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The Pace of Development Finally, to press the case for dismantling the U.S. drug development system, opponents argue that the system is not effectively performing its core function: producing effective treatments and cures. Given that the leading drug companies came up with Covid-19 vaccines in record time, using breakthrough technologies, this case is much harder to make now. But undeterred, the Porter report states, “Rather than producing breakthrough, lifesaving drugs for diseases with few or no cures, most companies focus on small, incremental changes to existing drugs in order to kill off generic threats to their government-granted monopoly patents.”34 But in reality, new drug approvals have significantly accelerated. The FDA’s Center for Drug Evaluation and Research’s five-year rolling approval average stood at 44 new drugs per year in 2019, double the five-year rolling average of 22 drugs approved, as happened in 2009. And the number of drugs in development globally increased from 5,995 in 2001 to 13,718 in 2016.35 Moreover, the share of drugs that are new has risen since the 1970s, not fallen.36 At the end of the day, the America’s private-sector-led drug development system, coupled with the support of university research and the National Institutes of Health, has made the United States the medicine chest of the world, responsible for more new drugs than any other nation. As much as the drug populists would like us to think otherwise, the truth is the current system is not just working; it’s the envy of the world.

Generic Problems The Department of Defense is worried about the quality and safety of generic drugs and is in talks to start up a testing program, my colleague Riley Griffin and I reported last week. And we learned through our reporting that Kaiser Permanente, a huge health system, has been quietly having generic drugs tested for the last two years as well. So what does this mean? Why test these less expensive pills and injections that make up 9 out of 10 medications Americans take? Of course, it’s important to understand that the majority of generic drugs are safe. But, increasingly, more of them appear to have issues than might make people uncomfortable. The University of Kentucky started a program in 2019 to test drugs purchased through the college’s network of hospitals and clinics. More than 10% of drugs have been flagged with potential problems, Robert Lodder, a pharmaceutical sciences professor who co-leads the testing effort, told me. This syncs with what the independent testing lab Valisure has said. The New Haven, Connecticut-based company used to run an online pharmacy that it sold in 2021. David Light, chief executive officer of Valisure, said the lab also found issues with about 10% of the drugs. The concerns that cause drugs to fall into the worrisome category can range from the seemingly sci-fi — such as heart and diabetes drugs that contained small amounts of a chemical that can cause cancer — to issues that can sound mundane but actually matter a lot. For instance, how exactly the human body absorbs some drugs has to be precise for the treatments to work. If a medicine isn’t made well, it may not dissolve in a way that allows the body to absorb it correctly. Light says he sees this issue a lot. In past testing, Valisure found multiple batches of the antiseizure drug lamotrigine that didn’t dissolve for at least 24 hours, meaning the body couldn’t absorb them effectively. This can be scary for someone with epilepsy who relies on the drug to regulate their condition. Dissolution issues can lead to a variety of poor patient outcomes that often aren’t pinned on the medication since absorption can’t be seen or felt by the patient. Valisure will now be taking their expertise to the Defense Department if plans for a partnership pan out. I’ll be interested to see what else they find. — Anna Edney

If a grocery store steeply discounted rotting cuts of meat or produce, would you buy them? Probably not. By the same logic, if a pharmacy tried to sell medications that are understrength or contaminated, few of us would go along. Bad meat you can smell or taste, but you can’t do that for bad meds. Unfortunately, we can’t be sure that our generic drugs are consistently safe and effective, because they aren’t independently tested before they’re sold. We simply assume they are safe. For decades, the U.S. Food and Drug Administration has used paperwork reviews and occasional plant inspections to ensure that companies make safe products. Because the agency believes that quality and safety are the manufacturer’s responsibility, it does not routinely test the medicines themselves. Pharmaceutical companies spend huge sums of money to create new drugs and secure the FDA’s approval for sale, so they can’t afford to slip up. But when a drug’s patent expires and competitors start offering low-cost generic copies, the FDA’s “honor system” can break down. In the cutthroat world of generic drug manufacture, the cheapest producer usually wins—whether they follow the rules or not. Intense global competition pushed most generic drug and ingredient production overseas to countries with low labor costs and weak regulatory controls. Once that happened, reports of contaminated or understrength drugs grew. Rather than recognize and respond to the threat, the FDA kept assuring the public that, “You can take a generic medicine as an equal substitute for its brand-name counterpart.” This statement implies that all generic drugs sold in the U.S. are equally safe and effective. Although most meet minimum quality standards, not all do. Currently, American patients, doctors and hospitals have no way to differentiate high-quality generic drugs and the companies that make them from the manufacturers that cut corners. The FDA’s approach to monitoring can take years to spot a problem. The only way to strengthen the process is to independently evaluate the quality of generic medicines in accredited labs before they are sold. There’s only one problem. The FDA is pushing back on calls for independent testing. Growing Problems Valisure, an independent drug testing laboratory, found dangerous contaminants in two widely sold generic drugs and some OTC products in 2019, according to Consumer Reports. Recalls followed. It found benzene, a carcinogen, in some hand sanitizers, and the FDA responded by subjecting Valisure—as opposed to the manufacturer—to an exhaustive multiweek inspection. The FDA accused the lab of operating without proper regulatory approvals, but documents obtained by Consumer Reports revealed that the agency thought Valisure was testing products to help companies secure FDA approval, work Valisure doesn’t do. Instead, Valisure performs independent quality testing to help purchasers make informed decisions. In 2021, FDA learned from its European counterpart that bioequivalence studies of approximately 100 generic drugs conducted by two Indian contract research organizations were flawed by irregularities. Europe suspended marketing of the products, but the FDA did not. Instead, it allowed the suspect drugs to continue to be sold with a special code to pharmacists that they shouldn’t consider them “automatically substitutable” for their brand-name counterparts. The FDA responded to concerns in an emailed statement: “Protecting patients is the highest priority of the FDA and Americans can be confident in the quality of the products the FDA approves. The FDA continues to work to build a safe, secure and agile drug supply chain so that American patients have the medications they need – medications that have been carefully reviewed by the FDA for safety, effectiveness and quality. Should healthcare systems choose to implement additional testing, it is imperative that such testing use validated methods conducted by validated labs, rather than risking invalid results.” In 2022, the U.S. Government Accountability Office reported that the FDA is struggling to conduct rigorous inspections of overseas plants. For example, domestic manufacturers are subject to “no-notice” inspections, but many foreign inspections are preannounced. Although the agency promised to do better, problems persist. According to Bloomberg, “years can pass between inspections.” While regulatory action is focused on India, China is making it nearly impossible for the FDA to properly inspect its plants. During the pandemic, China’s travel ban forced the FDA to conduct many inspections remotely, via the internet. In July, China enacted an “anti-espionage law” that gives authorities sweeping powers to label business activities they don’t like “espionage.” In October, China arrested a Japanese pharmaceutical executive who has worked in the country for 20 years. Actions like these may weigh on the minds of FDA inspectors in China. To determine if any suppliers of generic medicines to the military health system are selling substandard products, the Pentagon initiated a pilot testing program in 2023. Kaiser Permanente and a handful of academic medical centers are also testing some of their generic drugs. More health systems could follow.

Ongoing generics shortages The US generics market was valued at $90.4 billion in 2023 and is estimated to be expanding at a CAGR of 3.5% to reach $124.3 billion by 2032 — despite downward pricing pressure owing to the rising incidence of chronic diseases and the continued loss of patent protections.5 Branded prescription drugs are estimated to be nearly 2.5 times more expensive for US patients than for consumers in similar markets; and, because generics are cheaper, those low prices are threatening the sustainability of the market. Many producers have withdrawn from the market, leaving just one or two suppliers of many generic drugs. In addition, because competition is generally defined only by cost, most players still in the business outsource to contract manufacturers in Asia. However, quality and manufacturing problems have become real issues and have led to a large number of drug shortages for many important medicines. For some of these drugs, no alternatives are available, leading physicians to ration care and leaving some patients without much-needed medicines.

