نیروهای محرک تغییرات تکنولوژیکی در پزشکی : نوآوری های رادیکال ناشی از عوارض جانبی و تاثیر آنها بر جامعه و بهداشت و درمان

Technological change in medicine has complex interactions driven by demand- and supply side determinants. The epistemological position of this paper is that scientific research generates in medicine vital radical innovations (new drugs/therapies) that are associated, a posteriori, to moderate and/or severe side effects. These side effects spur feedback mechanisms, which support a co-evolution of innovation in parallel technological pathways: 1) incremental innovations with lower side effects and higher efficacy; 2) emergence of new radical innovations induced from severe side effects. Empiricist-positivist arguments support this stance and show the main role of society and healthcare in the patterns of technological innovation in medicine. Critical evidences are the foundation to state main inductive theoretical implications between observed facts.

The analysis of the underlying driving forces of technological innovation in medicine is a complex task but important, very important to understand and support drug discovery industry ([26]; p. 30ff; [2]; p. 188ff; cf. also [12] and [14] for efficient political economy of R&D across countries; [11] for the vital role of democratization to support economic and technological change; [8] and [9] for an accurate description of technometric approaches to evaluate the impact of technological innovations on geo-economic systems). Dynamics of technological change in medicine are different from electronics, mechanics, and other scientific fields, and within the broad medical field, patterns of technological innovation in pharmaceuticals are different from biotechnologies and health technologies (cf. [67]; p.4ff). In addition, the linear model of technological innovation does not capture all determinants of technological innovations in medicine since technological change is driven by complex demand- and supply-side factors that can act simultaneously in specific spatial-temporal contexts. Several works have provided many valuable insights into the origin and diffusion of technological innovation in medicine (e.g.[67]), however some driving forces of the technological change are not been accurately explored and/or are under-researched. This paper, in order to analyze how medical innovations occur, claims the following epistemological position: Scientific research generates in medicine vital radical innovations (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 technological change that generates parallel pathways represented, respectively by: a co-evolution of the innovation A (incremental innovations with lower side effects and higher efficacy) and a possible new technological paradigm (emergence of new radical innovations to treat severe side effects, called adverse effect-induced innovations). The study here provides empiricist-positivist arguments to support this stance. The analysis focuses on patterns of innovation in fertility control drugs in order to understand some driving forces of technological innovation in medicine and to analyze the effects on society and healthcare. Main findings of this study can be generalized to understand driving forces of patterns of technological innovation in medicine.

