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Intellectual Property and Public Health

Abstract and Keywords

This chapter considers the relationship between intellectual property (IP) and public health with a primary focus on US patent law and international law. The first part focuses on health innovation and considers the limits of patents and other exclusionary rights as a source of incentives for innovation to address certain public health priorities. It considers four categories of innovation that present a mismatch between public health priorities and private incentives for innovation: vaccines, anti-infectives, neglected diseases, and nonexcludable innovations. The second part considers conflicts between IP and public health arising from restrictions on access to patented technologies. It examines market and policy mechanisms to facilitate access to patented technologies, including price discrimination, public and private insurance, price controls, and legal restrictions on patents.

Keywords: Intellectual property, public health, vaccines, anti-infectives, neglected diseases, price discrimination, insurance, price controls, TRIPS Agreement, limits on patents

1. Introduction

*The phrase “public health” suggests that health is a public good that might be provided through collective action and initiatives of social planners. The phrase “intellectual property,” on the other hand, suggests a particular solution to the problem of innovation as a public good: Giving innovators rights to exclude free riders so that they can capture the value of their innovations through private market transactions. The domains of public health and of intellectual property (IP) overlap when innovation might advance public health goals, or when public health goals call for the use of recent innovations that are still under patent. Within these zones of overlap, although IP may promote advances that improve public health, the priorities and strategies of public health advocates may differ from those of IP advocates. These differences have provoked notable conflicts in recent years. Conspicuous recent battlegrounds have included negotiations over IP provisions (and related public health exceptions) in international trade agreements.1 But similar conflicts arise in debates over purely national laws.

This chapter considers the relationship between IP and public health with a primary focus on US patent law and international law. Although national patent laws vary in ways that are significant for public health, US law is a useful benchmark because international trade agreements increasingly require other countries to conform their domestic laws to afford protections similar to those available under US law.2 The first part of this chapter focuses on health innovation and considers the limits of patents and other exclusionary rights as a (p. 932) source of incentives for innovation to address certain public health priorities. The second part of this chapter considers conflicts between IP and public health arising from restrictions on access to patented technologies.

2. Public and Private Interests in Health and the Limits of Intellectual Property Incentives

Governments have good reason to take an active interest in the health of their citizens. Poor health imposes burdens not only on individuals, but also on communities. Individuals with communicable diseases expose other community members to risks of contagion. Disease and unhealthy behaviors may undermine productivity or interfere with the care of dependents, leading to poverty and aggravating other social problems. Maintenance of good health may require social infrastructure that is difficult to provide without state involvement, such as the provision of clean water and sewage disposal, or remediation of environmental contributors to disease. Public education may be necessary to change unhealthy behaviors, such as smoking, substance abuse, poor nutrition, and use of toxins. Disease outbreaks may overwhelm the resources of individuals, who turn to communities and place strain on social safety nets. Disease prevention measures, such as vaccinations, may be less costly and more effective, but difficult to implement on an effective scale without government subsidies or coercion.

Effective treatment or prevention of health problems may call for research and development of new technologies.3 Governments promote health research in a variety of ways, including performing research in public institutions, paying others to perform research in the form of grants, tax breaks, or prizes, and creating incentives, in the form of patents or other exclusionary rights, for others to develop and market new inventions.4

Patents protect firms from competition for a period of time, allowing them to charge higher prices to consumers and thereby increase returns on their investments in research and development (R&D). But these higher prices exclude some consumers from access to patented products who might have used them if they were available at competitive prices. In some markets, these higher prices come directly out of the pockets of consumers, although in the case of health products the payer may be a public or private insurer, spending tax revenue or spreading the costs of treatment across the insurance pool. Either way, the effect is to dampen the price sensitivity of insured individuals and to rely more heavily on collective decision mechanisms to control the demand side of the market.