Generic medicines are the backbone of the U.S. prescription drug market, supplying more than 9 out of every 10 prescriptions. And the production of generic medicines overall has been remarkably stable – even during challenges such as the COVID-19 pandemic. Nonetheless, drug shortages, which hit crisis proportions between 2010 and 2011, can be a challenge for manufacturers, providers, and patients. Due to aggressive efforts by industry and the Food and Drug Administration (FDA), the incidence of shortages has declined, but recent reports suggest a rise in shortages in 2023. As AAM’s latest white paper explains, drug shortages are not limited to generic markets. They affect roughly 3% of brand-only markets and 4-6% of generic/brand and generic-only markets. Nonetheless, evidence suggests that some generic drugs may be particularly susceptible to drug shortages due to unique challenges facing the generic industry. Manufacturing generic drugs is highly competitive and frequently low margin. Indeed, there are external issues including disruptions in the supply chain, regulatory delays, or changes in competitive intensity that make producing certain generics financially unsustainable. In fact, the risk of drug shortages compounds as the long-term sustainability of generic manufacturing faces threats. Prices for generic drugs are decreasing, purchasers are becoming more concentrated, new generics are not adopted by payers as historically predicted, some generics never launch due to limited commercial opportunities, and registered manufacturing sites are declining. The combination of these factors forces generic manufacturers to reconsider production of lower-margin, often older, medicines to ensure continued financial sustainability of the overall pipeline. Generic product discontinuations have risen to over 3,000 since 2010 and appear to be on the rise. At their core, drug shortages reflect challenges to the long-term sustainability of generic medicines. While each drug shortage is unique, most stem from the increasing fragility of the generic drug market. This instability often is caused by market and pricing factors that undermine the sustainability of generic manufacturing and government policies that compound challenging market dynamics due to unpredictable reimbursement or administrative burdens. Regulatory and manufacturing challenges place additional burdens on generic manufacturers such as delaying the supply of materials to manufacture. The result is a strain on supply chains and providers left without sufficient supply for patients. As FDA Commissioner Dr. Robert Califf recently noted, We have got to fix the core economics if we’re going to get this situation fixed.

The Hatch-Waxman Act of 1984, which gave rise to the modern generic drug market, was one of the most significant cost-reducing policy innovations of the last 40 years. In 2021 alone, the use of generic and biosimilar drugs saved $373 billion in health expenditures. More than 90% of prescriptions filled that year were for generics or biosimilars, up from just over 18% the year that Hatch-Waxman was passed. Today, however, generic drugs seem to be a victim of their success. Important categories of drugs — from antibiotics to chemotherapies to saline solution — experience persistent shortages and inadequate quality. Why? Prices have dropped so low that manufacturers don’t have the resources to produce adequate quantities of drugs or ensure compliance with quality standards. Such shortages are becoming a feature of the generic pharmaceutical industry. The dominance of a small number of group purchasing organizations (GPOs), the middlemen who buy drugs and supplies for hospitals, clinics, surgery centers, and home health agencies, is often cited as a cause of the problem. GPOs, so the story goes, use their near monopoly to drive prices too low. The obvious solution to that problem would be to restore normal market competition, perhaps by breaking up mammoth group purchasing organizations into smaller, competing entities or by eliminating price caps and quality regulations that inhibit rapid responses to shortages. In our respective roles as a health care economist who studies health systems (J.B.R.) and a management consultant who advises them (R.S.R.), we often see the pernicious effects of excessive pricing power in the health sector. The prices of hospital and insurance services are higher than they should be, and valuable innovations are derailed due to the market power of providers and payers. We are skeptical, however, that GPO pricing power explains the chronic shortages of generic drugs. Related: Drug shortages reached a record high as 2023 drew to a close Suppose a GPO has a great deal of pricing power, enough so that it can make generic manufacturers a take-it-or-leave-it offer. What price would such a GPO choose? The GPO doesn’t want drug shortages or sub-par quality, as those alienate their customers, the health systems and clinics whose patients need the drugs. GPOs would, therefore, offer a price just high enough to ensure adequate supply at adequate quality. A lower price reduces supply, and a higher price reduces margins. GPO pricing power alone should not lead to persistent shortages, even if it does enable the GPO to force generic manufacturers to sell at low prices. An alternative explanation for persistent shortages highlights the incentives for group purchasing organizations to ensure adequate supply. After all, a large GPO that wants to eliminate shortages could offer drugmakers a payment conditional on setting up adequate production capacity or inventory for vulnerable drugs. The complication is that the extra capacity or inventory resulting from these payments would also help other GPOs avoid shortages. Because the benefits of GPO payments spill over to competitors, the incentives for GPOs to ensure supply are inadequate, leading to chronic shortages. The same dynamic weakens GPO incentives to ensure adequate drug quality. Economists call this type of market failure a common-agency problem. According to economic theory, market competition alone will not solve common-agency problems. For example, breaking up GPOs into smaller entities worsens the spillover problem. Government action is needed to jump-start the market. Such action may include subsidies to ensure the supply of shortage-prone drugs, incentives for hospitals and clinics to create reserves in the event of supply chain disruptions, and enhanced quality monitoring. Nongovernmental players can also play a role. The Biden administration recently proposed a plan that relies on the creation of two non-governmental organizations to monitor supply chain resilience: one for manufacturers and one for hospitals. Sufficiently large private players can amplify the actions of the government. For example, a public commitment by one of the very large GPOs to pay prices adequate to ensure uninterrupted supply for a specified period could help draw manufacturers back into the generic market. The example of generic drugs illustrates that market-based innovation is necessary but not always sufficient to make health care better and cheaper. Sometimes, markets need some help to do their job.

II. The Legal and Industry Framework that Incentivizes Product Hopping In this section, I describe the incentives for product hopping created by patent law and state substitution laws. Patent law enables companies to make large investments in cutting-edge products without the fear that their work will be immediately copied by others who, having made no research and development (R&D) investment, could afford to sell the same product for much less. Patents are vital to our innovation economy, as they allow businesses to engage in developments that would be unsustainable otherwise. Many people assume that, without patents, certain products would be far less expensive. The truth is that, without patents, those products would never exist in the first place. In the pharmaceutical industry, the ability to charge higher prices during the patent period is critical because it allows a company to recoup the enormous costs of bringing a drug to market and provides a powerful profit incentive to develop next-generation medicines. During the limited period in which a novel therapeutic drug is both approved for sale and has patent protection, a manufacturer must recuperate the expenses of R&D, securing patent protection, and navigating the arduous FDA approval process—in addition to similar costs for the unsuccessful majority of drug candidates. The average brand drug takes over 10 years and $2.6 billion to achieve FDA approval. Moreover, only 10 to 15 percent of drugs that begin clinical trials are eventually approved by the FDA.2 For most brand manufacturers, this means that they will never recoup their R&D costs; in fact, 80 percent of marketed brand drugs never earn enough sales to cover these costs.3 However, after a developer has already blazed a trail to FDA approval for the brand drug, generic versions are entitled to a much simpler process. The 1984 Hatch-Waxman Act4 created the abbreviated new drug application (ANDA), a process of granting approval for generic drugs when they can show bioequivalence with the original.5 Generics can rely on the brand name’s previously submitted safety and efficacy data, skipping the most expensive step—the clinical trials.6 With ANDAs, generics can bring a drug to market for $1 to $2 million, a far cry from the $2.6 billion needed for a brand drug’s costs of research, development, and FDA approval.7 State substitution laws make it even harder for a brand to recover costs outside of the patent period because the laws result in brand companies losing 80 to 90 percent of their sales to generic versions. These laws allow and sometimes require pharmacists to substitute a generic drug when a patient brings a prescription for the brand name. As a result, state substitution laws enable generics to free ride off their brand-name counterparts, not only with respect to R&D and FDA approval, but for marketing as well. Brand-name manufacturers engage in extensive marketing efforts, often spending hundreds of millions of dollars to promote their drugs to physicians 8 and the general public.9 When generic drugs are automatically substituted for brand drugs under state substitution laws, the generic companies reap the benefits of years of the brand companies’ marketing efforts without bearing any costs. Generic companies typically spend very little on advertising. Instead, they can free ride on the reputation established by the marketing efforts of the brand companies and let automatic substitution laws generate their sales for them. Brand companies, understanding that automatic substitution laws grant generics a regulatory windfall, often have no incentive to develop new indications for existing drugs or to continue marketing their drugs after the patent period expires and generics enter the market. To do so would essentially be handing over 80 to 90 percent of their sales directly to generic competitors. And a perverse consequence of these laws is that the more effective the brands are at promoting their drugs to prescribers, the more money generics make when pharmacists substitute the generic for the brand. This legal framework incentivizes brand companies to focus their marketing efforts on newer versions of their drugs, which have more patent life remaining. To obtain a patent on the new version, the new drug must be different and innovative; for example, new versions may be extended release drugs that improve patient compliance and reduce the likelihood of adverse events, scored versions of tablets that allow for increased dosing flexibility, or variations in dosage strengths that allow the drug to be used to treat new indications. The brand companies hope to retain their customers by attracting them away from drugs that are about to go off patent. Thus, incentives under patent law—incentives to innovate in order to obtain the exclusionary patent period—motivate brand companies to create new drugs instead of handing over the majority of their sales to the generic companies. As the FTC has explained, these new drugs can, in turn, benefit consumers: “The threat posed to existing brand drugs by generic competition can incentivize the brand company facing a dramatic loss of sales to develop new and innovative drugs that benefit consumers.”10

