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Virtual monopolies exist in almost every healthcare sector: from hospitals and health systems to medical groups and single specialties backed by private equity. With so much consolidation of power and influence, U.S. healthcare has become a conglomerate of monopolies; the subject of this continuing series. When it comes to claiming market control, pharmaceutical companies stand apart from healthcare’s other monopolies. Whereas hospitals and health systems rely primarily on mergers and acquisitions, drug companies employ a slew of powerful tactics: from legislative protections and legal loopholes to stonewalling would-be competitors and more. But there is one thing that unites all healthcare monopolies: As their powers expand, they become complacent. And when that happens, innovation dies and Americans pay the price, both with their wallets and their health. Exorbitant vs. unfair pricing The rising price of prescription drugs has sparked outrage for more than a decade. That’s largely because medications aren’t like other expensive products. Take a $250,00 sports car or a $20,000 handbag. Both are exorbitantly priced. Meaning, these retail prices far exceed the cost of production. At the same time, if people are willing to pay—despite a near-endless array of less-expensive options—then these prices are market driven and, therefore, fair. By contrast, monopolistic pricing in healthcare is both excessive and unfair, leaving millions of patients with only one choice: pay up or suffer. Drug companies know that’s not really a choice, and they take full advantage. Last year, Americans paid $460 billion for prescription drugs, accounting for 16.7% of all healthcare expenditures. But don’t assume that the large (and ever-rising) price tag for U.S. medications reflects massive improvements in drug efficacy. When the Institute for Clinical and Economic Review (ICER) studied price increases for some of the most expensive drugs, it found 70% of those increases (accounting for $805 million) were unsupported by clinical evidence. To explain why drug prices are rising rapidly while drug innovation lags, it’s helpful to look at how biopharmaceutical research and development (R&D) has changed. The golden era of drug R&D In the 20th century, pharmaceutical manufacturers made massive R&D investments in a collective quest to discover the next generation of lifesaving medications. Among those innovations were birth control pills, which received FDA approval in 1960 and have reduced maternal mortality worldwide by nearly a third. Similarly, statins, which were patented in 1985, have cut the risk of heart attack and death from heart disease by a quarter. The HIV/AIDS treatment zidovudine (better known as AZT), introduced in 1989, has saved millions of life years. These and other 20th-century advances were accomplished through a grueling, expensive and risky R&D process—an approach that remained the industry standard for decades. Back then, drug company CEOs understood that R&D costs were high and the risk of failure higher still. But they also knew that success would save millions of lives—and prove profitable, too. The downfall of drug innovation Yesterday’s model of drug development is a rarity nowadays. In the 21st century, most drug companies have replaced moonshots with chip shots: strategies aimed at minimizing risk. Rather than chasing the elusive game-changing drug, today’s biopharma giants focus on monetizing easy wins. In fact, a recent report found 9 in 10 major drug companies spend less on R&D than on marketing and sales. Even Covid-19 vaccines—the most celebrated innovation of the 21st century—were brought to market with minimal risk to drug makers. The federal government underwrote most of the development costs through decades of NIH-funded research and it unburdened participating companies by fronting $18 billion as part of “Operation Warp Speed.” Drug innovations of the 20th century contributed mightily to longevity gains, adding nearly 30 years to the average American’s life between 1900 and 2000. In this century, however, drug companies have gotten comfortable. And as complacency set in, drug innovation eroded. Unsurprisingly, U.S. life expectancy has remained relatively unchanged for the past two decades. But even as the impact of new drugs stalled, spending accelerated. In 2022, the median price for a new FDA-approved medication surpassed $220,000 with the average list price for more than 1,200 prescription drugs rising nearly 32% from July 2021 to July 2022. The pharmaceutical industry understands there are two keys to ensuring profits: minimizing risk while driving prices skyward. To accomplish that, they’ve mastered a series of useful tactics. Here are four: 1. Purchase new rights to old drugs Many long-established medications are now sold as generics. Most of those are manufactured by a single, small company for modest profits. But many mid- to large-sized drug manufacturers have begun to purchase the rights to these generics, using their market powers to hike the price and keep the added revenue as profit. That’s exactly what Nostrum Laboratories did with nitrofurantoin, first created in 1953 to treat bladder infections. Nirmal Mulye, CEO of Nostrum Laboratories, bought the rights and raised the medication’s price 400% without any additional R&D investments. When asked about the price increase, Mulye told the Financial Times: “I think it’s a moral requirement to make money when you can … to sell the product for the highest price.” That self-serving mindset has become standard in the pharmaceutical industry today. 2. Buy a guaranteed future winner Rather than pursuing a generic drug, large drug manufacturers frequently purchase rights to new drugs from small startups. These drugs are almost ready for clinical use. All that’s missing is funding to complete the FDA-mandated clinical trials—a pricey process most startups can’t afford. Drug giants are happy to step in because they know that market success is all but guaranteed, and they can price the medication exorbitantly high once the FDA approves it. Sofosbuvir, a drug used to treat Hepatitis C, is a telltale example. It’s owner, Gilead Sciences, reportedly paid $11 billion to acquire the rights from a small company named Pharmasset. But rather than pricing a course of treatment at $33,000, as Pharmasset had planned, Gilead charged $100,000 per patient. Monopolistic pricing allowed the company to recoup its investment in less than 18 months with $200 billion in projected revenue over the drug’s lifespan—nearly a 2,000% return on investment. 3. Exploit patent and drug-approval laws U.S. patents are designed to reward entrepreneurs and industries willing to invest huge sums of time and money toward creating something new and valuable. Those same laws have been contorted in recent decades by the drug industry, which uses them to manufacture marketing opportunities for medications that add minimal clinical value. Consider the cost-benefit of chemotherapy agents. In the 21st century, the FDA has approved more than 90 new oncology drugs. Last year, 6 of 8 newly launched cancer drugs had prices over $200,000 per year. Compare that cost with the average gain in life expectancy for patients with cancer: a mere 73 days. Much of that time is spent in pain, dealing with debilitating side effects while being isolated from loved ones. Many of today’s high-priced drugs are fast-tracked through the FDA’s accelerated approval program, which doesn’t require measurable clinical improvement in outcomes—only the possibility that they might add value. Half the time, the drugs approved through this process prove useless for the patient (but highly profitable for the companies selling them). And regardless of how companies obtain approval or how ineffective the drug is, when patents are set to expire, manufactures extend monopolistic control and high pricing through legal suits, minor molecular modifications, and various “pay for delay” schemes with potential competitors. All of these paths are legal. All of them protect monopolistic pricing. 4. Lobby to preserve favorable U.S. laws Drugs sold in Europe—even ones invented and manufactured in the United States—cost a third to half of what Americans pay for the same medications. That’s because a 2003 “non-interference” law called the Medicare Prescription Drug, Improvement, and Modernization Act (MMA) prohibits the federal government from negotiating drug prices. Congressional leaders during that time were influenced significantly by campaign contributions and lobbying efforts. Health-sector spending on lobbying rose 70% from 2000 to 2020, accounting for more than $5 billion, driven mostly by pharmaceutical manufacturers. In most European nations, prices are negotiated by the government based on a drug’s efficacy. A recent study by the National Academy of Medicine concluded that a similar “value-based drug pricing” program in the United States would reduce spending 11% to 37%.

Do Patents Always Encourage Innovation? One of the most visible arguments in favour of patents is that they are crucial for innovation. Patents are provided for a new invention. Often used interchangeably, there exists a fine line between invention and innovation. An increased number of patents may not automatically result in increased innovation. This could be one of the possible explanations of the “patent puzzle”: in spite of the enormous increase in the number of patents and in the strength of their legal protection, the US economy has seen neither a dramatic acceleration in the rate of technological progress nor a major increase in the levels of R&D expenditure (Boldrin and Levine 2013). Patents and other forms of intellectual property may sometimes impede innovation, restricting economic growth. Knowledge is the essential ingredient to stimulate any kind of R&D. This is also visible in Paul Romer’s endogenous growth theory, which has laid emphasis on R&D for economic growth. A patent fundamentally restricts the transfer of knowledge and technology by providing monopoly power to the patent holder. The monopolisation of knowledge means a very small pool of entities possesses the requisite knowledge for future research. New innovators not only face immense competition from the incumbent firms who already have the first mover advantage, but they may also be vulnerable to legal action from the existing patent holders. Additionally, to ensure exclusivity at least until the end of the patent protection period of the base patent, firms may file for a multitude of patent applications called “patent clusters” (on process, reformulation, etc.), which protect the product in addition to the base patent with the aim of creating several layers of defence. Using data from a large‐scale survey of patent applications, Torrisi et al (2016) discover that a substantial share of patents remained unused, and a substantial number of patent applications were filed to block other patents. On the other end are “patent trolls”; they are individuals or companies who buy up patents with the sole intention to threaten accused infringers with (often dubious) lawsuits. They have no intention to manufacture or market the patented invention but only to collect royalty or licensing fees (Nair 2014). Further, forward linkages may extend protection to other non-patented areas and limit innovation. For example, if a chemical compound is patented, all those drugs that could use that particular compound as an ingredient will be indirectly affected. This hinders future research and invention. Also, as discussed previously, patents lead to wasteful expenditure. Duplication of work and lack of coordination is common. Multiple entities may be engaged in single research simultaneously when it is most likely that only a single one of them would be granted the patent. When pharmaceutical companies engage in evergreening of drugs, they devote a significant part of their R&D expenditures to incrementally modified drugs. Also, firms may strategically use “patent thickets” that not only deter competition but also make subsequent innovation a highly challenging and costly business. Cumulative innovation from existing patents is contingent on patent disclosure. However, much of the legal scholarship on patent disclosure is critical of theory and disclosure is in fact inadequate (Sampat 2018). All these inefficient activities result in wasteful deployment of financial resources, which could have been used for new innovation. Ironically, the monopoly profits, which are supposed to incentive R&D in an ideal scenario, may often disincentivise it. Today’s innovators should not encroach upon future R&D. A balance is crucial for intergenerational equity. For optimal allocation to invention, it would be necessary for the government or some other agency not governed by profit-and-loss criteria to finance research and invention (Arrow 1962).

