unparalleled. This technological progress in medicine isdue to several simultaneous interwoven factors. Studieshave showed as the introduction of a first-generationinnovation in medicine is “probably never the optimalversion” ([26]; p. 31) because some adverse effects can bedetected only ex-post, after a vast use in clinical practice bymedical staff and patients. In general, medical innovation,after the introduction on the market, has a lot of uncer-tainty about the efficacy ([26]; p. 31–32) and feedbackmechanisms play a vital role for incremental innovationsrepresented by new generations of drugs. In particular,clinicians and patients provide main information onshortcomings of new drugs originated in the Research labsto support further Development of medical innovations([28]; p.91ff). In fact, in medicine the development processof innovations continues after the introduction on themarket ([26]; p. 31). In addition, we have seen that inpresence of severe side effects in clinical practice from theuse of first-generation drugs (e.g. higher breast cancer riskin the case of previous versions of OCs), the feedbackmechanisms can spur new technological paradigms to treatthese severe adverse effects (called innovations induced byadverse effects). Some main instances are also the recentexperience of the adverse effects of COX-2 inhibitors9 that

have been salutary for chemoprevention since significantlyreduces the risk of precancerous polyps recurring in thecolon or rectum ([36]; p. 443).

The analysis of the main case study of oral contraceptivepill provides main inductive theoretical implicationsamong the relationships of observed facts. In particular:

a) R&D in medicine spurs new technological innovations(drugs) that improve the wellbeing of societies (e.g. 1stgeneration of OCs). Ex-ante the innovative drug shoulddeliver several benefits to societies.

b) A posteriori, after extensive use in clinical practice, newradical innovations (drugs) can be associated to severeadverse effects (due to initial high uncertainty aboutthe effective therapeutic effects). Some drugs caninduce cancers a fortiori (e.g. higher breast cancer riskdue to 1st generation of OCs).

c) The severe adverse effects (and initial therapeuticuncertainty) triggered by first-generation of drugs spurintensive feedback mechanisms for technologicalchange that supports parallel pathways: a) incrementalchanges on first-generation innovation to reduce themoderate side effects and increase the efficacy; b) someparallel scientific and technological forces can break-out10 technological paradigms (in related fields) by theinsurgence of new paradigms to solve severe adverseeffects (radical innovations induced by severe adverseeffects, e.g. the first targeted therapy to treat breastcancer).

These interlinked relationships create a dynamicvirtuous circle of technological change driven by sideeffects: i.e. radical innovations induced by adverse effects. Infact, patterns of technological innovation in medicine,driven by demand- and supply-side factors, spur bothincremental innovations and new radical innovations thatsolve new needs and improve the wellbeing of societies. Asimilar pattern has been also showed by Shine ([74]; p.137ff). In short, established drugs, their side effects inclinical practice and new emerging innovations are inter-woven elements of the dynamic process of technical changeand technological progress in medicine. According to Sahal([70]; p.71): “the innovation process in a wide variety offields is governed by a common system of evolution. Typi-cally, the process of technological development within anygiven field leads to the formation of a certain pattern ofdesign. The pattern in turn guides the subsequent steps inthe process of technological development. Thus innova-tions generally depend upon bit-by-bit modification of anessentially invariant pattern of design. . . . technicaladvances . . . are expected to occur in a systematic manneron what may be called innovation avenues that designatevarious distinct pathways of evolution”.

Radical innovations induced by adverse effects aredriven by feedback mechanisms associated to other deter-minants such as continuous advances in basic biomedicalsciences and molecular biology. In fact, the convergence of

Table 2Rate of scientific growth measured by number of scientific output.

Keywords % Period

Breast cancer 8.5 1993–2011Breast cancer and OC pill 7.05Breast cancer and tamoxifen 4.9Breast cancer and trastuzumab 58.67 1998–2011

9 COX-2 selective inhibitor is a form of non-steroidal anti-inflammatorydrug that directly targets COX-2, an enzyme responsible for inflammationand pain. 10 Ref. [18].



research fields in molecular and cell biology (genomics,11

genetics12 and proteomics13 – Fig. 3) has played a vitalrole to understand disease biology and to support theinsurgence of new technological paradigms that havegenerating a revolution in clinical practice. The current R&Dprocess inmedicine is not linear, and Gelijns and Rosenberg[26] show the drawbacks of the linear model to describethe technological change in medicine; a modern R&Dprocess, underlying radical innovations induced by adverseeffects, can be represented by several interwoven phasesand sub-phases as in Table 4.

The first phase in drug discovery process starts with theunderstanding of the complex biology of disease to iden-tify genes that are active in diseased tissue but not inhealthy tissues/organs. After that, the causes of the diseaseare investigated to find the target in order to design a newform of targeted therapy. A main phase in the R&D processin medicine is played by Development phase driven bycontinuous interaction between clinical research andclinical practice that supports new drugs by small scien-tific advances, rather than drastic breakthrough ([28]; p.67). Adverse effects by extensive use of new drugs enter inthe R&D process of drug discovery by multiplicity oflearning process that is a critical determinant underlyingtechnological change in pharmaceuticals and biomedical

