作者：Nina Rawal博士 全球医疗已经取得了很大的成就，但仍有很大提升空间 在过去几十年中，全球医疗领域取得了一些重大进步，霍乱等传染病的死亡率已经减半，脊髓灰质炎在全世界几乎完全根除。自2000年以来，5岁以下儿童的疟疾死亡率下降了69%。这些不仅挽救了无数生命，减少了人类痛苦，而且大大加强了印度和几个非洲国家的经济。这是世界医疗组织（WHO）、全球防治疟疾、结核病和艾滋病基金、比尔和梅林达盖茨基金会等参与者的大规模努力的结果。他们都为长期健康改善目标投入了大量资源。 医疗领域仍存在着巨大的挑战，传染病仍然导致全球四分之一的人死亡，每年约有500万儿童在5岁之前死亡。除了结核病和麻疹等传染病，以及日益严重的抗菌素耐药性问题，中低收入国家越来越努力改善与生活方式相关的疾病，如糖尿病、心血管疾病和痴呆一，即所谓的双重疾病负担。中低收入国家已经占全球所与生活方式相关死亡的70%，预计这一数字将持续增加。因此，在考虑未来的全球健康问题时，寻找对糖尿病和痴呆症具有成本效益的解决方案将是至关重要的。低收入国家和高收入国家面临不同疾病的观念差距越来越大，不过对中低收入国家具有成本效益的创新也可能对高收入国家产生大规模影响。Aravind眼科护理系统是一个非常好的例子，以最低的成本提供世界上最好的医疗结果；Leveraged Freedom轮椅，是一种比西方竞争对手更好的轮椅，价格却便宜一半，也是一个很好的例子。 “他们变得富有是因为他们很健康”——这是健康对一个国家提升经济繁荣阶梯的重要性 除了减少人类痛苦和提高个人生活质量外，健康还与GDP发展相关。事实上，健康的人造就了更健康的工人，他们可以为社会和经济增长做出更大贡献。日本等国家的经验表明，实行全民医疗保险导致了更强劲的财政增长，他们变得富有是因为他们健康。潜在的经济增长、将税收收入用于医疗保健的意愿以及对其引入的全系统视角也是重要因素。目前，195个国家中只有58个国家提供全民医疗保险，全球约有60亿人可以部分或全部自费支付医疗费用。 对于每天生活费不到2.50美元的27亿人口来说，这一等式几乎不可能平衡。当疾病袭击没有医疗保险的人时，贫困是一个最常见的结果。 展望未来，中低收入经济体的增长速度快于高收入国家，很快将占全球经济总量的50%。政府投资于健康不仅在财务上有意义，而且还增加了公司为这一细分市场开发产品的吸引力。 公平是医疗挑战的根源 公平获得医疗服务和产品可能是围绕全球医疗中最复杂的问题。一些人会认为，必须首先解决获得基本医疗的问题。这一挑战需要一套不同于这里概述的工具。然而，高质量和具有成本效益的产品，这份白皮书的重点，提供了无与伦比的可伸缩性，也可以允许关注最需要的医疗服务。 根据当前的国际知识产权(IP)立法，专利保护药物和其他治疗方案由拥有知识产权的公司控制，产品的分销由他们自行决定。低收入或无法负担药品成本的国家不能获得药品，除非公司决定降低价格，或其他利益相关方，如世卫组织或非政府组织介入，为药品购买提供资金。这是导致关注全球疾病的制药公司数量有限的主要原因之一。 印度和巴西等国对知识产权制度提出了质疑，认为它不成比例地针对了世界上最贫穷的人口。这些国家已经发展了大型仿制药产业，在这些产业中，药品的生产成本只是品牌药品的一小部分。印度仿制药公司现在是全球参与者，在药物逆向工程和低成本生产方面拥有强大的知识。 目前的系统在开始时通过为新疗法的开发提供激励而初衷良好，但在抗生素耐药性等领域的相关性也在逐渐降低。展望未来，我们有理由相信新的方法将会被发现。人们能够负担得起的低成本解决方案也会降低违规复制的动机。 医疗研发的长期资金不足，导致可用的治疗方案减少，医疗需求大量未得到满足 制药仍然是最可扩展的治疗方式，但这是一项困难的业务。一种药物从临床前阶段过渡到已批准产品的可能性仅为5%左右，总平均成本约为15亿美元。为了补偿风险和成本，制药公司享有其市场销售产品的溢价利润率。由于上述原因，中低收入国家支付高价药品的能力有限，导致制药公司将其研发工作集中在主要影响高收入国家的疾病上。从而导致医疗相对缺乏创新，高收入国家也无法获得药品。只有不到5%的私人研发支出属于全球医疗领域。宏观经济、政治风险和缺乏系统数据等问题也导致全球医疗被置于主流商业研发组织的聚光灯之外。 风险投资（VC）模式将科学转化为商业产品方面的力量 与此同时，在癌症和罕见疾病等领域正在取得巨大的进展。突破性的科学发现诸如基于基因治疗和免疫学的技术，针对以前无法治疗的疾病正在被转化为可治疗的和新疗法。罕见病与医疗领域的相似之处，都被认为是没有吸引力的创新市场。每种疾病很少被认为代表有限的市场机会。每一种疾病只有少数患者被认为代表着有限的市场机会。为了解决创新水平低的问题，引入了减少临床试验规模要求和监管审查时间的监管激励措施，结果是显著的，例如，2018年美国食品和药物管理局批准的59种新药中，有31种用于罕见疾病。此外，将患者分为更小、更同质的群体，再加上精准医学的发展，影响了其他医学领域应用相同的靶向药物开发方法——这是如何为特定人群进行创新也能对其他群体产生重大影响的一个例子。 VC和其他融资模式在这个时代发挥了重要作用，尤其是通过资助未经证实的高风险技术，并证明它们的临床效益。VC是资本和知识的结合，知道如何建立和加速科学类公司的市场。VC投资者将支持公司在临床和商业战略、商业、业务发展、融资、建立正确的网络，确定正确的董事会和顾问，所有的目的是加快开发过程和加速收入的产生。 典型的生命科学VC基金将投资周期设为5-8年。之后他们将出售给大型制药公司，或通过该公司在证券交易所上市进行交易。退出是VC过程不可分割的部分，因为它允许投资者反过来将资本返还给其投资者，或者在常青基金的情况下，投资于新公司。因此，大型制药公司和大型医疗器械公司在生态系统中的作用至关重要，它们是VC支持的初创公司的买家。 初创与大型药企合作模式显著提高了整个制药行业的创新率 在过去的几十年里，创新过程从大型制药公司和大型医疗设备公司广泛外包到小型的、通常是VC支持的初创公司。这一根本性转变在制药行业最为明显——自2013年以来，美国食品和药物管理局批准的新药中，有2/3最初由较小的生物制药公司开发，导致大型制药公司成为外部来源创新的大买家，随着时间的推移，各方在复杂的模型中分担开发和其他风险。VC初创公司-大型制药公司合作模式显著提高了整个制药行业的创新率。因此，创新产品的收购或许可对于大型制药公司保持创新并获得优质定价的追求同样重要。 除了通过对每家公司的广泛尽职调查和主动所有权模型掌握风险因素外，VC模型主要围绕能够获得溢价定价的产品构建。在罕见疾病的案例中，VC投资者发现了一个有吸引力的利基，鉴于患者相对缺乏，临床试验规模要求往往较小，同时有机会应用健康经济论证来获得溢价定价。 它还侧重于产品而不是服务，这主要是因为产品更容易跨地域、国家和文化进行扩张。 当然，VC模型并不完美，高风险高回报模式在过去几十年中产生了好坏参半的结果。此外，它有时与贪婪和非包容性文化有关。本文论述了VC方法论和工具箱的优点，它们绝不依赖于上述类型的组织文化。 在全球医疗领域进行VC的机会 鉴于VC在罕见疾病和肿瘤等具有挑战性领域的成功，但它回避了一个问题：VC模式可以做些什么来加速创新和解决全球卫生领域的市场失灵？ l 通过开发新产品和解决方案，挽救生命，减少人类的痛苦。 l 跨国家和区域扩大创新产品。在单独资助创新的能力下，中低收入国家可以获得大规模的健康收益 l 影响投资的案例已经提出，全球医疗是财政和社会回报可以一致的很好的例子。这个领域的创新产品可以挽救生命/减少人类的痛苦，也有助于中低收入国家的经济发展。 l VC投资者有机会在不那么拥挤的空间中，以合理的估值进行创新。为中低收入国家设计的低成本体外受精或糖尿病护理方案在高收入国家也可能具有有吸引力的市场潜力。 l 将更大比例的风险资本直接投入中低收入国家的方式。尽管许多创新最初可能来自欧美，但一些最具创新的解决方案应该来自当地国家本身，这些国家通常不在VC投资者或其他利益相关者的地图上。因此，资本流入有助于加强地方创新环境。
How does venture capital operate in medical innovation?P Lehoux,1 F A Miller,2 G Daudelin3While health policy scholars wish to encourage the creation of technologies that bring more value to healthcare, they may not fully understand the mandate of venture capitalists and how they operate. This paper aims to clarify how venture capital operates and to illustrate its influence over the kinds of technologies that make their way into healthcare systems. The paper draws on the international innovation policy scholarship and the lessons our research team learned throughout a 5-year fieldwork conducted in Quebec (Canada). Current policies support the development of technologies that capital investors identify as valuable, and which may not align with important health needs. The level of congruence between