Hickey and Ward, 01-30-2024, (Kevin J. Hickey, Legislative Attorney, and Erin H. Ward, Coordinator of Research Planning/ALD). "The Role of Patents and Regulatory Exclusivities in Drug Pricing," Congressional Research Service, . – MoState JG

Debate Critics of product hopping deride it as an anticompetitive practice that inhibits the entry of generic and biosimilar competitors, allowing a brand to maintain its dominant market position (and higher prices) without substantial benefits for consumers.449 In particular, critics contend that by shifting product demand from the previous product to a new product, the market for a generic form of the previous version dissipates by the time the generic can enter the market.450 All fifty states have enacted drug product selection (DPS) laws, which aim to lower consumer prices by allowing, and sometimes even requiring, pharmacists to fill a prescription written for a brand-name drug with a generic version of that drug.451 Typically, pharmacists may only substitute a generic drug for a branded drug if the generic version is “AB-rated” by FDA.452 To receive an AB rating, the generic must be therapeutically equivalent to the branded drug, which means it must have the same active ingredient, form, dosage, strength, and safety and efficacy profile.453 The generic must also be bioequivalent—in other words, the rate and extent of absorption of the generic cannot significantly differ from that of the brand drug.454 Thus, if the brand’s new version of a drug, for example, changes the form of the drug (e.g., capsule to tablet) or the dosage of the active ingredient (e.g., 10 mg to 12 mg) from the older version, the generic product may not receive the AB rating required to be substitutable by pharmacists.455 Even if the generic is eventually able to obtain an AB rating to allow substitution, that process may take years to achieve.456 Thus, the “hop” to a new product can prevent automatic substitution with a generic product, thereby giving the brand an additional period during which it is substantially unaffected by generic competition. Defenders of product hopping counter that manufacturers have legitimate reasons to create new patented products and encourage doctors to prescribe the new product instead of an old product for which there is generic competition.457 One commentator has argued that patent law encourages brands to create new drugs or switch to new versions of drugs because they receive an exclusive period during which they may charge higher prices.458 That period is critical, it is argued, to recoup the estimated $2.6 billion average cost of bringing a new drug to market— compared to the $1 or $2 million its costs to bring a new generic product to market.459 Once a branded drug’s patents expire, however, the brand may lose 80% to 90% of its sales to generic drug manufacturers.460 Thus, according to one commentator, brands have little incentive to keep marketing a product that is subject to generic competition; doing so would arguably transfer approximately 80% of the sales to their generic competitors. That is, even if the brand succeeds in convincing a doctor to prescribe the old product, DPS laws would allow a pharmacist to substitute a generic product instead.461 Given these economic realities, defenders argue that the brand would be effectively paying to market its competitors’ products.462 On this view, product hopping aims at maximizing profits for the brand (which can be used for additional R&D) and preventing freeriding by generics, not at preventing fair competition.463 Commentators also respond that generic manufacturers could reduce the impact of product hopping by marketing their own products.464 In that view, generic manufacturers choose to rely on DPS laws for sales.465 Instead, one commentator argues, the generic companies could advertise and promote their own products in the same way that brand manufacturers do. 466 In any event, patients and doctors can arguably choose to use the generic version of the old product if the brand’s new product is not worth the cost.467

Because later-filed patents often claim aspects of a drug other than its active ingredient, these patents are sometimes called “secondary” patents.386 Critics of evergreening maintain that, by obtaining secondary patents on minor improvements or ancillary aspects of a pharmaceutical product, manufacturers effectively extend patent protection beyond the 20-year term set by Congress. In doing so, according to these critics, secondary patents unfairly shield pharmaceutical products from generic or biosimilar competition, thereby resulting in higher drug prices.387 In the view of evergreening critics, moreover, many of these secondary patents are of questionable validity.388 While secondary patents tend to be challenged more frequently by generics and more successfully than patents covering a pharmaceutical’s active ingredient, 389 the combination of secondary patents and a strong primary patent creates a barrier to generic entry because a generic manufacturer may delay or decline entry when faced with the prospect of defeating both patents.390 In 2019, the cost of litigating a Hatch-Waxman lawsuit was estimated to be around $5 million in cases involving over $25 million in risk.391 Commentators have suggested that these costs can be compounded when there are several patents at issue, even if some of those patents are relatively weaker.392 Thus, critics of evergreening argue that the costs of invalidating even comparatively weak patents strengthen the branded product’s position in the market and can lengthen its effective period of exclusivity.393 Defenders contend that there is nothing inherently suspect about secondary patents, which must meet the same requirements for patentability and pass through the same examination procedures as any other patent.394 Those requirements bar secondary patents on any obvious variation of the primary patent or on another product or invention already available to the public.395 “[I]t is often the case,” defenders contend, “that the value of a follow-on patent is comparable to, or might even exceed, that of a primary patent.”396 One example arguably supporting this view is the drug Evista (raloxifine). Evista was “initially studied as a potential treatment for breast cancer” but, in 1997, FDA approved the drug for the prevention of osteoporosis.397 At that time, there were a few years left on Evista’s initial patent, which was filed in 1983.398 One commentator has argued that if the brand could not patent the new use of the drug (i.e., for prevention of osteoporosis), insufficient incentives would have existed to make the investment in R&D necessary to bring the drug to market for the new use. 399 Thus, critics of the notion of “evergreening” argue the term is imprecise and unfairly pejorative, creating an inaccurate impression that secondary pharmaceutical patents somewhat exploit the patent system.400 Defenders also argue that the ability to receive a patent on a later-developed drug formulation provides a significant incentive to improve on or address problems with the original formulation. For example, the original formulation of Lumigan, which is used to treat glaucoma, could cause sufficiently severe red eye that patients would discontinue its use.401 Researchers subsequently developed an improved formulation with significantly decreased risk of this side effect.402 Defenders of secondary patents contend that without the possibility of patent protection for improvements, there would have been little incentive to perform this sort of research due to the significant costs involved.403 Secondary patents are also defended as necessary to recoup development costs. One study found that even though the patent term can last as much as twenty years, delays in PTO and FDA approval decrease the nominal Orange Book patent term to 15.9 years on average, and generic competition can result in an effective market exclusivity of 12.2 years.404 This effective market exclusivity is less than the sixteen years that another commentator suggests is necessary to recoup the brand’s costs for research, development, and clinical testing.405 Moreover, as secondary patents tend to be improvements to primary patents, they are typically narrower than those primary patents.406 Thus, brands argue that when the primary patent expires, any other company—including a generic—may enter the market and produce the invention covered by that primary patent, assuming the generic can design around any unexpired secondary patents.407 Doctors and patients can then decide whether the benefit conferred by a product covered by a secondary patent is worth the increased cost over the generic version of the product formerly covered by the primary patent.408 Defenders also note that congressional action has decreased the cost of challenging patents, potentially reducing the effect of later-filed secondary patents. After Congress enacted the AIA in 2011, generic and biosimilar manufacturers can use PTAB processes such as IPR,409 which was intended to “provid[e] a more efficient system for challenging patents that should not have issued; and reduc[e] unwarranted litigation costs.”410 Generally, any person who is not a patent’s owner may file a petition for IPR beginning nine months after the patent issues.411 The PTO then decides whether to initiate review of the patent.412 If review is initiated, then the patent challenger must prove that the patent is invalid by a preponderance of the evidence413—a lower requirement than the clear-and-convincing-evidence standard used when challenging the patent in court.414 The statute requires that the PTO’s final decision be issued not more than one year after the decision to institute review.415 The median cost for litigating an IPR to that final decision is $324,000. 416 Thus, IPR provides a faster and less expensive method to challenge issued patents, as compared to litigating patent validity in the courts.