Exponential growth in medical knowledge and the introduction of innovative drugs over the past fifty years are unparalleled. This technological progress in medicine is due to several simultaneous interwoven factors. Studies have showed as the introduction of a first-generation innovation in medicine is “probably never the optimal version” ([26]; p. 31) because some adverse effects can be detected only ex-post, after a vast use in clinical practice by medical staff and patients. In general, medical innovation, after the introduction on the market, has a lot of uncertainty about the efficacy ([26]; p. 31–32) and feedback mechanisms play a vital role for incremental innovations represented by new generations of drugs. In particular, clinicians and patients provide main information on shortcomings of new drugs originated in the Research labs to support further Development of medical innovations ([28]; p.91ff). In fact, in medicine the development process of innovations continues after the introduction on the market ([26]; p. 31). In addition, we have seen that in presence of severe side effects in clinical practice from the use of first-generation drugs (e.g. higher breast cancer risk in the case of previous versions of OCs), the feedback mechanisms can spur new technological paradigms to treat these severe adverse effects (called innovations induced by adverse effects). Some main instances are also the recent experience of the adverse effects of COX-2 inhibitors9 that have been salutary for chemoprevention since significantly reduces the risk of precancerous polyps recurring in the colon or rectum ([36]; p. 443). The analysis of the main case study of oral contraceptive pill provides main inductive theoretical implications among 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. 1st generation of OCs). Ex-ante the innovative drug should deliver several benefits to societies. b) A posteriori, after extensive use in clinical practice, new radical innovations (drugs) can be associated to severe adverse effects (due to initial high uncertainty about the effective therapeutic effects). Some drugs can induce cancers a fortiori (e.g. higher breast cancer risk due to 1st generation of OCs). c) The severe adverse effects (and initial therapeutic uncertainty) triggered by first-generation of drugs spur intensive feedback mechanisms for technological change that supports parallel pathways: a) incremental changes on first-generation innovation to reduce the moderate side effects and increase the efficacy; b) some parallel scientific and technological forces can break-out10 technological paradigms (in related fields) by the insurgence of new paradigms to solve severe adverse effects (radical innovations induced by severe adverse effects, e.g. the first targeted therapy to treat breast cancer). These interlinked relationships create a dynamic virtuous circle of technological change driven by side effects: i.e. radical innovations induced by adverse effects. In fact, patterns of technological innovation in medicine, driven by demand- and supply-side factors, spur both incremental innovations and new radical innovations that solve new needs and improve the wellbeing of societies. A similar pattern has been also showed by Shine ([74]; p. 137ff). In short, established drugs, their side effects in clinical practice and new emerging innovations are interwoven elements of the dynamic process of technical change and technological progress in medicine. According to Sahal ([70]; p.71): “the innovation process in a wide variety of fields is governed by a common system of evolution. Typically, the process of technological development within any given field leads to the formation of a certain pattern of design. The pattern in turn guides the subsequent steps in the process of technological development. Thus innovations generally depend upon bit-by-bit modification of an essentially invariant pattern of design. . . . technical advances . . . are expected to occur in a systematic manner on what may be called innovation avenues that designate various distinct pathways of evolution”. Radical innovations induced by adverse effects are driven by feedback mechanisms associated to other determinants such as continuous advances in basic biomedical sciences and molecular biology. In fact, the convergence of research fields in molecular and cell biology (genomics,11 genetics12 and proteomics13 – Fig. 3) has played a vital role to understand disease biology and to support the insurgence of new technological paradigms that have generating a revolution in clinical practice. The current R&D process in medicine is not linear, and Gelijns and Rosenberg [26] show the drawbacks of the linear model to describe the technological change in medicine; a modern R&D process, underlying radical innovations induced by adverse effects, can be represented by several interwoven phases and sub-phases as in Table 4.The first phase in drug discovery process starts with the understanding of the complex biology of disease to identify genes that are active in diseased tissue but not in healthy tissues/organs. After that, the causes of the disease are investigated to find the target in order to design a new form of targeted therapy. A main phase in the R&D process in medicine is played by Development phase driven by continuous interaction between clinical research and clinical practice that supports new drugs by small scientific advances, rather than drastic breakthrough ([28]; p. 67). Adverse effects by extensive use of new drugs enter in the R&D process of drug discovery by multiplicity of learning process that is a critical determinant underlying technological change in pharmaceuticals and biomedical sciences to reduce shortcomings of new drugs (innovations). The multiplicity of learning process in clinical research and practice reduces initial therapeutic uncertainty of groundbreaking drugs. Nelson [58] argues that in almost all technological fields the professional knowledge is acquired by learning by doing and using, associated to practical activities (pp. 487–488). In particular, the gradual R&D process that drives innovations induced by adverse effects 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 is enhanced by underlying forces of learning processes in which biomedical basic research and clinical research advances have vital continuous feedbacks from clinical practice, based on participation of patients, clinicians and medical staff: this learning process is based on strongly intertwined relationships, with causal arrows going both ways, among basic biological research, clinical research and clinical practice (cf. [30], [34] and [47]). Hence, these innovations induced by adverse effects are driven by the so-called “ ‘learning via diffusion’ …. The increased adoption of a technology paves the way for improvement in its characteristics” ([71]; p. 114). Another essential aspect of the technological change in medicine is the collective and cumulative learning (cf. also [56]; pp. 521–523; [44]) and path-dependence [15] and [59] in drug discovery that also support the co-evolution of innovative drugs. Fig. 4 shows that the incidence and mortality of some typologies of cancers (e.g. liver, pancreas, thyroids, etc.) have been increasing and this might be due to adverse effects of established and/or new drugs. This is the background for future technological change and medical R&D in order to spur innovations induced by adverse effects.However, it is also important to note that these driving forces of continuous drug discovery process based on radical innovations induced by adverse effects contribute to increase the cost in healthcare. Shine ([74]; p. 140) shows that since 1990s health care costs in US have been sharply increasing and 25–40% of cost increases are from applications of innovation and new technology. Jain [37] (p. 320) argues that R&D costs for drug discovery are also increasing exponentially (at a pace of 10.8% per annum, whereas revenue from new drugs is growing at the rate of 7%), with a development process of new drugs (over the past decade) of about 11–15 years and less than 10% of drugs deliver acceptable commercial returns (cf.[1]; p. 392). Literature shows that the technological change in medicine is complex and the study here has analyzed the main role of feedback mechanisms that spur two parallel pathways of innovation: first, incremental innovations with lower adverse effects and/or higher efficacy; second, radical innovations induced by adverse effects to treat severe adverse effects generated from previous “technologies… in a primitive condition” ([27]; p. 8). The specificity of the patterns of technological innovation in medicine, with pros and cons for societies as whole, has driving the scientific and technological progress and generating a revolution in clinical practice. This technological change in medicine tend to be costly due to increasing costs for R&D process (e.g. adoption of high-tech instruments and equipment) that affect prices of new drugs and budgets of healthcare. These factors also affect the direction of new patterns of technological innovation that may reduce the intensity and/or focus on cheap drugs with lower efficacy. As modern economies need cost effectiveness medical drugs and technologies, health policy of countries should be designed to reduce costs in healthcare and at the same time to support the incentive to innovation in drug discovery industry [14]. As forces of technological progress cannot be stopped, some health policies that may be useful to support the dynamics of technological change in medicine as well as to reduce the economic and social costs for societies are: □ strategies focused on rational use of innovative drugs by an accurate and transparent information of all lung-run side effects to clinicians and in particular users; □ strategies focused on prevention and chemoprevention [36] and [82]. These health policies could not hamper the drug discovery process and simultaneously could generate fruitful long-run socio-economic effects for societies in terms of higher wellbeing and quality of the life. In all, this study shows as technological change in medicine has some determinants and patterns that are a terra incognita which deserve further scientific analysis to understand and support the modern progress of medicine and therefore of society.