Patents have been particularly popular with drug-developing firms.5 For governments, patents offer a mechanism to provide profit incentives for innovators without significant (p. 933) expenditures of public funds (apart from the nontrivial cost of operating a patent system). But as many commentators have noted, patents may fail to provide adequate incentives for important categories of health innovation.6 This section considers, in detail, four categories of innovation that present a mismatch between public health value and private incentives for innovation. The first example, vaccines, involves significant external benefits. The second, anti-infectives, involves significant external costs. The third, neglected diseases, involves a mismatch between social value and profits for innovations addressed to health problems that primarily affect poor people. The fourth, nonexcludable innovations, involves innovations that cannot easily be made subject to exclusive rights.

2.1 Vaccines

Vaccines are a cornerstone of many public health programs because of their cost-effectiveness in preventing the spread of infectious diseases.7 Individuals who are stricken by infectious diseases present a threat of infection to the larger community. Vaccines are preparations of killed or weakened pathogens (such as viruses or bacteria) that are administered to individuals to protect them against infection. Vaccines work by provoking an immune response in the individual, but without causing a full infection. Vaccines prepare the immune systems of vaccinated individuals to resist future infections in the event of exposure to a more virulent version of the same pathogen.

Vaccines offer both private benefits to the individuals who receive them (by protecting them from infection) and external benefits to the larger public (by making it unlikely that vaccinated individuals will infect other community members).8 Moreover, effective vaccines may decrease the future use of anti-infective treatments that present considerable external costs, considered in subsection 2.2. As more community members are vaccinated, disease outbreaks become less likely, and even unvaccinated individuals may benefit from the “herd immunity” of the community. Many once-common infectious diseases have been largely eradicated by vaccines, including smallpox, yellow fever, polio, measles, and tetanus.

Other infectious diseases, such as influenza, have been more challenging vaccine targets because the pathogens that cause them are constantly mutating, requiring continuous innovation as old vaccines become ineffective.9 Despite these challenges, influenza vaccines have reduced the severity of influenza outbreaks among vulnerable populations. (p. 934) International networks of public health researchers have pooled resources and samples to monitor outbreaks and to update influenza vaccines.10

Despite the considerable benefits of vaccines, some individuals choose not to be vaccinated (or not to have their children vaccinated).11 Private demand may understate social value, especially for vaccines that target infectious diseases prevalent in impoverished communities. Healthy individuals of limited means might choose not to pay for a vaccine to prevent possible future harm in the face of other more urgent needs. Even when the costs of vaccines are subsidized by the state or covered by insurance, healthy individuals may choose to rely on herd immunity to avoid the discomfort, inconvenience, and possible adverse side effects of vaccines. Herd immunity may make this choice rational for individuals, yet as more individuals make the same choice, herd immunity is compromised. In the US, diseases such as whooping cough, measles, and mumps that had largely disappeared as a result of childhood vaccinations are once again on the rise as growing numbers of parents choose not to have their children vaccinated.12 In some cases the perceived risks of vaccines may have been exaggerated by misinformation, such as repeatedly discredited but persistent reports that childhood vaccinations cause autism.13

Weak private demand for vaccines may be fortified by public health initiatives. Many states mandate vaccinations as a condition for enrollment in schools or day care centers,14 although often these laws have exceptions that limit their reach.15 Some states have passed laws authorizing more coercive measures in public health emergencies.16 In the US, the Affordable Care Act requires private insurers to provide coverage of preventive care, including some vaccines, without charging a deductible or co-pay.17 Governments may also fortify demand by purchasing or subsidizing vaccines. In the US, the federal government purchased more than half of all childhood vaccines according to a 2003 estimate.18 But although government purchases may stabilize demand, governments may also use their (p. 935) purchasing power to extract lower prices from suppliers, diminishing incentives to develop these products.19

Although private firms have developed a number of novel patent-protected vaccines in recent years, including vaccines against human papillomavirus, meningitis, and influenza,20 many vaccines have had significantly lower profit margins than other pharmaceutical products.21 The number of firms producing vaccines for the US market fell from 26 in 1967 to five by 2005, leading to shortages.