It’s disappointing to see yet more studies published by activist-funded industry critics that fail to recognize the nature of competition in the biopharmaceutical market and use cherry-picked data to draw misleading conclusions. In a May 2022 article, William Feldman et al. assert that regulatory and patent reforms are needed to “fix” the market for brand-name inhalers. The authors claim that manufacturers of inhalers have employed certain “lifecycle management” strategies to limit competition and maintain their market dominance. Another article, published in September 2022, ignores the fact that manufacturers invested hundreds of millions of dollars to develop and manufacture hydrofluoralkane (HFA)-based metered-dose inhalers in order to comply with an FDA rule issued as a requirement of the Clean Air Act. Rather the authors inaccurately assert that manufacturers made the changes just to thwart competition. These articles perpetuate the same old myths that patent protections for new innovations somehow block all competition or are simply used to force patients onto new products. This is untrue. In fact, brand medicines face competition not just from generic and biosimilar versions, but also from other forms of the same medicines as well as other branded competitor medicines. The reality is that not only were the new HFA-based metered dose inhalers an important option for patients, but they also allowed payers to leverage competition to drive down prices. The real problem is that despite health plans and pharmacy benefit managers benefitting from these lower prices, they don’t share the savings directly with patients. We can build a better health care system for patients without gutting critical incentives for innovation. Here’s what you need to know. 1. In the first article, the authors use an extremely narrow definition of competition in their analysis. Looking only at substitutable generics is a limited and incomplete approach to measuring the impact of competition on health care spending and patient benefit and costs. While patents and exclusivities might prevent a competitor from bringing an exact duplicate of a medicine to market during the term of the protection, they do not create a monopoly on treating a disease. In the case of inhalers, the study itself shows that from 1986-2020, the FDA approved 62 inhalers, including 9 generics. That’s an average of almost 2 new products per year — clearly demonstrating that patents are not blocking competition in the inhaler space. 2. The ten therapeutic classes and twenty different active ingredients in the cohort of products included in the Feldman et al. study represent meaningful differences in ease of use, patient device preference and disease control. Medicines compete through effectiveness and price for coverage by insurance plans, and these differences also matter to physicians and patients who consider these factors when choosing a treatment. Patient-perceived satisfaction with their maintenance inhaler device is an important factor driving patient compliance in chronic obstructive pulmonary disease (COPD), and is closely linked to improved health status. The result of this competition is that the net prices of brand medicines to treat asthma/COPD are in fact declining. Research specific to asthma/COPD shows that the average annual net cost of treatment for combination products, bronchodilators and glucocorticoids declined 32% to 62% between 2008 and 2021. 3. In addition, the research, development, and regulatory review of these medicines and delivery devices for asthma and COPD patients require substantial regulatory applications to FDA, based on costly and labor-intensive clinical trials. FDA approval standards for new combinations of medicines and drug device combinations must meet the same rigorous FDA standards as the initial approval, with no certainty of FDA approval. As of 2019 there were 54 medicines in development for asthma and 39 for COPD, many of them potentially first-in-class. Reflecting the significant unmet need experienced by patients with these conditions, asthma and COPD are estimated to cost the U.S. economy more than $130 billion annually due to hospitalizations, emergency care, and other medical expenses, lost productivity, and premature deaths. Proposals that would discourage ongoing and post-approval research and development could stall the development of new treatment options for the more than 40 million patients living with asthma and COPD in the U.S. 4. The authors themselves acknowledge that a key barrier to the availability of substitutable generics for inhalers is largely due to the significant regulatory and scientific complexity, not patents and exclusivities. To address this the FDA has issued guidance specifically intended to help developers of generic inhalers and has taken additional steps to help sponsors develop complex generics, including generic inhalers, for example through its Drug Competition Action Plan. The authors also acknowledge that one generic manufacturer was successfully able to bring a product to market even with active patent listings in the Orange Book, clearly demonstrating that patents are not a de facto barrier to direct competition. Another came to market several years after the last patent expired due to regulatory challenges. 5. Despite what the authors and other industry critics claim, there is nothing unusual or problematic about a medicine or device being covered by multiple patents resulting from inventions throughout the product development process, including after the initial FDA approval. Patents are available for many types of inventions, in biopharma and other technologies. Regardless of the technology, they must meet the statutory requirements for the invention being new, useful, and non-obvious. Patents aren’t just simply granted for each patent application but are thoroughly vetted and reviewed by the U.S. Patent and Trademark Office (PTO). That means a company cannot simply add patents to existing products or obtain patents for trivial changes. Drug-device combinations to treat COPD are no exception. The authors’ suggestions of policies such as allowing only one patent to be honored by the FDA (“one-and-done”) reveal a fundamental misunderstanding of the complexity of drug development and the patent system. 6. The second article uses many of the same faulty arguments to suggest how the federal government should undermine critical incentives for innovation. The authors suggest that FDA should “refrain from banning HFA-based metered-dose inhalers” as though the agency has discretion to ignore the Clean Air Act’s requirements, while completely ignoring the fact that other types of inhalers existed on the market during these decisions that provided other options for patients. The authors also make contradictory statements, acknowledging that “payers have leverage, since they can always use formulary design to steer patients away from new metered-dose inhalers toward older dry-powder equivalents… which do not emit greenhouse gases”. 7. Our IP system — including patents and statutory exclusivities — is the foundation for incentivizing the development of new treatments and cures for patients, and should be celebrated, not undermined. Policymakers should consider policies that both protect future innovation and benefit patients rather than taking activist-funded academics at their word. They can start by addressing the real problems highlighted by the authors. This includes ending the perverse incentives that allow pharmaceutical supply chain middlemen to tie their fees to list prices, sharing savings negotiated by pharmacy benefit managers and health insurers directly with patients at the pharmacy counter, and making patient out-of-pocket costs more predictable.