a given health technology-based venture and the mandate of venture capital is highly variable, explaining why some types of innovation may never come into existence. While venture capitalists’ mandate and worldview are extraneous to healthcare, they shape health technologies in several, tangible ways. Clinical leaders and health policy scholars could play a more active role in innovation policy. Because certain types of technology are more likely than others to help tackle the intractable problems of healthcare systems, public policies should be equipped to promote those that address the needs of a growing elderly population, support patients who are afflicted by chronic diseases and reduce health disparities.VENTURE CAPITAL AND NEW MEDICAL TECHNOLOGIESAs industrialised countries develop strat- egies to expedite the commercial transla- tion of biomedical discoveries1 and bring technological innovations closer to the clinic, policy initiatives that give a greater role to venture capital warrant careful examination.2 Such policies may include fiscal incentives to attract venture capital as well as the creation of funds dedicated to help health technology-based ventures grow.3–5Drawing on the international innov- ation policy scholarship and a pro- gramme of research that examined the evolution of five Canadian health technology-based ventures over an 11-year period, this paper clarifies how venture capital operates and influences the kinds of technologies that make their way into healthcare systems. Our research entailed extensive document analyses (ie, annual reports, press releases, media coverage) and in-depth interviews with technology developers, capital investors, regulators and policymakers. This quali- tative data set enabled our team to examine, from a health policy standpoint, the impact of business models, capital investment and economic policy on tech- nology design processes.In this paper, our aim is to provide health services and policy researchers with the key lessons that pertain more specifically to the way current policy arrangements in systems of innovation support the development of technologies that capital investors identify as valuable, and which may not align with important health needs. While health services and policy scholars wish to encourage the cre- ation of technologies that bring more value to healthcare, they rarely fully understand the mandate of venture capi- talists and how they operate. A better understanding of how this form of finan- cing ultimately affects healthcare systems would help health services and policy scholars play a more active role in innov- ation policy.Policy expectations towards venture capitalIn the past decades, North American and European countries actively sought to increase the size of their venture capital markets.6–10 The levels of venture capital available to Canadian life sciences companies have more than doubled from 2001 to 2010.11 In Europe, the UK enjoyed in 2009 the second largest venture capital market, accounting for 21% of all investments. In the same year, 20% of the UK £677 million of venture capital was invested in the health sector.4Examining panel data of 17 European Union coun- tries, Faria and Barbosa6 found that venture capitalists are “more willing to support innovation only after the initial and more uncertain stage of technology devel- opment has been overcome.” This tendency partlyexplains why the Horizon 2020 Programme protected up to €320.14 million in 2014 to help innovative firms to gain access to various types of risk financing.5To foster the growth of technology-based ventures, venture capital typically steps in after entrepreneurs have fleshed out their core innovative idea with the financial support of governments, relatives and 'angels’ (eg, wealthy individuals who finance entrepre- neurial activities).3 As figure 1 indicates, venture capital provides both early-stage and late-stage finan- cing, which precedes more substantive sources of capital such as public markets.The innovation policy scholarship posits that venture capital-backed ventures are likely to outper- form non-venture capital-backed ventures.6–8 The main arguments are that 'investors