Lower profit margins for vaccines relative to therapeutic products may be a function of differences in demand. It may be easier to persuade sick patients to pay for treatment than it is to persuade healthy patients to pay for prevention.22 Although demand for vaccines may rise during a disease outbreak, it may subside quickly as the immediate threat of infection recedes, making it difficult to predict sales.23 It may be especially challenging to maintain demand for an effective vaccine that controls disease outbreaks.24 Vaccine mandates may paradoxically undermine public confidence and support for vaccination.25 These demand-side factors inevitably limit the profit expectations from vaccine development.

Additional factors on the supply side may make vaccine development more costly and risky than new drug development. It may take longer to complete the clinical trials that are necessary to show that a vaccine is effective in protecting healthy patients against possible future infection than it takes to show therapeutic efficacy of a drug in patients who are already sick.26 Because it would be unethical to expose research subjects to disease intentionally, researchers must wait for the occurrence of a natural disease outbreak in order to measure the difference in infection rates between treatment and control groups. Since not all research subjects will be exposed to the disease in the real-world context of such a study, a larger study population may be necessary in order to make statistically meaningful observations. If the vaccine confers herd immunity, this possibility may further complicate the study design and perhaps require the use of controls in remote communities.

Regulators may sometimes be willing to approve new vaccines on an accelerated basis based on observations of surrogate endpoints (such as antibody assays) rather than clinical endpoints (ie, actual infections), particularly if they believe they may soon face a pandemic.27 But although easing regulatory requirements may accelerate product approval and reduce R&D costs, it may also diminish consumer confidence in the product, fuel (p. 936) perceptions that vaccines are unsafe, and make it difficult for vaccine developers to get liability insurance.28 Governments have sometimes sought to shore up incentives for vaccine production by offering firms legal protection from products liability and replacing it with a government compensation scheme,29 but such measures may further undermine public confidence in both vaccine makers and the government.30

Delays in bringing a new vaccine to market not only defer profits, but also limit the time remaining between product launch and patent expiration. Patents have long been an important source of lucrative exclusivity in product markets for pharmaceutical firms, with the most valuable patents being early filed patents on the active ingredient in a new product.31 Later-filed patents on improvements, such as new formulations, methods of treatment, or combination products, are easier for competitors to avoid infringing; they are also more vulnerable to validity challenges.32 Patents ordinarily expire 20 years after their filing dates, but patent term extensions of up to five years are available to restore some of the time lost during clinical trials and regulatory review of new drugs.33 Recent estimates of the time necessary to develop a new vaccine range from eight to 18½ years,34 diminishing the time left between product approval and patent expiration and reducing incentives to develop vaccines.35

On the other hand, in the US, even without patents, vaccine developers have a significant advantage over drug developers in forestalling generic entry. This is because US law imposes greater regulatory obstacles and delays prior to licensing competing versions of biologics (including vaccines) under the Public Health Services Act36 than it imposes prior to approval of competing versions of small molecule drugs under the Food, Drug, and Cosmetics Act.37

In the case of drugs, the Hatch–Waxman Act of 198438 provides a streamlined pathway for approval of a generic version of a previously approved product (the reference listed drug) through the use of an abbreviated new drug application (ANDA).39 An ANDA applicant (p. 937) must show that the generic product is bioequivalent to the reference listed drug, but need not include full reports of clinical trials showing safety and efficacy for the generic product.40 An ANDA may be submitted to the US Food and Drug Administration (FDA) as early as four years after the original approval date of the reference listed drug if the application includes a challenge to the validity or infringement of a patent on the drug.41 If the patent holder responds by suing for patent infringement, FDA must stay approval of the ANDA until 7½ years after the original approval date.42 The effect is to provide the reference listed drug with 7½ years of “regulatory exclusivity” before FDA will approve an ANDA even if the patent infringement action is ultimately unsuccessful.43

Prior to 2010 there was no comparable abbreviated approval pathway for competing versions of biological products such as vaccines, which are regulated under the Public Health Service Act rather than the Food, Drug, and Cosmetics Act. With the enactment of the Biologics Price Competition and Innovation Act of 2009, the US created an abbreviated approval process for products that are “biosimilar” to previously licensed biological products on somewhat different terms than those available for generic drugs under the Hatch–Waxman Act.44 The new regulatory approval pathway permits approval of products that are “biosimilar” to and/or “interchangeable” with previously licensed biological products, after a 12-year period of regulatory exclusivity for the reference products. Some critics have argued that the 12-year period of exclusivity is excessive,45 while others have argued for even longer periods.46