Role of IP in the Pharmaceutical Industry - Introduction Emphasizing the pivotal role of intellectual property (IP) in fueling economic innovation cannot be overstated. In general, IP aims to champion and strengthen the right to protect original invention that comes from human intelligence by bestowing upon it the status of property. These rights provide latitude for innovators, venture capitalists, and individuals harboring original ideas to bring forth their inventions and partake in the marketplace, thereby fostering economic expansion and industrial growth by means of healthy competition. This article will closely examine the complex relationship between IP and its significant role in the business operations of the pharmaceutical sector. We'll examine the unique difficulties it faces and the critical role IP plays in defending that sector. IP and the Pharmaceutical Industry Rationale The pharmaceutical industry is different from many other economic sectors in that it stresses more importance on scientific knowledge advancement than on production techniques. Thus, the capabilities of a company's research and development department (R&D) is the major factor that determines its success. Because of this, pharmaceutical businesses typically rely primarily on investment in addition to consumer sales as their primary source of income. Against this backdrop, pharmaceutical companies employ familiar IP safeguards, such as trademarks, patents, and trade secrets, to shield their products from replication, prohibit unauthorized usage, and secure a level playing field in the competitive landscape. Nevertheless, the emphasis diverges in that the primary goal of securing their IP assets is to instill confidence among investors and consumers alike, recognizing that success hinges largely on fostering a trusting public relationship. Challenges of a Pharmaceutical Company in Relations with IPR Bluntly put, delving into the research, synthesis, and introduction of a new drug into the marketplace stands out as one of the most expensive and risky corporate endeavors for the pharmaceutical industry. The costs can soar into the hundreds of millions or even thousands of millions of dollars. According to The Association of the British Pharmaceutical Industry, only one to two compounds out of a thousand successfully pass through all stages of R&D clinical trials to become a marketable medicine. The exorbitant cost and risk associated with the failure to develop a commercial medicine are undeniable, particularly in scenarios where the drug in development fails to meet rigorous safety standards or is abandoned after years of substantial investment in the project. In light of this context, one can envision a catastrophic scenario in which a chemical compound is reverse engineered by competitors, or worse, the trade secret is leaked or publicly disclosed without proper patent protection. It underscores the critical necessity for pharmaceutical companies to embrace a meticulous approach in safeguarding their intellectual assets. Consequently, adopting a robust Intellectual Property rights framework provides the means to protect the substantial investments, time, money, and effort invested by both the innovators and investors in a project. How IP Plays Its Role Safeguarding Medical Innovation Upon successfully developing a medicine ready for commercial use, the paramount concern lies in ensuring that the product remains immune to emulation through reverse engineering or leaks. The conventional solution to mitigate these risks often involves pursuing a patent application or treating the information as closely guarded trade secret. Propels Competition and Economic Growth and more As reiterated earlier, safeguarding the products of human intellect plays a pivotal role in granting grounds for fair competition and serves as a catalyst for the development of innovations that spur economic growth. The pharmaceutical industry aligns with these fundamental principles of Intellectual Property, and given its involvement in health-related matters, it carries substantial societal and individual implications. Promotes Consumer and Investor Trust The major determinant of a pharmaceutical company's success lies in fostering public and investor trust. Without the safeguard of Intellectual Property rights, a pharmaceutical company becomes susceptible to damage to its reputation through imitators selling identical products, posing significant health risks and damaging public relations. Given the extensive time and financial resources required for drug development, a pharmaceutical company heavily relies on its reputation to instill confidence in investors regarding the potential returns on their investments. IP protection plays a crucial role in solidifying a healthy relationship between the company and the public as well as with corporate stakeholders. Allows in Tackling Solutions for Worldwide Challenges Engaging in the development of globally beneficial products such as vaccines and medicines is a highly corporatized, time-consuming, and expensive endeavor. Pharmaceutical companies heavily depend on investments to excel in their pursuit of scientific knowledge, enabling them to produce innovative solutions for addressing emerging or challenging-to-cure diseases. Intellectual property rights play a crucial role in fostering the motivation to navigate the complex process of transforming medical innovation into life-assisting medications. Impose Bans on Infringers Intellectual Property Rights empower pharmaceutical companies to take decisive actions against entities involved in the development of counterfeit products. Without the presence of such rights and corresponding legal frameworks, addressing issues with implications for both public relations and public health would become exceedingly challenging. Conclusion The complex relationship between IP and the pharmaceutical business highlights the critical role of IP in protecting innovation and creating an environment conducive to economic growth. As pharmaceutical businesses face the daunting hurdles of discovering and bringing new treatments to market, the protection of intellectual property becomes increasingly important. Beyond fighting counterfeiting and preserving market exclusivity, intellectual property plays an important role in fostering consumer and investor trust. The tangible impact of intellectual property extends beyond company success, affecting global health solutions and serving as an effective instrument for problem-solving.

Robust IP Protection Regime The drug development and approval process is expensive, lengthy, and risky.197 According to a recent study, it costs $2.6 billion to develop a new drug.198 Drug development also takes 10–15 years, and few drugs ever reach the market. A pharmaceutical company developing a new drug incurs the full costs of R&D, but it often does not capture the full benefits because as soon as the new drug is released, other firms can quickly replicate it. The existence of such knowledge spillovers means that incentives need to be created for a pharmaceutical company to invest in the necessary R&D to create a drug in the first place. To encourage socially desirable levels of R&D, a commonly used policy tool is patent protection.199 Patents, a form of IP protection, grant exclusive rights to commercialization of an invention for a specific period, typically 20 years. In the pharmaceutical industry, where drug development is lengthy and costly, patents are especially important to stimulate R&D investments. Patents enable pharmaceutical companies to recover their R&D investments and generate profits to sustain future R&D efforts.200 Using data from the Carnegie Mellon Survey on Industrial R&D, a 2008 study provides evidence that patent protection leads to higher private returns on R&D, which in turn stimulates future R&D investments in the pharmaceutical industry.201 Another study of 60 countries from 2000 to 2013 finds that patents are associated with earlier release of new drugs.202 And a third study using data on the launches of 642 drugs in 76 countries from 1983 to 2002 finds that a higher length and strength of patent protection significantly accelerates drug diffusion, spurring market entry in high-income countries.203 It also appears that IP protection on research tools in biomedical innovation seldom hinders the pursuit of scientifically promising projects, meaning that patents do not impede future innovation.204

A paper in the American Economic Review studying cancer clinical trial investments reveals that lags in commercialization tend to cause pharmaceutical R&D investments to be redirected away from drugs targeting early-stage cancers. There are more incentives to focus on the development of late-stage, rather than early-stage, cancer drugs due to shorter clinical trials for late-stage drugs and the fixed-term nature of the patent system, which provides a longer effective patent protection for drugs with a shorter time between invention and commercialization. While patents provide a fixed period of market exclusivity, “since in many industries firms file patents at the time of discovery (‘invention’) rather than first sale (‘commercialization’), effective patent terms vary: inventions that commercialize at the time of invention receive a full patent term, whereas inventions that have a long time lag between invention and commercialization receive substantially reduced—or in extreme cases, zero—effective patent terms.”205 Since it takes a longer time for early-stage cancer drugs to reach the market, their effective patent terms are shorter than those of late-stage drugs, so this combination of clinical trial length and patent system design may under-incentivize longer projects. To stimulate more long-term cancer research, the authors endorse: 1) policies to allow pharmaceutical companies to rely on surrogate endpoints in clinical trials, 2) a restructuring of the patent system to start the clock at commercialization (i.e., time of FDA approval rather than time of invention), and 3) R&D subsidies for projects with long commercialization lags.206

One 800-square-foot laboratory at Rutgers University in central New Jersey is equipped to make more than 1 billion prescription pills a year. Its manufacturing process is faster, cheaper and more precise than traditional methods, potentially reducing reliance on factories abroad. The technology also can be used to make drugs currently in shortage, including cancer treatments. Why, then, isn’t this major manufacturing innovation more widespread? Most drugs are made using batch manufacturing, a laborious, multistep process that stretches across continents. Storage and shipping between stages can compromise quality. Reliance on overseas manufacturers, meanwhile, is risky: About 80% of key drug ingredients are made outside the US, predominantly in China and India, where US regulators have uncovered serious breaches of manufacturing standards. Should China cut off pharmaceutical exports, as some policymakers have warned, the domestic stockpile of lifesaving medication would run out in a matter of weeks. Advanced manufacturing processes can help. One method, known as continuous manufacturing, can develop a new drug product in weeks — something that would take months by batch processes — all in a single facility. The basic technology has been used for decades in other industries. Applied to pharma, it could have pronounced benefits. Quality is monitored constantly using near-infrared sensors, compared with traditional sampling of pills. Automation limits waste, saves energy and improves accuracy, thereby lowering operating costs by up to 40% and capital expenses by 75%. The scale of potential change has been compared to the auto industry’s transition to the assembly line. Some of the world’s largest drugmakers are among the earliest adopters, including Pfizer Inc., Eli Lilly & Co. and GSK Plc. Johnson & Johnson invested millions of dollars in the continuous manufacturing lab at Rutgers. Other companies exploring advanced techniques include the Mark Cuban Cost Plus Drug Company, whose Texas facility can pivot from one drug type to another in a matter of hours, according to recent testimony to Congress by its chief executive officer. Despite these early efforts, barriers to broader adoption of continuous manufacturing remain. Upfront costs for new equipment are high, prohibitively so for the low-margin generics currently in shortage. Meanwhile, companies that have invested in batch manufacturing for existing drugs are reluctant to switch. Any change in process must be approved not only by the Food and Drug Administration, but potentially dozens of regulators around the globe, which introduces delays and uncertainty. Could the government do more to speed this transition? For starters, the FDA could take more action to earn the industry’s trust. The agency supports continuous manufacturing and generally approves such processes more quickly than the traditional kind. Yet drugmakers still cite the prospect of costly delays as a chief deterrent. The FDA should accelerate the application process by eliminating duplicative reviews for minor changes and establishing site-based, rather than product-by-product, approvals for advanced facilities. It should also reduce inefficiencies during the review process and better align with global regulators on approvals. Such measures would go a long way toward gaining the buy-in of senior management, which tends to prioritise research and development over manufacturing investment. As for Congress, it should revive a bill to establish so-called centers of excellence, like the one at Rutgers, nationwide. In addition to training workers and conducting basic research, such institutions would give manufacturers of generics and smaller branded drugs access to expertise and production capabilities unavailable in-house. Allowing companies to deduct R&D costs immediately — a once-standard practice that Congress has now inadvertently outlawed — would also boost innovation and investment in the field. Continuous manufacturing won’t make sense for every pharma company or drug product. It could revolutionise the industry all the same. Policymakers should ensure they aren’t standing in the way of progress.