can identify firms with hidden value’, that their investments operate as a 'signal of the quality of the ventures for uninformed third parties’, and that they bring 'external resources and competencies that would be out of reach’ without their endorsement.7 Informed by such literature, pol- icymakers rely on 'two pillars’ to foster the venture capital market. First, they seek to increase the 'demand’ for venture capital by providing 'generoussubsidies’ and fiscal advantages to entrepreneurs so as to augment 'birth rate’ of innovative firms.7 Second, they seek to increase the 'supply’ of venture capital through 'co-investment schemes, the launch of new government-owned venture capital companies and favourable tax treatment of capital gains’.7 Along those lines, the UK government created many funds since 2000, including the High Technology Fund, the Early Growth Funds and the Enterprise Capital Funds. Such funds played a particularly important role in early-stage financing in the following years, witnessing a peak in 2008 during which 68% of all early-stage venture capital investments were publicly backed.4How venture capital operatesThe two-pillar innovation strategy implies that public resources, either through taxation or 'hands-off ’ financing, are put to the service of venture capital, whose mandate largely conditions how capital-backed technology development processes unfold. Venture capitalists commit financial resources for a specified period of time to small privately held companies with few tangible assets and that rarely generate revenues alongside their initial research and development activ- ities. What makes venture capital risky is the 'illiquid’ nature of the investment during this period, meaning that the resources invested cannot be easily with- drawn.8 12 13 The window of opportunity for a 'liquidity event’ such as acquisition by another company or an initial public offering—which provides the ability to sell shares to the public—is generally within 5 years.11 These so-called 'exit’ events enable venture capitalists to recoup their investments and generate a return. Venture capital is very costly capital and the overarching principle is to generate the highest returns possible while knowing that most ventures fail.10 Song et al9 found that only 36% of American ventures created between 1991 and 2000 had survived after 4 years and this rate fell to 21.9% after 5 years. The returns from a subset of firms have to be much greater than average to make up for the expected failures, and yield above 20% returns for the investment portfolio as a whole.8 11 For instance, the top 25th centile of capital-backed UK firms generated returns ranging from 50% to 78% between 2003 and 2009, while the bottom 10 generated returns ranging from −14% to 0%.4To successfully fulfil their mandate, venture capital- ists generally seek to both pick winners and build them (see box 1).14 This means that they do not simply carefully choose entrepreneurs, but they also engage in 'value-adding activities’.15 These activities include 'coaching’ the ventures by providing the mar- keting and strategy support these young firms usually lack, professionalising their management by support- ing the recruitment of seasoned managers, and facili- tating alliances with key third parties within the industry. By having a seat at the Board of Directors of the fledgling firm, capital investors occupy an influen- tial position from which they shape its governance (ie, advisory committees, nomination of high-level execu- tives, partnerships) and seek to align technology developers towards their own vision.10 13 All of these value-adding activities are geared at augmenting the value of the investment, a process that entails shap- ing both the firm and the technology being developed.16 17Venture capitalists exert control over technology design processes by setting the 'term sheet’, which defines the milestones (eg, clinical trials, regulatory approval, sales) at which money is made available.13 This has direct implications for technology design pri- orities. Among the early-stage health technology com- panies we studied, for example, one clinically led firm had to modify the