As we show in more detail in the next section, the profits of (especially) the big pharmaceutical industries and their shareholders are often excessive. A major cause of these excesses are the strong commercial monopolies granted to the pharmaceutical industry through their patents. Most of the economic studies we discuss are (rightly) critical of the current system of drug production. Yet, it is often the case that the crucial role of patents is not adequately analyzed or acknowledged. Two key factors explain why these patents lead to huge profits and high drug prices. First, the often comprehensive monopolies create a powerful market position for their owners. Second, this strong position significantly weakens the negotiation space of governments and governmental agencies.Footnote6 They need to negotiate with pharmaceutical companies about the reimbursements these companies will receive for the drugs they deliver. It is true that governments around the world have been trying to reduce the (growth of the) costs of medicines for decades.Footnote7 In spite of this, as specified in the next section, drug prices have continued to rise to amounts that already are, or will soon become, definitely unsustainable. In addition, some general features of the theory and practice of patenting reinforce these conclusions. Overly broad patents inappropriately extrapolate the significance of the inventions on which patent applications are based and thus strengthen the monopolies of the pharmaceutical companies. Seth Shulman’s (Citation1999) book Owning the Future still offers an eye-opening (if also depressing) critique of the unjustifiable broadness of a host of approved patents. The many product patents grant their holders an even stronger protection. They provide an exclusive right of commercially exploiting the product as produced by any (known or, as yet, unknown) process. Thus, the holders of a product patent are rewarded for an unspecified range of hypothetical inventions, which they have not actually made available. Therefore, the protection awarded through a product patent can never be “sufficiently supported by the description of the actual invention,” as is required by patent laws and regulations. In fact, product patents effectively patent a concept and hence they are illegal (Radder Citation2004, 283–286). Finally, pharmaceutical companies employ a number of tactics to expand their monopolies beyond the usual patent validity of twenty years. For instance, by re-patenting a drug on the basis of “improved formulations,” “new indications” or “combinations with another drug” (Van der Gronde et al. Citation2017, 12). A consequence of these thus strengthened monopolies is a substantial weakening of the negotiation space of the public stakeholders.

1. Medical research without patents: It’s preferable In this section, we argue that abolishing patents on the results of medical research is not only possible but also preferable. In debates on this issue, it is often declared to be an undeniable fact that medical research without patents is simply impossible. Generally speaking, the actual manufacture of drugs is much cheaper than the research and development (R&D) required to get a drug approved and registered. Therefore, the pharmaceutical industry claims it needs a period of patent protection, usually 20 years, that first, gives them the opportunity to test their drugs and have them approved; and second, grants them an exclusive legal right to sell the approved drugs (or to license others to sell them). The basic claim, then, is that only this patent system allows the pharmaceutical industry to recover its high R&D investments. In this sense, David Resnik writes: If companies could no longer patent products, they would greatly decrease their R&D investments, which would lead to a drastic reduction in the funding for scientific research. Since governments do not have the money that would be needed to compensate for this reduction in private funding, it is likely that scientific research—and the public interest—would suffer greatly. (Resnik Citation2020, 173) Thus stated, this argument applies to all product patents, but it is also frequently used with respect to the patenting of drugs as the products of medical research.Footnote2 The aim of our article is to refute this argument. Briefly stated, our refutation consists of two steps. The first addresses the first sentence of the above quotation. We show that the excessive profits (resulting from highly overpriced drugs) made by the pharmaceutical industries and their shareholders are made possible by substantial public investments. In the second step we argue that the money that will be saved in a system with normal rather than excessive profits can be employed to establish a publicly funded and regulated R&D system for drugs (and possibly for other results of medical research). Thus, our second step explicitly questions the second claim of the above quotation. In an abstract way, the claim that drug research without patents is economically impossible is clearly false. The reason is that, apparently, there is a huge amount of money available that is being paid for our current drugs by governments, insurance companies and individual patients. In principle, this same amount could be spent on the basis of a different system, a system without patents. Of course, in practice the abstract possibility of creating a new public system is not enough. In addition, we have to demonstrate that medical research without patents is scientifically, socially and morally preferable, that it is economically and financially profitable, and that it is socio-politically and organizationally practicable. This section argues for the scientific, social and moral preferability of such a policy change. For this purpose, we provide a concise review of the problems of the current system of drug research, which is strongly dependent on the interests of private, and usually big, multinational pharmaceutical companies. Our review is based on a large body of academic literature that analyzes and critically assesses the role of these pharmaceutical companies. For a start, there are the many general criticisms of the commercialization of medical research. In addition to patenting practices, they address a whole range of dubious aspects of this commercialization. In particular, these studies analyze and assess many cases of the epistemic and moral corruption that occurs as a consequence of conflicts between epistemic and moral standards, on the one hand, and the economic and financial interests and power of the big pharmaceutical companies, on the other.Footnote3 In a recent article, Bennett Holman advocates a balanced overall view of the relations between industry and academia, which takes into account both the more positive assessments by policy researchers and the more critical evaluations by philosophers of science. He is, however, unreservedly negative about the specific case of the past and current impact of pharmaceutical industries on medical research. In this case, “we have in-depth accounts of numerous drug disasters” (Holman Citation2021, 9). To illustrate, consider how Lisa Cosgrove and coauthors summarize the results of their study of the development of vortioxetine, a new anti-depressant. The economies of influence that may intentionally and unintentionally produce evidence-biased—rather than evidence-based – medicine are identified. This is not a simple story of author financial conflicts of interest, but rather a complex tale of ghost management of the entire process of bringing a drug to market. This case study shows how weak regulatory policies allow for design choices and reporting strategies that can make marginal products look novel, more effective, and safer than they are, and how the selective and imbalanced reporting of clinical trial data in medical journals results in the marketing of expensive “me-too” drugs with questionable risk/benefit profiles. (Cosgrove et al. Citation2016, 257) This and many similar studies have been crucial in raising academic and public awareness of the questionable practices of the pharmaceutical industries. However, in addition to these studies we need a more general analysis and assessment of our entire system of drug production, thus including the research, development, manufacture, marketing and sale of drugs. A common claim in support of patenting the results of medical research is that it is the pharmaceutical companies that bear all, or almost all, of the risks and expenses of the system of drug production. Therefore, granting them a monopoly on the sales of approved drugs is seen to be justified. However, a more detailed account of what constitutes this entire system shows that a vast amount of public money is already being invested in this system. Because this fact is crucial for the purpose of increasing general awareness about the urgency of a substantial change in our healthcare policies, we provide a brief sketch of the stages of drug research, development, manufacture, marketing and sales. First, there is the creation and maintenance of a public infrastructure of medical education and research. This is a stage that is usually overlooked in discussions and policies of drug pricing, perhaps for the reason that it is difficult to put an accurate price on having an appropriate infrastructure available. However that may be, the amount of invested public money must be huge (especially in the wealthy parts of the world). Hence these public contributions should not be overlooked, nor, as is usual in mainstream economics, should they be defined away as an “externality” that is irrelevant to the price of the produced goods. Second, this infrastructure enables the actual performance of medical research at (public or nonprofit) universities and research institutes. It includes both basic and application-oriented research. A significant part of this public knowledge is used by pharmaceutical industries in the subsequent stages of the system of drug production. A common arrangement is that public medical researchers who have a promising idea about potential drugs enter into a contract with private companies. A basic element of this contract is the application for a patent that, if granted, will be held by the involved companies. Again, it is difficult to quantify accurately the total public expenses that have facilitated the medical research that is later privately exploited by commercial parties.Footnote4 What we can conclude, however, is that during the past decades the public contributions to early-stage drug research have significantly increased as compared to the private contributions. Consider the following two examples. Mark Robinson has provided a carefully documented study of the development of translational biomedical knowledge in the US between 2003 and 2014. He concludes that in the case of translational medicine (broadly, the research to turn basic science into clinical applications) the partnerships between universities and pharmaceutical companies must be understood as part of a larger strategy of R&D externalization, through which companies could outsource projects onto partners, enabling companies to retain a pipeline of R&D innovation without the costs and risk of executing these projects internally.Footnote5 To a significant extent, this externalization implied the transfer of translational research from the private to the public sector. A similar conclusion is drawn by Irene Schipper, Esther de Haan and Roberta Cowan. Their detailed report focuses on drugs developed with Dutch public money. It provides a wealth of information about the public funding of biomedical R&D in the Netherlands, including a case study of the development of a drug for a type of lymphomic cancer. Their report shows that the strategy of large pharmaceutical companies has been shifting from “Research & Development” to “Search & Development.” That is, these companies are “stepping away from playing a part in early drug development, preferring to leave this phase to universities and publicly funded research institutes.” The conclusion is that these findings “contradict the pharmaceutical industry’s mantra that it pays for all expensive clinical trials” (Schipper, de Haan, and Cowan Citation2019, 10). This brings us to the third stage, the stage of testing the effectivity, safety and possible side effects of potentially useful drugs, usually by means of RCTs (randomized controlled/clinical trials). The estimates of these costs vary widely, in part due to lack of transparency on the side of the pharmaceutical companies. However that may be, what is clear is that these companies try to limit these costs, both with the help of a range of epistemically and morally unacceptable methods (see the literature mentioned in note 3) and by means of their strategy of passing on risks and expenses to the public sector. Fourth, to have their drugs approved and registered for general use pharmaceutical companies need to submit the results of their tests to regulatory agencies. The task of these agencies (for instance, the Food and Drug Administration in the US and the European Medicines Agency in the EU) is to assess the (claimed) effectivity, safety and side effects of proposed drugs. Relevant for our article is that their decision procedures do not take into account the financial aspects of the new drugs and the question of what they add in terms of clinical value. These regulative organizations clearly serve the public interest in the availability of effective and safe drugs. Even if most of their budgets are covered by the fees of their users, the remaining public investments constitute a necessary condition for an appropriate system of selling drugs, which also serves the pharmaceutical industry. The final stage concerns the manufacture, marketing and sale of approved drugs. As in the first stage, there is a substantial public contribution by means of an infrastructure that takes care of the education of physicians, pharmacists and their associated personnel. The general approval of a drug does not tell you when its prescription is appropriate for particular patients. Without the knowledge and skills of physicians and pharmacists (made possible by a publicly funded knowledge infrastructure) a working system of prescribing and selling effective and safe drugs is unthinkable. As a matter of fact, drug producers (and their economic results) depend on such a “market infrastructure” to a much larger extent than most other manufacturers (for instance of soap or chocolate). Their extensive advertising, lobbying, pampering and bribing activities show that pharmaceutical companies are sharply aware of this fact. Therefore, in analyzing and making healthcare policies, this fact should play an equally significant role.