sciences to reduce shortcomings of new drugs (innova-tions). The multiplicity of learning process in clinicalresearch and practice reduces initial therapeutic uncer-tainty of groundbreaking drugs. Nelson [58] argues that inalmost all technological fields the professional knowledgeis acquired by learning by doing and using, associated topractical activities (pp. 487–488). In particular, the gradualR&D process that drives innovations induced by adverseeffects is affected by the progress of “Learning in practice”and “Advances in biomedical scientific understanding” (cf.[56]; p. 512, passim). In general, R&D of drug discovery isenhanced by underlying forces of learning processes inwhich biomedical basic research and clinical researchadvances have vital continuous feedbacks from clinicalpractice, based on participation of patients, clinicians andmedical staff: this learning process is based on stronglyintertwined relationships, with causal arrows going bothways, among basic biological research, clinical researchand clinical practice (cf. [30,34,47]). Hence, these innova-tions induced by adverse effects are driven by the so-called “ ‘learning via diffusion’ .. The increased adop-tion of a technology paves the way for improvement in itscharacteristics” ([71]; p. 114). Another essential aspect ofthe technological change in medicine is the collective andcumulative learning (cf. also [56]; pp. 521–523; [44]) andpath-dependence [15,59] in drug discovery that alsosupport the co-evolution of innovative drugs.

Fig. 4 shows that the incidence and mortality of sometypologies of cancers (e.g. liver, pancreas, thyroids, etc.) havebeen increasing and this might be due to adverse effects ofestablished and/or new drugs. This is the background forfuture technological change and medical R&D in order tospur innovations induced by adverse effects.

Table 3OLS results.

Explanatory variable Dependent variable (number of scientific output)

Breast cancer (BC) BC & oral contracept. pills BC & tamoxifen BC & trastuzumab

Year (bi) 783.67*** (37.32) 3.61*** (0.36) 61.18*** (4.76) 85.25*** (4.52)Constant �1559851.13*** (74715.75) �7172.34*** (724.033) �121397.25*** (9535.15) �170393.70*** (9057.87)R2 adjusted 0.96 0.85 0.90 0.97Durbin–Watson 2.015 1.998 2.029 1.907F test sign. 0.00 0.00 0.00 0.00N. cases 18 18 18 13

***Parameter is Significant at 0.001.Note: Source by SciVerse [73] over 1993–2011 and 1998–2011 (Trastuzumab).

Fig. 3. Convergence of scientific fields driving drug discovery pathway [13].

11 Genomics is a discipline in genetics that studies the genomes oforganisms. In particular, it determines the entire DNA sequence oforganisms and fine-scale genetic mapping efforts.12 Genetics studies the molecular structure and function of genes in thecontext of acellor organism.13 The proteomics is the systematic analysis to understand the role ofprotein profiles of tissues.



Table 4Modern R&D process in drug discovery.

trials are an important tool to strengthen the understanding of the drug and to give guidance to prescribers and patients on the safe and appropriate use under various clinical conditions.

Source: adapted by Ref. [4].



However, it is also important to note that these drivingforces of continuous drug discovery process based onradical innovations induced by adverse effects contribute toincrease the cost in healthcare. Shine ([74]; p. 140) showsthat since 1990s health care costs in US have been sharplyincreasing and 25–40% of cost increases are from applica-tions of innovation and new technology. Jain [37] (p. 320)argues that R&D costs for drug discovery are also increasingexponentially (at a pace of 10.8% per annum, whereasrevenue from new drugs is growing at the rate of 7%), witha development process of new drugs (over the past decade)of about 11–15 years and less than 10% of drugs deliveracceptable commercial returns (cf. [1]; p. 392).

Literature shows that the technological change inmedicine is complex and the study here has analyzed themain role of feedback mechanisms that spur two parallelpathways of innovation: first, incremental innovations withlower adverse effects and/or higher efficacy; second, radicalinnovations induced by adverse effects to treat severeadverse effects generated from previous “technologies. ina primitive condition” ([27]; p. 8).

The specificity of the patterns of technological inno-vation in medicine, with pros and cons for societies aswhole, has driving the scientific and technologicalprogress and generating a revolution in clinical practice.This technological change in medicine tend to be costlydue to increasing costs for R&D process (e.g. adoption ofhigh-tech instruments and equipment) that affect pricesof new drugs and budgets of healthcare. These factorsalso affect the direction of new patterns of technologicalinnovation that may reduce the intensity and/or focus

on cheap drugs with lower efficacy. As modern econo-mies need cost effectiveness medical drugs and tech-nologies, health policy of countries should be designedto reduce costs in healthcare and at the same time tosupport the incentive to innovation in drug discoveryindustry [14]. As forces of technological progress cannotbe stopped, some health policies that may be useful tosupport the dynamics of technological change in medi-cine as well as to reduce the economic and social costsfor societies are:

, strategies focused on rational use of innovative drugs byan accurate and transparent information of all lung-runside effects to clinicians and in particular users;

, strategies focused on prevention and chemoprevention[36,82].

These health policies could not hamper the drugdiscovery process and simultaneously could generatefruitful long-run socio-economic effects for societies interms of higher wellbeing and quality of the life.

In all, this study shows as technological change inmedicine has some determinants and patterns that area terra incognitawhich deserve further scientific analysis tounderstand and support the modern progress of medicineand therefore of society.

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Mario Coccia is an economist at the National Research Council of Italy,visiting scholar at Georgia Institute of Technology (USA) and visitingprofessor at the University of Piemonte Orientale (Italy). He has beenresearch fellow at the Max Planck Institute of Economics, visitingprofessor at the Polytechnics of Torino (Italy), visiting researcher at theUniversity of Maryland (College Park), Institute for Science and Tech-nology Studies at the University of Bielefeld and Yale University. He haswritten extensively on Economics of Innovation and Science; his researchpublications include more than one hundred and eighty papers in severalsocio-economic disciplines.


Driving forces of technological change in medicine: Radical innovations induced by side effects and their impact on society and healthcare

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