key goal of its labour monitoring system, which was to reduce unnecessary caesarean sections, and instead develop medicolegal functional- ities for physician insurers who were more likely to purchase the system.18 This redesign of the system enabled their business to expedite sales and generate revenues.As table 1 indicates, the level of congruence between a venture that seeks to bring to the clinic a new technology and the mandate of venture capital varies. The heart ablation catheter venture deployed an international cadre of clinical investigators that generated the evidence required for regulatory approval in different countries and, by offering to investors credible prospect of rapid and continued expansion, it was able to secure several rounds of capital investments. By developing a revenue- generating technology for medical specialists, this venture replicated a business model that is well estab- lished in the biomedical sector. Among the three examples, it is the home monitoring system venture where the level of congruence between the mandate of venture capital and the innovation was the lowest. Such a technology creates value for hospitals that do not generate revenues out of hospitalisations and have incentives to prevent deterioration of chronically ill patients, such as Health Maintenance Organizations (HMOs) in the USA or publicly funded integrated healthcare systems in Canada or the UK.Among the ventures that are developing an innov- ation to support the provision of clinical services, those that are seen as more congruent with the goal of venture capital and less risky possess similar characteristics; their innovations address very large and reachable markets, enable physicians to generate revenues, and will ultimately be acquired by an estab- lished medical device manufacturer (for an exit to take place).18The mandate of venture capitalists may, in principle, prove compatible with supporting ventures that address important health needs. But this is likely to happen by accident, not by design. Survey findings indicate that up to 85% of capital investors consider 'not at all or somewhat important’ public health impact.19 Investors also contend that regulatory requirements decrease the 'chance that an investment will be made in a 'new area’’ and increase the chance an investment will be 'made in a 'me-too’ space’ (eg, where a slightly different technology is already imple- mented and marketed).19 To strike lucrative 'home- runs’ within a predefined period of time, venture capitalists seek indeed to 'de-risk’ the deal at the outset by enforcing stringent agreements.18By and large, venture capitalists affect the kinds of technologies available to patients, clinicians and healthcare systems by investing in certain ventures and not in others, managing their growth and con- trolling the progression of their innovative products (see box 2).The centrality of venture capital in innovation systems While venture capital is not designed to fulfil 'society’s most urgent public health priorities’,20 it occupies a central position in what innovation policy scholars define as 'innovation systems’.21 Figure 2 illustrates the relationships between key milestones in the health technology development pathway and the institutions that define the 'rules of the game’, that is, the specific requirements that players have to fulfil.22 The rules set by these institutions have both constrain- ing and enabling effects. For instance, regulatory agen- cies exert control over the safety of medical devices, but by enabling market access, they also provide economicworthtotechnology-basedventures (as reflected in the value of their share).18While institutional rules are often described as hin- drances by investors and technology developers, such rules contribute to the stability and functioning of innovation systems: they provide incentives for innov- ation, supply information, reduce uncertainty, foster cooperation and make available mechanisms to handle conflicts.21 Without such rules, venture capitalists and technology developers would simply be unable to cooperate, trust each other, succeed in developing and commercialising a new medical technology, and