The Biologics Price Competition and Innovation Act does less to lower the regulatory entry barrier to follow-on competition for biologics than the Hatch–Waxman Act did for generic versions of small molecule drugs.47 A more extensive showing is necessary to get an agency determination that the biosimilar product is “interchangeable” with the reference product.48 Although experience with the new statute remains limited, it seems likely that the (p. 938) regulatory entry barrier for follow-on biologics will remain much higher than that facing manufacturers of generic drugs, and the availability of this abbreviated approval pathway will be delayed by a much longer period of regulatory exclusivity. As a result, developers of new vaccines and other biologics may enjoy longer periods of market exclusivity than developers of new drugs.

There are reasons to worry that private demand for vaccines may provide inadequate incentives for vaccine development from the perspective of a social planner who takes account of the full social value of vaccines. Even with patents and regulatory exclusivity to protect them from price-lowering competition, vaccine developers may be unable to charge prices that reflect the full social value of these products because of weakness in private demand as a result of individual resource constraints, misinformation, avoidance of side effects, and choices to free-ride on herd immunity. Social planners might therefore choose to promote vaccine development and utilization through other mechanisms that do not depend on private demand, such as research funding and government subsidies or mandates of vaccine purchases.

2.2 Anti-infectives

Penicillin and other antibiotics were a major success story for the pharmaceutical industry that promised to end the scourge of infectious diseases.49 Like vaccines, therapeutic interventions against infectious disease also have spillover benefits for public health. When antibiotics and antiviral medications work for individuals, they also benefit communities by making treated individuals less likely to infect others.

In addition to this positive externality, use of anti-infectives has external costs that raise public health concerns. A particular source of concern has been the development and spread of resistance. Although resistance was once thought to arise primarily from new mutations in infectious microbes, evidence suggests that resistance genes are ancient, diverse, and readily transferred between organisms.50 Human use of anti-infective agents has accelerated the spread of resistance by giving a selection advantage to those strains within the microbiome that are resistant to those particular agents. Resistant microbes that survive treatment may spread their resistance to other microbes through gene transfer mechanisms51 and may infect others, spreading the prevalence of resistant strains in the community.

From a public health perspective, resistance is an external cost of the current use of anti-infectives that diminishes their future effectiveness in treating other infections at a later time, threatening to deplete the arsenal of effective drugs against future disease outbreaks.52 To the (p. 939) extent that resistance is more likely for older products that are available at generic prices than for newer products that are still under patent, it may disproportionately undermine cost-effective treatments.53 Resistance traits that protect microbes against one drug may also confer cross-resistance against other similar drugs, including drugs that may be developed in the future by other firms. Current use of anti-infectives thus imposes significant costs on future patients, future payers, and future product developers. Infections that are resistant to multiple drugs are particularly costly to treat.54 Use of anti-infectives may seem like a relatively cost-effective way to treat current patients, but it has external costs that relegate future patients to rely on more expensive, and less effective, care.

This framing of the problem suggests two different kinds of policy response. First, we might promote further R&D to develop new anti-infective agents. Second, we might promote parsimonious use of existing agents in order to slow the development of resistance. These strategies could conflict: For example, restrictions on use could limit expected profits from developing new agents.

Mechanisms for promoting R&D include IP protection, public funding of research and promotion of public-private partnerships to overcome research obstacles, reducing regulatory obstacles to new product approvals, and tax incentives.55

Public health advocates have typically proposed different mechanisms to slow the spread of resistance. These mechanisms include education campaigns directed at healthcare workers and the general public to discourage excessive use of anti-infectives; clinical guidelines to avoid inappropriate and subtherapeutic use of anti-infectives; use of diagnostic tools to avoid ineffective use of anti-infectives that nonetheless contributes to resistance; campaigns to reduce transmission of infections through simple measures such as hand washing, vaccination, and use of mosquito nets and condoms; and more extensive use of regulatory controls that limit inappropriate use of antibiotics through FDA restrictions.56 (p. 940) Although some evidence supports the effectiveness of these measures,57 it is challenging to achieve the widespread compliance that may be necessary to make a dent in the rapidly growing problem of resistance.