By far, the United States has the highest prescription drug prices in the world. Aggressive price increases by large drug manufacturers in the U.S. market widen the price gap every year. The drug manufacturers who defend this practice argue that any attempt to mitigate these high prices will “harm innovation.” But they make this claim without establishing the relationship of “Big Pharma” profits to innovation and to improvements in public health. Indeed, despite the claim that profits from large companies fuel innovation, high-value drug development emerges most often from unprofitable startup companies with fewer resources and substantially smaller revenue streams. In this paper, we undertook a detailed review of 428 FDA drug approvals and financial data from more than 4,000 pharmaceutical companies to examine trends in drug innovation between small and large pharmaceutical companies. We found the following: The majority of new drug development now takes place at startups with little to no commercial revenue. Contrary to the claim that raising prices on old drugs drives innovation, large pharmaceutical companies, generally defined as those with $10 billion or more in annual sales, rarely discover new drugs. Large companies have bureaucratic research and development (R&D) processes, in which scientists have comparatively little incentive to innovate. Researchers at emerging firms, on the other hand, may be driven to innovate by the remunerative model such firms use — i.e,. researchers share more fully in the economic rewards of successful drug development. Therefore, the majority of new drugs are now discovered and brought into human clinical trials by emerging startup companies — defined as those with $500 million or less in annual sales, or less than $200 million in annual R&D spending — funded by venture capital and hedge funds. In 2020, early-stage, unprofitable companies brought nearly 62 percent of new industry-originated drugs approved by the FDA to the clinic, with no less than 54 percent of drugs brought to the clinic by emerging firms in each of the last seven years (2016–2022). Emerging companies are taking their innovations to market without the help of Big Pharma. Large companies that fail to discover drugs in-house often assert that the venture capital used for drug innovation would disappear if large companies sold drugs at lower prices. This claim assumes large companies will purchase the rights to sell drugs developed by emerging companies, whether through licensing agreements to sell on the emerging company’s behalf or by acquiring the emerging company altogether. But this model of drug development, which peaked in the 2010s, is quickly fading as emerging companies increasingly bring new innovations to market on their own. Our analysis found that, in 2013, 23 percent of emerging companies that originated novel drugs retained marketing rights to those drugs through the entire FDA approval process. By 2022, that percentage had more than tripled, to 75 percent. In fact, some drugs originated by profitable companies are now licensed to emerging companies to sell. Of the 17 drugs originated by established companies in 2022, four are currently marketed by emerging companies. Emerging companies innovate more while earning less revenue and spending less on R&D. Startups rely on venture capital to develop new and innovative drugs with a higher level of accountability than large companies, spending less per innovative drug developed than large, inefficient companies. Our analysis shows the pharmaceutical industry is rapidly evolving in favor of agile startups that embrace new ways of innovating and are free of the bureaucratic processes that plague larger companies. In practical terms, emerging companies are developing new medicines with fewer resources, all while charging patients less. Our analysis found that, in 2013, 23 percent of emerging companies that originated novel drugs retained marketing rights to those drugs through the entire FDA approval process. By 2022, that percentage had more than tripled, to 75 percent. As we have discussed previously, the reason for this efficiency is that the most talented biopharmaceutical scientists gravitate toward startups. At biotech and pharma startups, a top scientist will receive stock options, which can translate into substantial wealth if the company successfully takes a drug candidate through the FDA approval process. These economic opportunities are largely absent at large companies. Furthermore, bureaucratic decisionmaking at large companies creates diseconomies of scale, in which promising drugs are abandoned because they do not fit into a larger corporate strategy or existing product lines. Contrary to their rhetoric, large pharmaceutical companies often fail to turn their enormous profits into innovative R&D. Instead, they acquire startups where the innovation has already taken place. In most cases, these smaller companies would have been able to gain FDA approval for their drug candidates if they had remained standalone companies. The pharmaceutical industry’s increasing reliance on emerging companies with smaller R&D budgets shows that policies to curb high drug prices — especially policies that target excessive price increases on older drugs sold by large firms — are unlikely to harm innovation. Furthermore, coupling such policies with those designed to reduce the costs and risks of drug development, such as allowing more drugs to come to market after successful Phase II studies, can give us the best of both worlds: a more innovative biopharma ecosystem and a more affordable one.

This paper contributes to the research on the macroeconomic origins of conflict. Based on a sample of 133 low and middle-income countries over a 30-year period, it analyses to what extent changes in a country’s commodity terms-of-trade (ToT) can explain an increase in the incidence and intensity of conflicts through their effect on aggregate income. While the evidence from previous studies on the link between macroeconomic conditions and conflict is rather inconclusive, we find a significant relationship. Our baseline model finds that a negative commodity ToT shock leads to an increase in the number of conflict events and fatalities in our sample. Moreover, the effect plays out over several years albeit with decreasing strength after the second year; and its magnitude is twice as large for Low-Income Countries and Fragile and Conflict-affected States when compared with the sample average. In addition, our results show that macroeconomic shocks are creating more violence in countries with higher inequality and in cases where fiscal policy faces relatively stronger constraints on financing a response to the initial shock to incomes. Our results are robust to a number of plausible variations in model specification. The paper’s results, in conjunction with previous studies that emphasize the economic cost of conflicts, suggest the presence of a fragility trap—a vicious cycle of worsening economic conditions and deteriorating conflicts. Effective policies and well-tailored external financial support could be expected to help countries address the challenge.

The world suffers from a large number of violent conflicts. According to the Uppsala Conflict Data Program Georeferenced Event Dataset (UCDP GED), 1 which identifies conflict events as incidences of the use of armed force by an organized actor against another organized actor, or against civilians that result in at least one direct death, 17,000 conflicts occurred in 2021. These claimed almost 120,000 deaths. And while the incidence of conflicts subsided somewhat after the surge associated with the Arab Spring, their frequency over recent years has remained almost twice as high as that experienced in the outgoing decade of the 20th century (Figure 1).

COVID-19 pandemic went from being the most extensive “Black Swan event”1 to the most prominent “Grey Rhino event”,2 and its domino effect is increasingly being studied by economists. Fernando and McKibbin estimate economic losses in 24 industrial countries over seven scenarios. The worst-case scenario sees a sharp fall in consumption and investment, leading to a sharp fall in stock prices and a sharp fall in bond profits (18). Hofman’s analysis concludes that COVID-19 pandemic impedes labor mobility, thereby reducing productivity, disrupting supply chains, inhibiting exports, leading to increased uncertainty, and directly causing a further decline in trade and manufacturing growth, severely affecting the world economy (19). Appleby argues that while fiscal subsidies and loose monetary policies implemented by many governments, especially those of large countries, will increase the fiscal burden on countries and bring about global inflation, attempts by some countries to initiate new trade frictions on the pretext of epidemic prevention and control will increase the cost of international trade (20). Li et al. conclude that containing the spread of the disease should be prioritized over restoring economic activity by conducting a longitudinal survey of people’s expectations of epidemic control and maintaining positive economic growth (21). In addition, several scholars have explored the macroeconomic or industrial economies of different countries and regions separately, arguing that the epidemic had a significant deterrent effect on economic growth and caused powerful shocks to capital markets, labor markets, and people’s living standards and that the right policy mix could reasonably reduce losses in all areas (22–36).