The pharmaceutical industry is facing an onslaught of drug shortages. Simply understanding the causes and consequences is not the goal. There is an urgent need to examine strategies, technologies, and regulations to help mitigate—and potentially eliminate—this issue. Manufacturers need to consider cutting-edge technologies and explore proactive measures to counteract drug shortages. The pharmaceutical industry should strive for innovation that revolutionizes drug manufacturing and ensures a stable supply of essential medications for patients worldwide. Emerging Technologies in Life Sciences Manufacturing Scalability in medication production involves optimizing manufacturing processes while maintaining quality, consistency, and regulatory compliance. Process optimization, continuous manufacturing, supply chain management, robotic process automation (RPA), modular manufacturing, and lean manufacturing principles are common solutions; however, emerging technologies are well-suited to address scalability. For example: Digital twins: This proactive approach helps to reduce production disruptions that often contribute to drug shortages. A digital twin—a virtual representation of a real-world entity or process—provides real-time insights into manufacturing processes by continuously collecting and analyzing data from sensors and other sources. Manufacturers are able to understand process behavior, identify anomalies, and optimize operations, with deviations from optimal conditions able to be quickly detected and rectified. A standout advantage of digital twin technology is predictive maintenance to ensure minimal downtime and continuous production. By closely monitoring the real-world equipment and assessing the digital twin’s performance, manufacturers can predict when maintenance is required and prevent breakdowns. Using digital twins, manufacturers can test various operational parameters, process changes and configurations, scale strategies, and detect potential disruptions in a controlled virtual environment. This simulation-driven approach helps identify vulnerabilities in the manufacturing process and devise strategies to mitigate risks. AI in supply chain management. AI is able to analyze historical sales patterns, real-time data, market trends, and external events to forecast demands more precisely and adapt to dynamic changes in the market. Other AI analytical capabilities in supply chain management include continuous monitoring of supplier data, transportation, and distribution channels. AI helps to identify potential disruptions or delays and enables manufacturers to take proactive measures to find alternative sources or routes and minimize the impact on the medication supply. VR/AR in manufacturing: While not a direct solution, virtual and augmented reality (VR/AR) addresses drug shortages by contributing to improved efficiency, enhanced training, and streamlined processes. It provides immersive and interactive training environments that enable workers to practice complex procedures and operate equipment in a safe setting. VR/AR provides step-by-step guidance for real-world scenarios to guide operators when precision and attention to detail are of great consequence. Regulators as Inhibitors and Enablers Regulations help to ensure product quality and patient safety while maintaining ethical standards. However, stringent regulations and rigid enforcement by regulators may hinder innovation in the life sciences industry. The complexity of regulatory requirements and the lengthy approval process can deter companies—particularly smaller ones with limited resources—from pursuing novel drug development or manufacturing approaches. Furthermore, the fear of regulatory scrutiny and potential delays could steer companies toward safer, more established paths that limit the exploration of groundbreaking technologies and methodologies to address issues such as drug shortages. On the other hand, regulatory agencies play a significant role in encouraging innovation when they embrace adaptive regulatory pathways and accommodate emerging technologies. For instance, AI and advanced manufacturing techniques have the potential to streamline production processes, reduce the likelihood of shortages, and improve overall quality. Regulatory agencies can seek input from technology experts to develop guidelines for compliance and innovation. Additionally, incentives such as priority review for innovative products may encourage manufacturers to invest in novel approaches that have the potential to alleviate shortages. Dialogue on AI and Advanced Manufacturing In March 2023, the FDA solicited feedback on artificial intelligence in drug manufacturing. The FDA’s willingness to engage in this dialogue demonstrates that regulations need to accommodate advancements and transformative change while ensuring patient safety and product quality. There are many challenges to consider. For example, it’s important to explain AI algorithms used in critical manufacturing processes and AI-driven decisions, especially when patient care is at stake. Additionally, determining accountability for cases in which AI-driven decisions result in adverse outcomes can be complex. Clear guidelines for liability and responsibility are necessary to ensure patient safety and consumer confidence. AI algorithms can inherit biases contained in the training data, introduce ethical concerns, and result in biased decisions. For example, when determining inclusion or exclusion criteria for clinical trials, AI-based selection could perpetuate unequal representation in clinical trials if the biases reflect existing health disparities. This could lead to inadequate representation of certain demographic groups, potentially resulting in drugs and treatments that are less effective or safe for underrepresented populations. The FDA's role in AI regulation is pivotal for successfully integrating AI technologies in the life sciences industry. Balancing innovation and safety, addressing ethical concerns, and collaborating with experts are essential. As AI continues to reshape health care, the FDA's guidance and oversight will help determine the benefits of AI-driven advancements while upholding ethical standards and patient safety. Conclusion Amid persistent drug shortages, the life sciences industry is poised for innovation, collaboration, and adaptive regulations. A path toward fortified drug manufacturing and supply stability may emerge with the synergy of drug manufacturers, emerging technologies, and regulatory bodies.

As we all know, a shared pursuit among nations globally is to make healthcare accessible to all. An effective and affordable healthcare opportunity is the fundamental right of every individual, and no one should have to fight for that. In such a pocket-challenging landscape, one key player is making significant strides in enhancing accessibility for patients around the globe – generic medications. The healthcare model in the country is a network of intricate systems. As we delve deeper into these systems, it becomes evident that generics play a pivotal role in making essential treatments more affordable and accessible to all. Let us explore the multifaceted impact of generics on healthcare accessibility, shedding light on how these cost-effective alternatives are transforming the healthcare landscape. Generics promote affordability: One of the most sought-after features of generic medicines is their affordable pricing. Generics are identical substitutes of brand-name drugs, similar in quality, safety, and efficacy at just a fraction of the cost. The reduced cost is a result of the elimination of the research and development process, which allows generic manufacturers to produce medications at significantly lower prices. This affordability factor is a game-changer, particularly for individuals in low-income or underprivileged communities who might otherwise struggle to afford essential medications. Generics promote competition and innovation: Generic medications making their way into the market create an environment of vigorous competition. As various manufacturers roll out generic versions of the same drug, the supply increases and prices naturally decrease. The repercussions of this not only benefit the consumer but also extend beyond that. Such a scenario fuels innovation in the market and challenges pharmaceutical companies to embark on the development of novel and improved medications, fully aware that generic alternatives will soon join the market. This ongoing interplay of competition fosters a healthcare industry that is dynamic and quick to respond. Generics promote wider access to essential medications: When it comes to the healthcare system, the cost barrier is a major obstacle preventing individuals from accessing crucial medications. Generic medicines break down this barrier, ensuring that life-saving drugs are within reach for a broader demographic. This is particularly important in treating chronic conditions such as diabetes, hypertension, and various infectious diseases. The widespread availability of generic options empowers patients to manage their health more effectively. Generics show promise in the fight for more accessible healthcare. Their significant contribution to the transformation of healthcare is highlighted by their capacity to reduce costs, increase access to necessary pharmaceuticals, promote competition, and support global health initiatives. It is critical to promote and support generics' position as a cornerstone in creating a more accessible and inclusive healthcare system for all, even as we continue to navigate the intricacies of the healthcare landscape.