The effects of resistance on incentives to develop new products are complex. Resistance could enhance incentives for further innovation by reducing competition from older, off-patent products that have become ineffective.58 On the other hand, improved understanding of resistance and cross-resistance presumably diminishes expected profits from new anti-infectives by limiting the expected duration of commercial demand for these products. Moreover, the possibility of future restrictions on use to preserve effectiveness may give rise to uncertainty about future sales.

A controversial argument asserts that longer patent terms for anti-infectives could do double duty, simultaneously promoting both innovation and parsimonious use of existing antibiotics.59 Higher prices for patent-protected anti-infective products could discourage low-value uses (such as the use of antibiotics in cattle feed to promote growth). Extending the patent term would prolong this effect. A longer patent term might also encourage patent holders to suppress use today in order to maximize the value of their products over a longer time horizon. Sales during the patent term are more lucrative for patent holders than sales following patent expiration, when competitors are able to enter the market and drive down prices. Patent holders can thus expect to capture more of the value of future sales that will occur during the patent term and to discount heavily the social value of deferred use of an anti-infective after patent expiration. The longer the patent term, the longer the period that the patent holder will take into account in assessing the value of raising prices to suppress current use in order to prolong the efficacy of the product over time.

This analysis invites a number of criticisms. One concern is that monopoly pricing for patent-protected anti-infectives may lead to price-gouging and restrictions on access in a pandemic. Proponents of extended patent terms may argue that this is a feature rather than a bug; the prospect of extraordinary profits in a pandemic may be what makes patent holders willing to suppress current sales in order to prolong the effectiveness of their products.60 But widespread access to an effective anti-infective may be vital during a pandemic to prevent devastating public health consequences. Governments could facilitate access through subsidies to purchasers or through public insurance programs.61 Governments could also institute price controls62 or grant compulsory licenses to lower-cost producers,63 and might face considerable political pressure to do so in a pandemic.64 But, if these measures (p. 941) are effective in avoiding deadweight loss, they also call into question the effectiveness of extended patent terms as a mechanism for promoting responsible stewardship over anti-infectives by patent holders. Another concern is that high prices might lead to subtherapeutic dosing in impoverished communities, accelerating the development of resistance.65

Others argue that reliance on IP could be counterproductive if patent holders seeking to maximize lucrative product sales accelerate the onset of resistance.66 Reimbursement policies could be redesigned to promote stewardship over anti-infectives by uncoupling financial incentives from sales volume, rewarding drug companies and hospitals with higher payments when they take measures to preserve the efficacy of existing antibiotics rather than paying them more for using these products more extensively.67

US law has been quicker to enhance innovation incentives than it has been to enhance incentives for conservation. Quite apart from the problem of resistance, Congress has repeatedly enacted legislation to defer competitive entry in the market for pharmaceutical products, including providing patent term extension of up to five years to compensate for some of the time necessary for clinical trials and regulatory review.68

US law further shelters pharmaceutical innovators from competition by controlling the timing of regulatory entry barriers for generic competitors. These regulatory provisions function as an alternative source of exclusivity to promote certain forms of R&D, such as the development of orphan drugs to treat rare diseases, the development of new chemical entities not previously approved for sale, or the testing of approved products for new uses or for use in children. The terms of protection vary for different kinds of innovation and have been adopted in somewhat different forms in different countries.69 Sometimes regulatory exclusivity runs concurrently with patent protection (in which case it may still provide valuable insurance against a ruling of patent invalidity or noninfringement) and sometimes it extends beyond patent expiration (in which case it may prolong the period of exclusivity).