Historically, disease events have been responsible for the greatest death tolls on humanity. The 1918 flu was responsible for more than 50 million deaths,1 while smallpox killed perhaps 10 times that many in the 20th century alone.2 The Black Death was responsible for killing over 25% of the European population,3 while other pandemics, such as the plague of Justinian, are thought to have killed 25 million in the 6th century—constituting over 10% of the world’s population at the time.4 It is an open question whether a future pandemic could result in outright human extinction or the irreversible collapse of civilization. A skeptic would have many good reasons to think that existential risk from disease is unlikely. Such a disease would need to spread worldwide to remote populations, overcome rare genetic resistances, and evade detection, cures, and countermeasures. Even evolution itself may work in humanity’s favor: Virulence and transmission is often a trade-off, and so evolutionary pressures could push against maximally lethal wild-type pathogens.5,6 While these arguments point to a very small risk of human extinction, they do not rule the possibility out entirely. Although rare, there are recorded instances of species going extinct due to disease—primarily in amphibians, but also in 1 mammalian species of rat on Christmas Island.7,8 There are also historical examples of large human populations being almost entirely wiped out by disease, especially when multiple diseases were simultaneously introduced into a population without immunity. The most striking examples of total population collapse include native American tribes exposed to European diseases, such as the Massachusett (86% loss of population), Quiripi-Unquachog (95% loss of population), and theWestern Abenaki (which suffered a staggering 98% loss of population). In the modern context, no single disease currently exists that combines the worst-case levels of transmissibility, lethality, resistance to countermeasures, and global reach. But many diseases are proof of principle that each worst-case attribute can be realized independently. For example, some diseases exhibit nearly a 100% case fatality ratio in the absence of treatment, such as rabies or septicemic plague. Other diseases have a track record of spreading to virtually every human community worldwide, such as the 1918 flu,10 and seroprevalence studies indicate that other pathogens, such as chickenpox and HSV-1, can successfully reach over 95% of a population.11,12 Under optimal virulence theory, natural evolution would be an unlikely source for pathogens with the highest possible levels of transmissibility, virulence, and global reach. But advances in biotechnology might allow the creation of diseases that combine such traits. Recent controversy has already emerged over a number of scientific experiments that resulted in viruses with enhanced transmissibility, lethality, and/or the ability to overcome therapeutics.13-17 Other experiments demonstrated that mousepox could be modified to have a 100% case fatality rate and render a vaccine ineffective.18 In addition to transmissibility and lethality, studies have shown that other disease traits, such as incubation time, environmental survival, and available vectors, could be modified as well.19-2

Overall, the risk seems substantial We’ve seen a variety of estimates regarding the chances of an existential biological catastrophe, including the possibility of engineered pandemics.17 Perhaps the best estimates come from the Existential Risk Persuasion Tournament (XPT). This project involved getting groups of both subject matter experts and experienced forecasters to estimate the likelihood of extreme events. For biological risks, the range of median estimates between forecasters and domain experts were as follows: Catastrophic event (meaning an event in which 10% or more of the human population dies) by 2100: ~1–3% Human extinction event: 1 in 50,000 to 1 in 100 Genetically engineered pathogen killing more than 1% of the population by 2100: 4–10%18 Note: the forecasters tended to have lower estimates of the risk than domain experts. Although they are the best available figures we’ve seen, these numbers have plenty of caveats. The main three are: There is little evidence that anyone can achieve long-term forecasting accuracy. Previous forecasting work has assessed performance for questions that would resolve in months or years, not decades. There was a lot of variation in estimates within and between groups — some individuals gave numbers many times, or even many orders of magnitude, higher or lower than one another.19 The domain experts were selected for those already working on catastrophic risks — the typical expert in some areas of public health, for example, might generally rate extreme risks lower. It’s hard to be confident about how to weigh up these different kinds of estimates and considerations, and we think reasonable people will come to different conclusions. Our view is that given how bad a catastrophic pandemic would be, the fact that there seems to be few limits on how destructive an engineered pandemic could be, and how broadly beneficial mitigation measures are, many more people should be working on this problem than current are. Reducing catastrophic biological risks is highly valuable according to a range of worldviews Because we prioritise world problems that could have a significant impact on future generations, we care most about work that will reduce the biggest biological threats — especially those that could cause human extinction or derail civilisation. But biosecurity and catastrophic risk reduction could be highly impactful for people with a range of worldviews, because: Catastrophic biological threats would harm near-term interests too. As COVID-19 showed, large pandemics can bring extraordinary costs to people today, and even more virulent or deadly diseases would cause even greater death and suffering. Interventions that reduce the largest biological risks are also often beneficial for preventing more common illnesses. Disease surveillance can detect both large and small outbreaks; counter-proliferation efforts can stop both higher- and lower-consequence acts of deliberate misuse; better PPE could prevent all kinds of infections; and so on. There is also substantial overlap between biosecurity and other world problems, such as global health (e.g. the Global Health Security Agenda), factory farming (e.g. ‘One Health‘ initiatives), and AI.

The likeliest thing to wipe out humans isn't climate change, it's the next pandemic. With the anti-vax movement, our growing resistance to antibiotics, and the speed at which air travel can spread disease – a modern version of the Black Death would decimate us We do love a bit of doomsday drama. Humans have been predicting the end of the world for as far back as we have records. Historically this fear of an impending apocalypse has been bolstered and exploited by religion (a great way to keep the masses in check), and more recently by the environmental movement, itself a quasi-creed, led by the likes of Al Gore, Dr Michael 'Climategate' Mann, and Extinction Rebellion. "Civilization will end within 15 or 30 years unless immediate action is taken against problems facing mankind," said Harvard biologist George Wald in the 1970s. "This [Climate Change] is the biggest crisis humanity has ever faced," said Greta Thunburg in 2019. Boris Johnson was singing from the same hymn sheet today at the launch of the United Nations Climate Conference. While Wald, and many before him, were quite patently wrong, and though it's too soon to say whether Thunburg's thundering rhetoric will prove prophetic: what is certain is that climate change has already wiped out countless species over billions of years – none of it, so far, caused by humans. We're overdue the next Ice Age; that really will throw a pick axe into the works and prompt a mass extinction. But perhaps the more interesting question is whether humanity will destroy itself before then? And if so, how? Telegraph Travel spoke to Dr Lewis Dartnell, an astrobiology research scientist and author of several popular science books. "I don't believe man-made climate change will ever lead to our extinction, or collapse human civilization," he says. "It will be very, very bad, but not existentially catastrophic. "Something like the outbreak of a particularly virulent virus or very infectious, lethal pandemic is a low probability event, but exactly the sort of thing that catastrophe analysis and disaster planners take very seriously." Low probability, perhaps. But it's happened before, and at eerily regular intervals... Humans: a potted history of pandemics Civilisation – which Wald predicted would disappear by the end of the 21st century – has been around for 6,000 years or so. "Historical records suggest that about once every 1,000 years, an event occurs which wipes out about a third of the human population," stated Dr Simon Beard, at the Centre for the Study of Existential Risk at the University of Cambridge, to the BBC. In the Middle Ages, this was the Black Death, when bubonic plague spread across Eurasia and claimed one in every three inhabitants. There was also a 'dramatic global cooling' at that time, incidentally; cause unknown. "Around 1,000 years before that, there was a similar event with the Plague of Justinian [an epidemic that afflicted the Byzantine Empire] and again, a lot of people died," Beard says. Go back further, some 76,000 years ago, and there was "quite likely a certain event on a much larger scale", Beard continues, a mysterious event which wiped out 90 per cent of the human population. Genetic evidence suggests our numbers may have dwindled to about 10,000. You might be wondering, based on this model, when we're next due a major population loss? One thousand years from the Black Death would bring us to 2350, but only half way into that timescale, we were dealt a pandemic even worse than that; the Spanish flu of 1918, which infected an estimated 500 million people worldwide, accounting, once again, for a third of the world's population. The next pandemic could be far worse History dictates that it is almost inevitable, sooner or later, that another particularly virulent disease strain will attack humans faster than we can formulate a cure, only this time, there's a big difference: air travel. The recent coronavirus outbreak provides a good example of how quickly a domestic bug can go international. "The very way we live in the modern world, in densely packed cities, with planes that effectively teleport us between continents – more than 4 billion of us a year – these are the ideal breeding conditions for pathogens to spread wide and far extremely quickly," says Dartnell. "Medicine may have advanced hugely in the past century or so, but where we live and how we move has made it easier than ever for diseases to spread. The quicker they can spread to lots of people, the less chance you've got to develop a cure in time or implement quarantine." Quarantine, after all, was the best weapon people had in the Middle Ages when the Black Death hit. "Eventually they closed the ports, and incoming ships would be made to bob from afar for 40 days," says Dartnell. "That's where quarantine originated." Just imagine the consequences today: several years of an incurable plague that air passengers spread globally within the first few days. Other factors As a species, we've never been healthier or lived longer. Advancements in medicine over the 20th century have been staggering, but amid these achievements is a poisoned chalice, Aside from the irony that keeping ever more people alive so successfully has led to an overpopulation crisis which at some point will break us, two of the drugs that have been so pivotal could at some stage be obsolete: vaccinations and antibiotics. "Many of the medical breakthroughs of the last century could be lost through the spread of antimicrobial resistance [when pathogens mutate to outsmart antibiotics, rendering them useless]," warns the World Health Organisation. "Previously curable infectious diseases may become untreatable and spread throughout the world. This has already started to happen." The Infection Diseases Society goes further, describing antibiotic resistance as "one of the greatest threats to human health worldwide." Dartnell agrees. "There is a genuine risk of antibiotic resistance taking us back to the pre-1920s era of medicine," he says. The problem stems partly from the overuse or misuse of drugs like penicillin, partly because we consume the meat and dairy of animals pumped with the stuff; and the solution - to keep developing new, better antibiotics - is too expensive and risk-addled for most major drug companies to invest in. Then there's the anti-vax movement, which has seen a growing number of people around the world refuse to vaccinate their children based on misinformation about them being harmful. "It's a catch 22," Dartnell remarks. "Our science and technology has got so good at preventing the infectious diseases that would have killed nine children out of ten before their second birthday a few generations ago, that people no longer fear them, to the extent that they are choosing to not vaccinate their own children. People have forgotten what the problem was in the first place." Grim. How can we ensure we don't go extinct? Ask a crocodile. In their current form, they have survived 280 times longer than we have. This is the first in a two-part series. Next, we examine overpopulation; the root of every problem mankind is currently facing, and hear from Dr Dartnell on what would happen immediately after an apocalypse, where in the world would be best to camp out, and how we would rebuild society.