per- suade physicians and patients that their technologies are trustworthy. Overall, and as underscored by figure 2, it is innovation policy, venture capital, financial markets, and legal and corporate governance frame- works that deeply structure upstream innovation pro- cesses.16 17 22–24 Long before health policy comes into play, the way venture capital interlocks with these institutions has lasting downstream consequences for healthcare systems.One key lesson for clinical leaders and health ser- vices and policy scholars is that, despite the fact that public policies increasingly encourage venture capital- backed technological innovation in health, handling the subtleties associated with the fulfilment of valu- able healthcare goals is neither part of venture capital- ists’ mandate, nor of their worldview. Examining recent data from the USA, Fleming20 observed two types of shift in venture capital investments. There has been a shift away from life sciences to other sectors, such as early-stage internet and consumer-oriented start-ups, and a shift within the life sciences from early-stage to later-stage investments. The first shift is conditioned by the standpoint from which the value of the firms is assessed—that of an investment port- folio—which remains largely indifferent to the soci- etal value of the innovation such firms may generate.24 The second shift underscores that the overarching goal of venture capital is not so much to foster the creation of innovation, but to extract economic value from innovative firms and technologies.2 6 16Bringing health policy considerations into innovation policyFor Robinson,25 the current emphasis on more sophis- ticated and cost-conscious purchasing in healthcare may have the 'potential to increase the social value of innovation’ by focusing technology developers on 'the preferences and pocketbooks’ of their customers. Beyond their cost, we believe the value of innovations will increase only if clinical leaders and health services and policy experts contribute much more actively than they have done so far to innovation policy. Policy efforts in the past decades have been devoted to the consolidation of Health Technology Assessment (HTA) and evidence-based decision-making.26 This is not sufficient: institutional arrangements that cur- rently prevail in systems of innovation push public policies to support the development of those tech- nologies capital investors identify as valuable. Capital-backed technology development operates according to rules that are foreign to the fulfilment of healthcare needs, and the consideration of healthcare system-level challenges.27The policy assumption on which governments, capital investors and technology developers currently operate is that publicly funded research should trans- late into private entrepreneurial activities because technological innovation contributes to a nation’s economic growth.1 2 28 This economic orientation in public policy establishes favourable conditions for venture capitalists to play an influential role in systems of innovation and shape key decisions about health needs.18 Nevertheless, if the key policy goal is to increase the relevance of innovations from a health policy standpoint, it is the knowledge and insights of health experts that should be fore- grounded. Their expertise could shape the processes and criteria on which key bodies allocate important resources to health innovation, and where articulating more clearly a 'demand’ for technologies that are valuable from a health system perspective matters (see box 3).Currently, the financial speculative rules at play too easily reconcile policy goals that are distinct—health and wealth—'without asking first what healthcare needs and challenges should be addressed’.29 Because certain types of technology are more likely than others to help tackle the 'intractable problems’30 of healthcare systems, public policies should be equipped to promote those that address the needs of a growing elderly population, support patients who are afflicted by chronic diseases and reduce health disparities. Such knowledge can only come from clinical leaders and health services and policy scholars. |