As previously noted, US law provides regulatory exclusivity for periods ranging from four to seven and a half years following the first approval of a new chemical entity,70 and for 12 years following the first approval of a new biological drug,71 before generic competitors may enter the market with an abbreviated approval application for a similar product. Orphan drugs for treating rare diseases and conditions affecting fewer than 200,000 patients in the US are protected from competition for seven years after initial product approval by a prohibition against FDA approval of another application “for such drug for such disease or condition.”72 These periods of exclusivity may be prolonged by an additional six months as a reward for conducting pediatric trials of new drugs.73

(p. 942) These periods of exclusivity were greatly extended for new anti-infectives with passage of the Generating Antibiotic Incentives Now Act of 2012 (GAIN).74 This legislation extends each period of regulatory exclusivity for an additional five years for a product that FDA has designated as a “qualified infectious disease product.” The statute defines this term as “an antibacterial or antifungal drug for human use intended to treat serious or life-threatening infections.” The statute specifically includes in this definition infections caused by a variety of resistant organisms.75 The GAIN Act also authorizes FDA to grant priority review76 and “fast track” status77 for these products, relieving innovators from some of the burden of the ordinary FDA approval process.

Although it is too soon to tell what impact these extended periods of exclusivity and accelerated regulatory review will have on the development and use of new anti-infective products, a number of new products currently in the development pipeline will qualify for these benefits.78 Perhaps prolonged exclusivity will encourage the sponsors of these products to charge higher prices in order to conserve on use of their products to prolong their effectiveness, or perhaps they will follow the more typical industry practice of setting prices to maximize current profits. Even if they recognize the social value of parsimonious use of their new products, product developers may face powerful incentives to sell these products at a brisk pace before they lose their effectiveness to the inexorable spread of resistance.

A recent report from the President’s Council of Advisors for Science and Technology suggests a more balanced approach that combines incentives and subsidies for new product development with improvements in stewardship to prevent overuse of existing products.79 It may prove easier to avoid overuse by adjusting the behavior and incentives of health care providers, hospitals and insurers than it is to get product developing firms to try to sell less of their products.

2.3 Neglected Diseases

Some diseases that public health social planners consider high priorities for innovation have nonetheless persistently ranked lower in the investment priorities of private drug companies because new treatments seem unlikely to be profitable. Perhaps the disease population is too small to cover the costs of R&D, or perhaps the disease primarily affects poor people without health insurance. The result may be a lack of appropriate therapies for diseases that impose a devastating burden on individuals and communities, particularly in the developing world.80 The World Health Organization (WHO) maintains a list of 17 neglected tropical (p. 943) diseases that mainly affect populations living in poverty.81 According to a recent estimate, on a worldwide basis one person in seven suffers from one or more of these neglected diseases.82

The diseases on the WHO list are communicable. Expenditures on prevention and treatment thus present, to some degree, the same externalities considered above for vaccines and anti-infectives. Although concentrated in the developing world, these diseases may spread elsewhere through travel. Some of these diseases affect small numbers of patients in developed countries with the capacity (or insurance coverage) to pay high prices for new drugs, but most affected patients could afford to pay very little, limiting the value of patents and regulatory exclusivity in making these products profitable.83

Public health advocates have suggested both “push” and “pull” strategies to promote innovation for neglected diseases.84 “Push” strategies subsidize innovation inputs through mechanisms like grants, R&D tax credits, and regulatory breaks to facilitate new product development, while “pull” strategies enhance rewards for research outputs through mechanisms like prizes, patents, or regulatory exclusivity, or advance purchase commitments. Nonetheless, legislative initiatives to promote innovation for treatment and prevention of neglected diseases have focused on fortifying exclusionary mechanisms in both developed and developing nations.