Artificial Intelligence Artificial intelligence may be used to simulate the propagation of viruses and forecast how an outbreak will likely develop. Effective resource allocation and the development of focused treatments are both possible with the help of this information. It helps researchers develop their applications related to pandemic situations. To improve viral disease detection and treatment, AI systems can examine patient data and medical imaging. Artificial intelligence can be used, for instance, to spot patterns in chest X-rays that might point to a COVID-19 infection [13]. Artificial intelligence can be used to find prospective medication candidates and forecast how they would interact with viral proteins. This can help find new treatments for viral illnesses and hasten the drug discovery process. It can be used to identify the most promising vaccine candidates and predict how they may interact with the immune system. This information can be used to develop more effective vaccines and improve vaccination strategies. The emerging uses of biomedical science in AI for pandemic control and prevention could fundamentally alter how we recognize, identify, and treat viral diseases. Artificial intelligence will likely become an even more potent weapon in the fight against pandemics as technology advances [14]. Personal Protective Equipment Personal protective equipment, which gives healthcare professionals and other essential personnel the ability to protect themselves against viral infections, has become an essential tool in pandemic prevention and control. The development of materials PPE is resistant to viruses and bacteria; these materials can increase or decrease PPE's effectiveness. New materials that can be used in PPE, such as fabrics that risk transmission, are being developed by biomedical scientists. Biomedical researchers are also creating PPE with improved fit and comfort which are easier to wear and more comfortable, like masks that don't irritate the skin or cause glasses to fog up. This can lower the risk of transmission and increase compliance with PPE requirements. Self-cleaning materials, like masks that are coated in a virus-killing substance, are being developed. This can increase PPE's effectiveness, lessen the need for frequent replacements, and have advanced sensors to monitor vital signs and spot early signs of infection. Biomedical researchers are creating sensors that can be incorporated into PPE. By doing this, viral diseases can be treated more effectively and earlier. They are also creating PPE that can be modified to meet specific needs, like masks that are made to fit the wearer's face. This can lessen the risk of transmission and increase the efficiency of PPE [15]. Nanotechnology Biomedical science and nanotechnology are two fields that have a lot of potential for cross-disciplinary collaboration and innovation. Innovative strategies for COVID-19 prevention and control have been developed as a result of the fusion of biomedical science and nanotechnology. Some examples of how these two fields have worked together to combat pandemics such as COVID-19 are as follows: With the help of nanotechnology, SARS-CoV-2 is being fought through infection prevention, detection, and treatment. Nanotechnology is a powerful tool with the potential to lower infections because it plays a significant role in the prevention, diagnostics, and therapeutic strategies for COVID-19 management. Among these strategies are the development of antiviral therapeutics or vaccines to introduce antiviral agents into the human body, diagnostic instruments for prompt, accurate, and focused diagnosis, and preventive measures and disinfectants based on nanomaterials. Nanomaterials, like metal nanoparticles, have a high surface-to-volume ratio because they are frequently smaller than one micrometer. Scientists are looking into developing vaccines using nanomaterials. Masks frequently contain nanomaterials like nanofibres and nanofibre webs to reduce the dispersion of large respiratory droplets and shield staff from patient-transmitted droplet transmission [16]. High-performance filtering masks (filtering face piece 2 (FFP2), FFP3, and N95) use a filtering face piece that combines an electrostatic charge and a web of polypropylene microfibers. By using filter materials like nanofibres and nanofibre webs and treating the filter surfaces with antimicrobial substances, the effectiveness of masks in fighting viruses and other microbes has been improved. The hydrophilic biocide film and partially gelled submicron polypropylene nanofibres used in the nanofibre filtering facepiece respirators (FFPR) effectively rendered pathogens inactive. Nanomaterials have also been used to create medical gloves for COVID-19 protection in addition to the mask. Due to the antibacterial properties of silver nanoparticles, for instance, some gloves have been created. It has been demonstrated that the veridical activity of silver nanoparticles (AgNPs) exists. Angiotensin-converting enzyme 2 (ACE2) receptors allow COVID-19 viruses to enter cells, so lowering ACE2 levels could help cut down on the number of infections. It was suggested that using nanotechnology in the gloves to catch the viruses before they enter the cells would be very beneficial [4]. Numerous opportunities exist for improving practicality and ensuring sanitation, thanks to nanotechnology. These nanomaterials include engineered water nanostructures and metallic nanoparticles, primarily titanium dioxide (TiO2) and AgNPs, which have antiviral properties and aid in COVID-19 protection. Deionized water, electrolyzed water, and hydrogen peroxide solutions for microbe inactivation are some of the active ingredients used to make engineered water nano-disinfectants. These nanosanitizers' effectiveness at eliminating microbes from surfaces and the environment was tested. Nanoparticles have drawn a lot of interest in the development of vaccines because of their simple functionalization, controlledrelease properties, photothermal and magnetic properties, and tunable size. They are now widely used by researchers to deliver targeted vaccines to immune cells like dendritic cells (DCs). Selective targeting of DCs with nanomaterials has been achieved using a variety of techniques, demonstrating great promise for the development of low-dose vaccines [17]. Similar to this, nucleic acids were delivered to the target cell using lipid-based nanoparticles. It enables the production of vital viral proteins for immunization or the inactivation of vital viral target genes. By inserting a plasmid containing a DNA sequence encoding the antigen(s) into the appropriate tissues, one vaccination technique has been developed. These vaccines have a problem with insufficient cell delivery. Nucleic acidbased therapeutic products have been administered using cationic lipid nanoparticles to address this problem [16]. The potential for biomedical applications of protein nanoparticles is great. The majority of them are obtained using recombinant technologies. Researchers created self-assembling protein nanoparticles (SAPNs) by oligomerizing monomeric proteins. It was demonstrated that SAPNs could be modified to produce a diameter resembling that of viruses, and as a result, they are recognized as a potential candidate for a vaccine against respiratory viruses. One of the most widely used nanomaterials for quick diagnostics is gold nanoparticles (AuNPs). For instance, in one study, gold nanoparticles were used to identify target viruses' double-stranded DNA (dsDNA). And nanomaterials based on carbon have been widely used to create platforms for COVID-19 diagnostics. Using carbon-based nanomaterials as COVID-19 antiviral therapeutics is possible [18]. Nanozymes are synthetic enzymes made of nanomaterials that function just like natural enzymes do. Because of their exceptional catalytic abilities, quick response times, and capacity for self-assembly, nanozymes are frequently used in the diagnosis and treatment of diseases. Antiviral therapy has a new window of opportunity thanks to nanotechnology. Nanoparticles are adaptable vectors for the targeted delivery of specific therapeutic drugs and viruses due to their flexibility. To improve drug bioavailability, drug delivery, and targeted antiviral activity, organic nanoparticles have been used to deliver antiviral medications like acyclovir, zidovudine, efavirenz, and dapivirine. Exosome delivery to the target cell for therapeutic purposes has recently attracted a lot of attention. They have been introduced as potential biological nanocarriers for COVID-19 treatment in several clinical applications. Coronavirus disease (COVID-19) has also been treated with peptide inhibitors [19]. Overall, the relationship between biomedical science and nanotechnology has led to the development of innovative solutions for pandemic prevention and control. These emerging applications have the potential to not only combat the current pandemic but also be useful for future disease outbreaks. However, it is important to continue to evaluate their safety and effectiveness through rigorous testing and research.