In the realm of healthcare, affordability remains a paramount concern worldwide. As medical expenses continue to soar, the spotlight falls on cost-effective alternatives like generic drugs and biosimilars, heralding a promising shift in reducing healthcare expenditure without compromising quality. Generic drugs are bioequivalent versions of brand-name medications, offering the same active ingredients, dosage, and intended use. Biosimilars, on the other hand, replicate complex biological drugs, providing a more affordable alternative to expensive biological therapies. Both generics and biosimilars are typically priced significantly lower than their brand-name counterparts, often resulting in substantial cost savings for patients and healthcare systems. The importance of generic drugs and biosimilars in healthcare cost reduction cannot be overstated. These alternatives typically cost 80-85 percent less than their brand-name counterparts, fostering competition and driving down prices. Such affordability extends accessibility to a broader demographic, ensuring that crucial medications are within reach for those who might otherwise struggle to afford them. The integration of generic drugs and biosimilars into healthcare systems has yielded significant cost savings. Studies have shown that increased usage of generics and biosimilars can lead to billions in savings for healthcare systems and patients globally. These cost reductions enable broader access to essential medications, allowing more patients to receive necessary treatments without financial strain. The cost-saving potential of these alternatives has been evident across various medical fields. For instance, in the United States, the introduction of generics has resulted in savings of over a trillion dollars in the last decade alone, significantly lowering overall healthcare costs. Similarly, biosimilars have demonstrated their cost-cutting prowess, offering reductions of up to 30 per cent compared to their reference biologics, thereby expanding treatment options for complex conditions like cancer, autoimmune disorders, and more. Moreover, the impact of generics and biosimilars extends beyond immediate cost reductions. Their introduction fosters innovation and research, as increased competition prompts manufacturers to invest in newer and more advanced therapies. This, in turn, leads to a more robust pipeline of affordable medications, catering to a broader spectrum of medical needs. Establishing robust monitoring and evaluation systems to assess the realworld effectiveness, safety, and cost-saving impacts of generic drugs and biosimilars is imperative. Continuous monitoring ensures that these alternatives consistently meet quality standards and deliver expected cost reductions over time. Offering flexibility in regulatory pathways and creating expedited approval processes specifically tailored for generic drugs and biosimilars can accelerate their market entry. Regulatory agencies can consider adopting fast-track approvals or priority review mechanisms, provided stringent safety and efficacy standards are met, to expedite the availability of these cost-effective alternatives. During public health emergencies or crises, the availability of affordable generics and biosimilars becomes crucial. These alternatives can mitigate shortages of critical medications, ensuring continuity in treatment and response to healthcare challenges. Launching comprehensive public awareness campaigns can dispel misconceptions and increase public confidence in generic drugs and biosimilars. Informative campaigns through various mediums can educate patients about the safety, effectiveness, and economic benefits of these alternatives, encouraging their preference when discussing treatment options with healthcare providers. By focusing on these additional strategies, healthcare systems can further optimise the integration of generic drugs and biosimilars, harnessing their potential to reduce healthcare costs while ensuring quality care and accessibility for patients. In conclusion, the integration of generic drugs and biosimilars into healthcare systems is an indispensable strategy for curbing escalating healthcare costs. Embracing these alternatives not only fosters financial savings but also amplifies access to life-saving treatments, promoting a healthier and more sustainable healthcare landscape for all. As the healthcare industry evolves, embracing innovation and costeffective alternatives will be crucial in ensuring a more accessible and equitable future for patients globally. Recognising and harnessing the importance of generic drugs and biosimilars is pivotal for building resilient, inclusive, and effective healthcare systems that cater to the needs of diverse populations across the globe.

Hongyan Liao et al, 05-10-2024 (Liao, H., Lyon, C. J., Ying, B., & Hu, T.), (2024). Climate change, its impact on emerging infectious diseases and new technologies to combat the challenge. Emerging Microbes & Infections, 13(1). -- MoState JG

Climate change can also extend or alter the geographic range of a pathogen reservoir via positive or negative effects on food supply, predator populations, and other factors that affect its current range and adjacent locales. For example, ecosystem damage may force a host population or its predators to range further to meet their basic environmental needs or to avoid increased competition or predation resulting from ecosystem changes. This may increase the number of infected hosts, their individual pathogen burden, and the chance for contact with a susceptible human or human-adjacent host population. Ecosystem damage can also have similar effects on human populations and domestic animals that may serve as gateway populations. In both cases, however, increased contact between a stressed host or susceptible host-candidate population may augment the risk for close contacts that lead to spillover events. For example, higher temperatures and meteorologic shifts associated with climate change can reduce surface water availability by decreasing the amount of rainfall or increasing the extent of evaporation, causing wildlife to frequent water source that they might otherwise avoid due to their frequent use by human or domestic animal populations, leading to direct or indirect contact between these groups [Citation18]. However, such resource competition may not be necessary to promote spillover events. Research indicates that climate change has caused the Australian black flying fox population, a key reservoir of Hendra virus, to migrate 100 km south over the past 100 years, likely leading to observed spillover events in southern horse populations that led to human infections [Citation19]. Climate change has also been linked to changes in the El Niño southern oscillation that have been linked to the geographic distribution of endemic cholera, in a manner that is not directly linked to increased rainfall and flooding [Citation20]. EID species diversity increases as one proceeds from the poles to the equator [Citation21], and environmental parameters that promote pathogen transmission at lower latitudes (e.g. increased temperature and precipitation) are hypothesized to drive this pattern [Citation21]. A recent study modelling potential connections between climate variables and pathogen prevalence has also suggested that elevated temperatures and greater precipitation will accelerate the transmission of bird- and bat-associated bacteria or viruses to wild and domesticated animals and humans [Citation22]. One example of the potential impact of this process was the recent COVID-19 pandemic, where a SARS-CoV-2 progenitor virus that probably originated in southeast Asian horseshoe bats (Rhinolophus sp.) is proposed to have spread to humans through an as-yet-unknown bridge host [Citation23]. Changing climate conditions can affect EID transmission chains and routes by altering the geographic range and population sizes of potential pathogen and host species, leading to novel interactions between these species that can lead to establishment of a new pathogen reservoir and increase the risk for subsequent zoonotic disease transmission to a human population [Citation8]. VBDs spread by blood-feeding arthropods such as mosquitoes, ticks, and fleas, are responsible for substantial morbidity and mortality as they transmit diseases (malaria, dengue, West Nile, and Lyme disease) that account for 22.8% of EID events worldwide [Citation1]. These insect vectors are sensitive to environmental changes (rainfall, temperature and severe weather events) associated with climate change [Citation24]. For example, temperature changes can affect the transmission period or the growth rate an insect vector (or its pathogen), by an analysis of mosquito-based transmission of dengue fever or Plasmodium falciparum malaria [Citation25]. Drinking water safety is a key factor affecting EID transmission. Climate change can increase rainfall and flooding to contaminate water supplies of a human or human-adjacent host populations leading to an increased risk for outbreaks of WBDs caused by enteric bacteria and parasites such as Salmonella and Cryptosporidium [Citation26]. In climate-vulnerable areas, for example, Bangladesh, drinking water safety could be threatened by climatic hazards, which leads to the prevalence of multiple WBDs and VBDs, such as cholera, dengue, and malaria [Citation27]. Climate effects can also worsen air pollution, and both these factors can cause and synergically exacerbate detrimental effects on the host immune system. This can enhance respiratory disease transmission by affecting the lifetime of air-borne respiratory droplets and the pathogens they carry and via detrimental effects on the respiratory mucosa and immune system of at-risk populations. Chronic exposure to air pollution can induce inflammation and oxidative stress and impair immune function to increase infectious respiratory disease burden, particularly in vulnerable populations such as young children and older adults and individuals with pre-existing respiratory disorders. Excessive exposure to small particulate matter (PM2.5) pollution, for example, can magnify the adverse effect of climate change on respiratory health by altering the immune response and exacerbating the development of existing respiratory disease [Citation28]. Chronic exposure to temperature and humidity changes can also influence innate and adaptive immunity by altering the regulation of specific immune responses. For example, extended exposure to elevated temperature can decrease the production of antigen-specific CD8+ T cells and antibodies [Citation29]. However, excess disease risk associated with air pollutants and meteorological factors can be complex, as evident from a study that found that excess risk for TB was positively associated with NO2 level and windspeed; negatively correlated with O3 level, temperature, and relative humidity; and was not detectably associated with PM2.5 or SO2 concentration or sunshine duration [Citation30].