Emerging applications of biomedical science Rapid Diagnosis Tests (RDTs) Rapid diagnostic tests (RDTs) for pandemic prevention and control have been developed and implemented in large part. Thanks to the contributions of biomedical science, scientists are working to develop new RDTs for the detection of emerging infectious diseases, such as COVID-19. They are also developing RDTs that are more accurate, sensitive, and specific than existing tests. For example, rapid diagnostic tests called COVID19 antigen tests identify specific proteins from the COVID-19-causing SARS-CoV-2 virus. Since the beginning of the pandemic, several fresh COVID-19 antigen tests have been created, including the Sofia SARS Antigen Fluorescent Immunoassay (FIA) and BinaxNOW COVID-19 Ag Card. The gene editing technique is used by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based RDTs to find viral DNA or ribonucleic acid (RNA) sequences in samples. These tests can be extremely sensitive and specific [5]. Examples of CRISPR-based RDTs for COVID-19 include the Sherlock CRISPR SARS-CoV-2 Kit from Sherlock Biosciences and the SARS-CoV-2 DETECTR assay from Mammoth Biosciences. To find a specific pathogen or antibody, fluorescent dyes are used in fluorescence-based RDTs. These examinations may be quite sensitive and precise. The LumiraDx SARS-CoV-2 Ag Test and the Gene Xpert Flu/RSV XC are two examples of RDTs that use fluorescence as an indicator. Isothermal amplification is when RDTs amplify specific RNA or DNA sequences to detect the presence of a pathogen. The use of expensive equipment is not necessary because these tests can be carried out at a constant temperature. The RT-LAMP COVID-19 Kit and the ID NOW COVID-19 test are two examples of isothermal amplification RDTs. Multiplexed RDTs can detect multiple pathogens or antibodies in a single test. These tests can be highly efficient and useful for surveillance and mass testing. Examples of multiplexed RDTs include the BioFire Filmarray Respiratory Panel 2.1 and the ePlex Respiratory Pathogen Panel [6]. Vaccines Messenger ribonucleic acid (mRNA) vaccines, a recent advancement in vaccine technology, have been used to combat COVID-19. These vaccines function by instructing cells to produce a tiny amount of harmless viral genetic material that stimulates an immune response. The mRNA vaccines from Moderna and Pfizer have the ability of COVID-19 vaccines to prevent COVID-19 infections, which has been demonstrated to be very high. Viral vector vaccines deliver the genetic material from the pathogen to the body's cells using a non-lethal virus [7]. Small particles are used in nanoparticle-based immunizations to deliver the vaccine's active components to the body's cells. Since the shape of the virus is mimicked by these particles, the immune system is better able to identify and combat the virus. The Novavax and CureVac vaccines, among others, are nanoparticle-based COVID-19 vaccines. Personalized vaccines are a new area of research that could revolutionize vaccine development. Because these vaccines are made specifically for each individual, they may be more effective and cause fewer side effects. While personalized vaccines are still in the early stages of development, they could be an important tool in the fight against pandemics in the future. To boost the immune response, adjuvants are chemicals that are added to vaccines. They function by encouraging immune system cells to more readily identify and react to the vaccine. Flu vaccines frequently contain adjuvants, and some COVID19 vaccines do as well. Antiviral Therapies Biomedical science has also contributed to the development of antiviral therapies for pandemic prevention and control. They use small-molecule drugs, monoclonal antibodies, RNA-based therapies, CRISPR-based therapies, and broad-spectrum antivirals. Small-molecule drugs are traditional pharmaceuticals that work by binding to specific viral proteins and preventing the virus from replicating. Some examples of small-molecule drugs include remdesivir, which is used to treat COVID-19, and Tamiflu, which is used to treat the flu. Laboratory-produced proteins called monoclonal antibodies imitate the immune system's capacity to combat infections. These treatments function by neutralizing the virus by concentrating on particular viral proteins [8]. The monoclonal antibody cocktail from Regeneron is one of the monoclonal antibody treatments that have been approved for use in COVID-19 emergencies. Targeting the virus' genetic material and limiting its replication are the principles behind RNA-based treatments. Lipid nanoparticles or other delivery systems can be used to deliver these treatments directly to the cells. For the treatment of COVID-19, some RNAbased treatments have produced encouraging outcomes in preliminary clinical trials [9]. The CRISPR-Cas systems, which are gene-editing tools, have recently been adapted for use in antiviral therapies. The CRISPR-based therapies work by targeting specific viral genes and disrupting their function, which can prevent the virus from replicating. While still in the early stages of development, CRISPR-based therapies could offer a new approach to antiviral therapy. Broad-spectrum antivirals are treatments that work well against a variety of viruses. These treatments function by focusing on conserved viral proteins that are present in all viruses. Ribavirin, which is used to treat hepatitis C, and favipiravir, which is used to treat influenza, are two examples of broad-spectrum antivirals [10]. Genome Sequencing Genome sequencing, which enables researchers to trace the spread of viruses and find novel varieties, has emerged as a crucial tool in pandemic prevention and management. Public health officials can identify and isolate infected people to stop the virus from spreading by using genome sequencing to track how a virus spreads from person to person. The genetic makeup of a virus can be determined through genome sequencing, which can also be used to create vaccinations that target particular proteins or genomic areas. This method was employed in the creation of COVID-19 vaccines, which focus on the virus' spike protein. The genetic makeup of a virus can be determined through genome sequencing, which can also be used to create vaccinations that target particular proteins or genomic areas [11]. The identification of viruses in animals that could be dangerous to human health is another purpose for genome sequencing. This "One Health" strategy can lessen the possibility of pandemics in the future by preventing the spread of zoonotic illnesses. Overall, new uses for genome sequencing in pandemic prevention and control have transformed our knowledge of viral infections and made it possible for researchers to create more potent treatments and vaccines. Genome sequencing is likely to become an even more potent weapon in the fight against pandemics as technology advances [12]. Pandemic prevention and control are rapidly improving thanks to artificial intelligence (AI), which enables researchers to examine massive amounts of data and forecast the spread of viruses. Here are some recently developed biomedical applications of artificial intelligence for pandemic control and prevention.

Emerging technologies and future directions in pandemic preparedness The landscape of pandemic threats continues to evolve, necessitating a dynamic and informed response that extends beyond our current knowledge base. The WHO blueprint list for pathogens with pandemic potential (revision in consultation) currently includes eight viral pathogens (COVID-19, Crimean-Congo haemorrhagic fever, Ebola virus disease and Marburg virus disease, Lassa fever, Middle East respiratory syndrome coronavirus (MERS-CoV) and Severe Acute Respiratory Syndrome (SARS), Nipah and henipaviral diseases, Rift Valley fever, Zika and ``Disease X'', representing a pathogen or pathogens that have not yet been shown to cause disease in humans.28).We know from genomic modelling that there are as many as 320,000 yet-to-be-characterized mammalian viruses, many of which possess zoonotic `Disease X' potential.29 This vast, unexplored virosphere represents a substantial challenge and underscores the need for continuous enhanced surveillance using for example, advanced next generation sequencing technologies. Scientific progress will be pivotal in shaping our preparedness for future pandemics, which are likely to differ significantly from previous outbreaks. The next response to a pandemic threat should leverage the latest advances in technology, including the expanding field of artificial intelligence (AI). AI's integration into pandemic preparedness and response strategies represents a paradigm shift in how we will approach future outbreaks, which are likely to differ significantly from those in the past. For example, the use of AI to predict protein structure and functionality from genomic data is currently being revolutionised by tools such as AlphaFold.30 In a pandemic scenario, rapid insights into the protein structure of a novel virus could significantly shorten the timeline for developing effective therapeutics and vaccines. AI algorithms are also adept at analysing vast amounts of data to model disease spread and predict future outbreaks, incorporating international travel patterns and climate change. AI tools can be used to enhance disease surveillance systems by analysing data from multiple sources, such as social media, news reports, and healthcare databases. AI-driven diagnostic tools also have the potential to provide rapid analysis of clinical data, such as imaging and laboratory results, to assist in the early detection of infectious diseases.31 During a pandemic, these tools could be pivotal in screening large populations quickly and efficiently. Conclusions Infectious diseases have been a significant health concern in the UK and around the world since the emergence of modern medical practice. The 20th century witnessed remarkable progress in combating such diseases, with the advent of antibiotics, vaccination, and improved hygiene. Today's infectious disease threats are increasingly shaped by anthropogenic change. The rise of antimicrobial resistance, the expansion of vector habitats due to climate change and the global growth and movement of people are increasing the risk of emerging infectious diseases. Accelerated innovation with new technologies and team science will be required to monitor and control the threat.

Claudia Martínez, 05-12-2022, Head Researcher @ Access to Medicine Foundation, "Generics companies are exploring new ways to increase access to medicine ," Access to Medicine Foundation, -- MoState JG

The COVID-19 pandemic has spotlighted the central – yet changing – role of the generics industry in the global health landscape. During this period of crisis, generic medicine manufacturers ensured existing medicines remained available in LMICs, and stepped up production of generic products needed to treat the virus, despite disruptions to global supply chains. In addition, they worked with R&D-based pharmaceutical companies to rapidly create generic versions of patented COVID-19 vaccines and treatments for distribution in LMICs. The generic medicine industry has long played a critical role in expanding access to essential medicines – but the nature and extent of that role is now evolving. Increasingly, generic medicine manufacturers acknowledge the proactive ways they can expand access to their products in LMICs, beyond the conventional model of producing drugs in high volumes and selling them at relatively low prices. As highlighted in the Access to Medicine Foundation's virtual workshop on 6 April 2022, companies are identifying opportunities to increase access, and are exploring commercially viable ways to launch products in LMICs. The workshop was joined by participants from eight multinational generic medicine manufacturers, as well as experts from global health organisations, procurement agencies, and government bodies. "It is vitally important that all healthcare sectors address inequality and improve access, which we have articulated in our new Strategic Direction. With this workshop we were able to take the unprecedented step of bringing top generic medicine manufacturers together to discuss areas where progress is most needed, and the necessary steps to solve the problem.” – Jayasree K. Iyer, CEO, Access to Medicine Foundation This workshop, which is part of the Access to Medicine Foundation's new research programme focused on the generic medicine industry, provided a first opportunity for open discussion about current and future roles and responsibilities of generic medicine manufacturers in improving access to essential health products for people living in LMICs. Ensuring access to generic medicines in LMICs: 3 key takeaways Participants shared examples of what companies are currently doing to expand access, and explored ways of finding solutions to common challenges. These insights, which are explored in greater depth in the meeting report, include developing networks and relationships to better understand local needs; exploring solutions around payment; investing in local manufacturing to ensure continuous reply; taking up licensing opportunities; and making use of collaborative registration procedures. The meeting report identifies three key takeaways from the workshop: GENERIC MEDICINE MANUFACTURERS HAVE MORE OPPORTUNITIES IN ENSURING ACCESS TO MEDICINE, BEYOND THEIR CONVENTIONAL ROLE By manufacturing drugs at high volumes and selling them for relatively low costs, the generics industry already plays a significant role in expanding access to medicine. However, simply producing a generic product does not guarantee access to that product in LMICs – and this is especially the case when it comes to low-income countries. As indicated by participants in the workshop, there is a broad consensus that generic medicine manufacturers have an opportunity to actively expand access to their essential health products in LMICs and ensure a continuous supply of high-quality generic medicines and biosimilars, beyond the traditional high-volume / low-cost business model. VIABLE BUSINESS MODELS THAT BUILD IN ACCESS TO MEDICINE CAN, AND SHOULD, BE DEVELOPED Generic medicine manufacturers can develop business models with long-term sustainability of access at their core, reconciling the need for commercial viability with approaches that result in greater access to generics and biosimilars in LMICs. Over recent decades, multistakeholder efforts to ensure universal access to treatments for diseases including HIV, TB and malaria have led to valuable insights, some of which can be used to inform strategies more widely; but viable business models can also be identified and implemented in disease areas that have not received such international attention and funding. Workshop participants highlighted a range of approaches to expanding access sustainably, including engaging in public-private partnerships to engage in regional procurement initiatives and build local capacity. There are ways to explore whether a new approach is viable, such as by starting small and scaling up; in other cases, companies can take a ‘leap of faith’. GENERIC MEDICINE MANUFACTURERS CAN BUILD ON THEIR STRENGTHS TO OVERCOME CHALLENGES SPECIFIC TO LMICS Particular challenges exist in LMICs that can deter generic medicine manufacturers, such as registration hurdles and lower commercial market potential. One common challenge is that, when the original brand-name product was not introduced or made widely accessible in many LMICs, launching the generic version in those countries can be a more uncertain prospect. To overcome such challenges and provide equitable access to their products, companies can capitalise on their at-scale manufacturing expertise and adaptive R&D capacities, while also developing new approaches to support broad access and affordability. For example, they can enter into partnerships to better understand demand for the product, and therefore align supply; they can leverage collaborative registration procedures; and they can adapt products to better suit the needs of patients living in LMICs. As part of the Foundation’s Strategic Direction for 2022- 2026, we are expanding the range of companies and healthcare sectors that we aim to mobilise in the global effort to overcome healthcare inequality, and this will include the generic medicine industry. The Foundation will engage companies that hold dominant positions in key regional markets, including some of the largest multinational players in the generic sector, to evaluate companies’ actions in access, identify opportunities to bridge key access gaps, and capture best practices. Informed by discussions in this workshop, as well as by conversations with a range of experts and stakeholders, the Foundation is developing an assessment framework that will outline generic medicine manufacturers' roles and responsibilities in expanding access to high-quality generic medicines and biosimilars.

“Product Hopping” Definition Critics of current pharmaceutical patenting practices have observed that patent evergreening can be used in conjunction with a practice they call “product hopping.”432 Product hopping is the process by which a brand, as the patents on an older branded drug are expiring, uses its current dominant market position to switch doctors, pharmacists, and consumers to a newer version of the same (or similar) drug with later-expiring patents. In other words, the brand forces a “hop” from one product to another.433 The new version of the product may be, for example, an extended release form or new dosage (e.g., moving from twice-a-day to once-a-day), a different route of administration (e.g., moving from capsules to tablets, or tablets to film strips), or a chemical change (e.g., moving to a different enantiomer).434 The switch to the new version may be accompanied by a marketing campaign or discounts and rebates to encourage doctors, insurers, and patients to switch to the new version; in some cases, production of the older version may be discontinued.435 Product hopping tends to take one of two forms: a “hard switch,” where the brand removes the original product from the market, and a “soft switch,” where the brand leaves the original product on the market alongside the new form. 436 The case of Abbott Laboratories v. Teva Pharmaceuticals USA, Inc.437 provides one example of a hard switch. That case involved Abbott’s changes to its drug TriCor, which was used to treat high cholesterol and triglycerides.438 Abbott allegedly lowered the drug’s strength, switched it from a capsule to a tablet, stopped selling capsules, bought back supplies of capsules from pharmacies, and marked capsules as “obsolete” in the national drug database.439 Once generics developed equivalents for the reformulation, Abbott allegedly again lowered the drug’s strength, stopped selling the original tablets, and again changed the code for the old tablets to “obsolete.”440 A soft switch allegedly occurred in Schneiderman v. Actavis PLC. 441 There, Actavis produced Namenda IR (IR), a twice-daily drug designed to treat Alzheimer’s disease.442 As the patents on IR neared expiration and generics prepared to enter the market, Actavis introduced a once-daily version of the drug, Namenda XR (XR), and allegedly attempted to encourage doctors and patients to switch from IR to XR.443 Although the generic versions would have been substitutable for IR, the differences in dosing (10 mg in IR and 28 mg in XR) meant the generic versions would not be substitutable for the new XR product.444 Initially, both IR and XR were on the market together.445 During that time, Actavis allegedly stopped marketing IR and “spent substantial sums of money promoting XR to doctors, caregivers, patients, and pharmacists.”446 Actavis also sold XR at a discount, making it much less expensive than IR, and issued rebates to ensure patients did not have to pay higher copayments for XR than IR.447 When it appeared the soft switch would only convert 30% of IR users to XR, Actavis allegedly implemented a hard switch by announcing it would discontinue IR and attempting to stop Medicare health plans from covering IR.448

Despite the standard “one-patent-one-product” model in intellectual property rights discourse, a common practice by innovators is to acquire numerous patents on different features of the same product to extend its monopoly life. In this paper, I systematically document the presence of imperfect intellectual property rights in the pharmaceutical industry, an industry often characterized by the standard model (Burk and Lemley, 2003). I show that the standard model does not hold: Multiple patents may cover a single product, with the scope and enforceability of each patent potentially uncertain, contributing to indeterminate periods of monopoly protection. In a sample of novel drugs, I find that nearly all drugs are covered by multiple intellectual property rights and that actual monopoly terms often last well beyond the fixed term of a drug’s initial molecule patent. I then offer, to my knowledge, the first causal estimate in any industry on the extent to which additional patents extend monopoly life. By exploiting the quasi-random assignment of patent ap- plications to examiners and variation in cross-examiner leniency, I determine that the average drug receives 3 years of additional monopoly life due to imperfect intellectual property rights, equivalent to 22 percent of mean monopoly term. I posit two mechanisms by which the accumulation of intellectual property rights on a single drug may delay generic entry: by introducing a binding later IP expiration and by increasing uncertainty in the scope and enforceability of remaining IP rights. Consistent with these mechanisms, I provide empirical evidence of non-monotonic generic entry patterns relative to IP expirations and a series of analyses illustrating that uncertainty in IP scope/enforceability is an important factor behind delayed generic entry. The paper’s analysis demonstrates that the strategic use of patents by innovating firms can substantially increase entry barriers into a market and lengthen monopoly durations. The results are in line with prior research on secondary patenting by branded manufacturers and patent challenges by generics. For instance, my finding that uncertainty in IP enforceability is an important mechanism for delaying generic entry complements work by Hemphill and Sampat (2011, 2012), who note that patent challenges may serve to limit evergreening behavior by branded firms, and research by Grabowski et al. (2017), who find both increased patenting activity and more challenges for the most popular new drugs. In recent work, Kyle et al. (2021) note that primary drug patents are the key patents impacting generic competition in India. My results are complementary to theirs. I show that in addition to primary patents, secondary Orange Book patents play a significant role in delaying competition in the U.S. drug market. The results of this paper have [has] important implications for consumer welfare, innovation incentives, and the design of intellectual property rights both broadly across sectors and within the pharmaceutical industry in particular. I find that more novel drugs receive longer monopoly extensions. That is, these imperfections allow pharmaceutical IP rights to approach a first-best system where monopoly terms are proportionate to innovation size. However, the extensions translate to only minimal increases in new molecules, relative to the substantial consumer welfare loss due to extended monopoly pricing. Thus, these imperfections in our patent system mean that firms can at least partially offset distortions of a fixed-term system by accumulating patents on a single product; yet at the same time, additional targeting may be necessary to achieve innovation policy objectives. Overall, this paper highlights that intellectual property rights are less rigid than we typically assume and these imperfections matter for discussions on optimal patent policy and innovation.