Hongyan Liao et al, 05-10-2024 (Liao, H., Lyon, C. J., Ying, B., & Hu, T.), (2024). Climate change, its impact on emerging infectious diseases and new technologies to combat the challenge. Emerging Microbes & Infections, 13(1). -- MoState JG

Climate change-a threat to public health Climate change is unequivocally acknowledged as an urgent global public health menace by the World Health Organization (WHO), as profound and enduring shifts in temperature, precipitation, humidity, and air and water quality are already exacting a devastating toll on human health, amplifying morbidity and mortality rates worldwide [Citation6]. Climate change can enhance transmission of food-, water- and vector-borne diseases (FBDs, WBDs and VBDs) by increasing the area in which or length of time when conditions remain favourable for outbreaks and transmission of emerging or reemerging infectious disease through effects on pathogen or host health, replication, and dissemination or migration [Citation7]. One recent modelling study of 3000 mammalian species found that their predicted migration patterns could lead to more than 4000 instances of cross-species viral transmission in the next 50 years if the world warms by 2°C, and thus climate change could easily become the dominant anthropogenic force in viral cross-species transmission [Citation8]. In fact, climate change-induced mortality and morbidity associated with infectious diseases are expected to rise globally [Citation9]. The impact of climate change on fungal infections has been reviewed elsewhere [Citation10], which also emphasizes the association of climatic factors and fungi-associated outbreaks. Here, we review the mechanisms of climate change altering the landscape of EIDs. At a global glance, we propose measures that have or could be taken to prevent or limit initial and subsequent transmission events. We also discuss emerging technologies that can be applied to generate more effective surveillance systems for early control of EID outbreaks. Effects of climate change on EID transmission A diverse array of factors can influence EID spillover and outbreak, including new mutations and viral recombination and reassortment events that alter the species-specificity of a pathogen, changes that affect the geographic ranges of environmental pathogens or animal vectors, and human migration and habit destruction events that can lead to new geographic overlaps between a human population and a pathogen or its vector(s) [Citation11]. Repeated direct or indirect contact between a human population and a pathogen or a pathogen reservoir are usually required to permit sufficient cross-species transmission and mutation and selection events to allow a pathogen to evolve a capacity for efficient human-to-human transmission [Citation12]. Spillover events leading to population-based transmission in humans can occur through periodic or continuous exposure to reservoirs of pathogens or via cyclic vector-host-vector transmission routes. Environmental encroachment events, due to climate change or other anthropogenic causes, and the inherent mutation rates of pathogens present in the affected regions create fertile opportunities for infectious agents to adapt to new ecological niches, interact with and adapt to new hosts through repeat exposure to promote zoonotic infection, host shift, and population-based transmission (Figure 2) [Citation11].

The correlation between climate change and the spread of pathogens According to the director of Harvard University Center for Climate, Health and the Global Environment, Dr. Aaron Bernstein, although there is no evidence that climate change had affected the coronavirus pandemic, climate change could increase infectious disease risks since it alters our relationship with other species. Global warming would force terrestrial and aquatic species to migrate towards the poles due to extreme heat. These migrations would lead to contact between the species that normally do not contact with each other. This would lead to the transmission of the pathogens to new species. Loss of habitat due to climate change would also lead to animal migrations and contact with new species (15). Climate change would also affect environmental biosecurity. Thus, monitoring infectious diseases, animal-human health, ecology, and environmental issues should be addressed with a holistic approach (18). Infectious diseases affect the ecology of hosts, vectors, and pathogens. Vibrio cholerae and Yersinia pestis are well studied examples of predictive waterborne and zoonotic disease modeling (19, 20). The endemic locations of infectious diseases that could be transmitted to humans by non-human vectors could change due to climate change. These changes due to global warming would increase and decrease the disease prevalence regions, potentially affecting the survival of the vectors (17).A recent study suggested that climate change would increase the likelihood of epidemics induced by animal-to-human transmissions in the future (21). It was reported that at least 10,000 viral species could infect humans, the vast majority of which currently infect only wild mammals (22, 23). However, changes in climate and land use would lead to the transmission of viruses to certain geographically isolated wildlife species (24, 25). Studies predicted that even global warming would remain below two degrees Celsius by 2070, infections by species with a high transmission potential to humans would significantly increase. Most intra-species transmissions would be a "dead end" for the viruses. However, those that would mutate and manage to find new hosts could be quite dangerous (26).Animal species would often migrate to residential or agricultural areas as they escape sweltering temperatures and other effects of climate change. Thus, the unprecedented interactions between these species would lead to transmission of pathogens, eventually infecting humans (27). The epidemics such as Ebola, HIV, bird flu, SARS, and most likely Covid-19 were induced by wildlife viruses. It was reported that rapid global warming, deadlier and more contagious pandemics could be on the horizon (27).

Mateo Aboy et al, 4-17-2023 (Aboy, M. Centre for Law, Medicine, and Life Sciences (LML), Faculty of Law, University of Cambridge, Cambridge, UK, Price, W.N. University of Michigan Law School, Ann Arbor, MI, USA & Raker, S. University of Michigan Law School, Ann Arbor, MI, USA). Mapping the patent landscape of medical machine learning. Nat Biotechnol 41, 461–468 (2023). -- MoState JG

The landscape of patents on MML has several implications for existing scholarship and for policy going forward. First, fears that patents would be unavailable for MML inventions seem to be largely unwarranted. Our results show that after a decade of relatively low growth, since 2013 MML patent grants have been growing rapidly, with a CAGR of 38.51%. In 2021, more than 700 patents were granted containing claims directed to AI/ML for medical applications. The allowance rate for these MML patents has steadily increased, from 48% in 2007 to 64% in 2012, and looks to be staying relatively high. The majority of the MML patents granted over the past 20 years are in force (81.73%), but 18.27% are now expired and are already in the public domain available for society to use freely. Second, the doctrinal instability around patentability of AI in the United States also seems not to have dissuaded MML patenting at the USPTO. Despite the relatively greater stability regarding subject-matter eligibility of the EPO compared with the US jurisprudence, our results indicate that the USPTO has been the patent office of choice over the past 20 years (87% USPTO versus 13% EPO in 2021). And even though AI/ML applications are often affected by 35 USC 101 subject-matter eligibility rejections based on Alice, our results indicate that the post-Alice allowance rates for MML inventions are likely to range between 55% and 70%. Inventors’ preference for the USPTO notwithstanding, the fact is that European-headquartered corporations are among the top MML patent owners. Over the past 20 years, MML patenting activity has been led by large corporations active in the medical technologies field, such as Siemens, Philips, Medtronic, Samsung and GE. More recently, we also find technology companies such as Google and Microsoft among the top MML patent owners, as well as universities such as University of California, Case Western Reserve and Stanford. The two clear leaders, Siemens and Philips, are two of the three largest manufacturers of MRI scanners (GE, the third, is fifth among MML patentees). This area concentration is congruent with the high rate of image-input patents and with the dominance of radiology among US Food and Drug Administration (FDA)-cleared or FDA-classified1 MML-based products (representing three-quarters of all FDA-listed MML products13). Nevertheless, despite this moderate imaging focus, MML patenting more generally is not especially concentrated: the top 20 S5 patentees together represent only ~28% of all MML patents. Third, patents referencing MML are actually about MML inventions. Given the hype over AI and machine learning, one might expect that many patents would reference these techniques in the abstract, but that the references would be buzzwords without real importance to the claimed invention. Although this might once have been the case, it is not today. In 58% of MML patents, AI/ML limitations appear in the broadest (independent) claims. This represents a sharp increase: merely a decade ago, only 20% of MML patents had such AI/ML limitations as part of the independent claims. Claim practice is also evolving as the technology does, with “machine learning” emerging as the most prevalent limitation since 2017, followed by “neural network,” “AI” and “deep learning.” Fourth, despite the MML hype, our results show that claims are relatively conservative. There are relatively few patents directed at fully automatic AI-based diagnosis. Most of the MML claims analyzed instead focus on measurement and analysis (27%) and detection and classification (36%). In the case of diagnosis, images are the most prevalent input signal to the AI/ML system. We suspect that this pattern may change, and the current focus on earlier clinical tasks reflects capabilities and the current state of knowledge—but for now, most MML patents are farther from clinical decisions, even as policy debates revolve around MML systems that focus on the point of care itself14,15. More work remains to be done. Further research is required to investigate the scope of protection for these MML patent claims, their validity in light of current subject-matter eligibility requirements and AI/ML prior art, and the sufficiency of disclosure of the patent specifications3. But an early look suggests that patenting remains an important player in innovation incentives for AI/ML in medicine, with a range of inventors actively seeking patent protection in surprisingly conservative applications.