Definition Evergreening, also known as patent “layering” or “life-cycle management,” is a practice by which drug innovators allegedly seek “to prolong their effective periods of patent protection through ... strategies that add new patents to their quivers as old ones expire.”377 As discussed above, because different aspects of pharmaceutical products (and improvements thereon) are patentable,378 dozens of different patents can protect a single pharmaceutical product. The average number of patents per drug has steadily increased since the Hatch-Waxman Act became law in 1984.379 On average, there are about 3 patents listed for each pharmaceutical product listed in the Orange Book. 380 Particularly profitable drugs are usually protected by more patents than average,381 and some of those patents may be added to the Orange Book relatively late in the life cycle of a drug (as opposed to when a new drug has just come to market). Because later-issued patents generally have later expiration dates (presuming they arise from a later patent application), these later patents, if valid, may extend the total effective exclusivity period for a drug or biologic. One comprehensive study of evergreening found that 78% of the drugs that had new patents added to their Orange Book listing were for existing drugs—not new market drugs just coming to market—and that such “evergreening” was particularly common for best-selling drugs.382 For example, a 2020 report from the U.S. House of Representatives Committee on Oversight and Reform investigated the pricing of Revlimid, a top-selling plasma cell myeloma drug made by Celgene Corporation.383 The staff report concluded that Celgene “stifled generic competition by filing for” numerous patents—including ten patents on Revlimid’s REMS program—“and enforcing those patents against potential generic competitors.”384 Another House Committee on Oversight and Reform investigation into Amgen’s biologic Enbrel, used to treat rheumatoid arthritis, concluded that “Amgen has leveraged its patent and lifecycle management strategies to prevent competitors from introducing lower-priced biosimilar versions of Enbrel.”385

The term “patent thicket”10 includes two key aspects of patenting activity: the dozens or even hundreds of patent applications that drugmakers file with the U.S. Patent and Trademark Office (USPTO), and the patents that are actually granted. The high volume of both filed patent applications and granted patents creates a complex web of both actual barriers and potential or likely barriers that generic and biosimilar competitors must avoid to stay in compliance with the law. This creates a great deal of uncertainty that deters generic and biosimilar competitors from entering the market, as well as uncertainty for Americans as to when they will have lower-cost medications.11 Patent thickets have significant negative consequences for the country, including: ■ Harming public health ■ Straining household budgets ■ Overstressing the U.S. Patent and Trademark Office ■ Creating uncertainty in the market A BIPARTISAN GROUP OF U.S. SENATORS NOTED RECENTLY IN A LETTER TO USPTO DIRECTOR KATHI VIDAL, “THE PATENT ACT ENVISIONS A SINGLE PATENT PER INVENTION, NOT A LARGE PORTFOLIO BASED ON ONE CREATION.”12 Granted patents allow drugmakers to block competition. Today, drugmakers secure dozens or even hundreds 13 of patents on each of their top selling drugs, in order to expand and protect their monopoly power. The 744 granted patents 14 on America’s ten top selling drugs give pharmaceutical companies substantial power in litigation and negotiations to keep lower cost generic and biosimilar alternatives off the market for longer, and out of the hands of the American public. Patent applications also form part of patent thickets and deter competitors. Generic or biosimilar companies do not only evaluate granted patents when assessing whether to enter the market, they must also track and review patent applications to make their decision.15 Currently there are over 140 patent applications filed on average for each of the 10 top selling drugs in America.16 Notably, over 66% of patent applications were filed after the U.S. Food and Drug Administration (FDA) approved the drug to be on the market, indicating that drugmakers are attempting to prolong the existing exclusivity for as long as possible. Primary patents – or the patents that cover the main active ingredient or molecule17 – are set to expire this decade on 7 out of 10 of America’s best-selling drugs.18 When a product is a (or even the) key source of earnings and growth for a pharmaceutical company, there is significant financial incentive to mitigate the negative impact on the bottom line – or at least to delay the inevitable. Excessive patenting on existing products is one key strategy drugmakers use to extend their monopolies and their revenue streams.19 Generics and biosimilar companies in turn may want to enter the market for the top selling drugs, but this entails significant risk and resources because of the dense patent thickets protecting the monopolies on these products. As a result, while they are litigating the patents, generic and biosimilar companies are more likely to enter into settlements with the branded company rather than wait for a final ruling, regardless of the strength of their case.20 In many cases, the certainty of the settlement and earlier revenues outweigh the risks of prolonged litigation.21

Continuation patents on FDA-approved drugs skyrocketed by 200% from 2000 to 2015, likely putting off generic competition, researchers found. Over this time period, the ratio of continuation patents increased from 0.6 for drugs approved in 2000 to 1.8 for drugs approved in 2015, while the ratio of the number of original patents per FDA approval increased by 15%, from 1.3 to 1.5, respectively, reported S. Sean Tu, JD, PhD, of West Virginia University College of Law in Morgantown, and colleagues. Overall, the ratio of the number of FDA-listed patents per drug increased by a relative 68%, they noted in a research letter in JAMA. Among 3,967 distinct patents on these drugs through 2021 listed in the FDA's "Orange Book," also known as the "Approved Drug Products with Therapeutic Equivalence Evaluations," 53% were original patents and 47% were continuation patents. While the ratio of the number of litigated original patents per approval increased by 63%, from 0.38 for drugs approved in 2000 to 0.62 for drugs approved in 2015, the ratio of litigated continuation patents increased 213%, from 0.22 to 0.69, respectively. Companies apply to the U.S. Patent and Trademark Office for a continuation, which is when the "patent holder adds new applications to a prior submission by offering minor clarifications or additions without substantial change to the underlying invention," the authors explained. Tu told MedPage Today that continuation patents are a pervasive legal strategy increasingly used in patent thicketing and are designed to increase costs for competitors and make it harder for generics to hit the market. "Not only are [companies]* filing and getting more continuation patents, they're [are] actually litigating these patents," Tu said. Of the 1,936 litigated patents in total, the number of original and continuation patents was similar: 985 and 951, respectively. "More continuation patents mean that generic firms seeking to challenge existing protections on brand-name drugs must contest and potentially litigate more patents," Tu and team noted.

Whether or not the proposed accord will live up to global expectations for fairness and solidarity remains to be seen, however, as currently formulated, it does not address international and national intellectual property (IP) regimens (patents, copyrights, industrial designs, trade secrets and data rights) that negatively impact equitable access to pandemic health technologies. This means that pharmaceutical firms will continue to enjoy IP exclusivities that pose direct obstacles to increasing manufacturing capacity, and ensuring adequate supply, affordable pricing, and equitable access to COVID-19 and future pandemic vaccines, diagnostics, therapeutics and other health products in low-income and middle-income countries (LMICs). Within the World Trade Organization (WTO) framework, despite a push for a temporary waiver of IP rights on COVID-19 medical countermeasures by many LMICs, the recent WTO Ministerial Decision offers only a highly conditional compulsory licensing (CL) solution for patents that only covers export of vaccines to eligible developing countries.3 4 Though there was an initial 6-month window to extend the ‘solution’ to diagnostics and therapeutics, including the outpatient antivirals now widely available in the global North, this deadline was not met and has been further extended. Thus, the current state of affairs falls far short of the vision of a world that works together to fight global health emergencies through IP waivers and technology transfer (TT) initiatives that support alternative producers in poorer countries in making vaccines, diagnostics, therapeutics and other medical countermeasures and providing them equitably and affordably to their populations.5 Moreover, we support investments in basic health systems to buttress other aspects of pandemic preparation and response— from surveillance, testing, treatment, tracing and isolation capacity for a variety of potential pandemic threats, to investments in new manufacturing sites—and detail how representative governance at the global level can advance not only procedural justice and legitimacy but also enhance efforts for equitable allocation and uptake of these technologies. Our proposal makes actionable key ideas in section 5 of the International Panel on Pandemic Preparedness and Response’s recommendations.6