An early effort to address neglected diseases in developed nations was orphan drug legislation enacted in the past 35 years in the US, Japan, Australia, and the European Union.85 As noted above, the US Orphan Drug Act provides seven years of market exclusivity for products to treat rare diseases and conditions affecting fewer than 200,000 patients in the US (or otherwise offering no reasonable expectation of covering development costs from sales in the US). In addition to this “pull” mechanism, the Orphan Drug Act provides “push” benefits to make drug development less costly, such as a streamlined regulatory approval process; substantial tax credits for R&D expenses; financial assistance with clinical trials; and coordination of public and private development efforts.86

Orphan drug laws have facilitated the introduction of more than 400 drugs and biologics in the US market since 1983.87 Some of these products have been quite profitable, although in some cases profits have been enhanced by off-label use or approval of new uses that are not for orphan indications.88 An outstanding example is erythropoietin, a product initially approved as an orphan drug for treating end-stage renal disease that was later used to treat chemotherapy-induced anemia and became the single biggest expenditure for the US (p. 944) Medicare program.89 Critics argue that the Orphan Drug Act is subject to manipulation by firms that get their products approved for narrowly defined indications while profiting from broader off-label use. Others argue that it has distorted product development incentives by diverting resources from other conditions that affect more patients towards the development of highly lucrative products for niche markets.90 These laws might improve the profitability of products with small markets in developed nations, but they have done little to stimulate the development of new products for neglected tropical diseases that prevail in the poorest nations.91

The US Congress specifically targeted the development of drugs for treatment or prevention of neglected tropical diseases of the developing world in a more recent statutory incentive for the pharmaceutical industry: tradeable priority review vouchers.92 This new incentive mechanism, which had recently been proposed in the literature,93 was tucked into an inconspicuous “other provisions” title at the end of a 2007 bill to reauthorize expiring legislation to permit FDA to collect user fees to cover its costs and was not thoroughly vetted in the legislative process. The way it works is that the sponsor of a new drug application for a product not previously approved by FDA for use in the prevention, detection, or treatment of a listed tropical disease94 may receive a tradeable priority review voucher upon receiving FDA approval of its application. The sponsor may use this voucher for another product or sell it to another firm. The holder of the voucher is entitled to receive priority review (ie, review within six months of submitting an application to FDA) for another product upon payment of a user fee to be established annually by FDA.95

A priority review voucher is a form of prize awarded to a sponsor for obtaining FDA approval for a product that targets a neglected disease. Because they are transferable, vouchers will likely be assigned to the sponsors of the most commercially significant products that are currently seeking FDA approval, thereby accelerating the availability of products for which there is significant market demand. But there is no reason to expect the size of payments for vouchers to bear any relationship to the social value of the neglected disease products that (p. 945) qualified for the vouchers. The value of the prize depends instead on the market for tradable priority review vouchers. Demand for priority review would depend on the expected duration of nonpriority review and the expected value of sales for a lucrative new product that might be made during the interval between approval dates under priority and nonpriority review. Greater backlogs and delays at FDA would thus increase demand for vouchers and increase the value of the prize. On the other hand, the supply of priority review vouchers may increase over time, because Congress has subsequently adopted the same mechanism as an incentive for the development of products for rare pediatric diseases.96 The current value of priority review vouchers is impressive. Although there is no guarantee that the result of priority review will be favorable, accelerating the date of new product approval could provide more time on the market prior to patent expiration without deferring generic entry. As of August 2015, FDA had issued six priority review vouchers and four of these had been sold for amounts ranging from $67.5 million to $350 million.97

The disconnect between the size of the prize and the value of the approved product is both a strength and a weakness of this particular prize system. The point of the system is to enhance incentives to develop products that are undervalued in commercial markets because they are targeted to meet the needs of poor people, and therefore cannot compete for the investments of pharmaceutical innovators who stand to make far greater profits from developing products for rich people. By offering innovators of these undervalued products vouchers that can be sold at a price determined by the value of other, more lucrative pharmaceutical products, the tradable voucher system takes a small step toward spreading the wealth.

On the other hand, as with any prize system, there is a risk that a prize of great value could be awarded for an innovation of little value. The value of the prize does not turn in any way on the value of the tropical disease product or its success in the regions where it is needed. Indeed, the first FDA-approved product to qualify for a tropical disease voucher was a malaria drug that had already been approved in 80 other countries.98 Although this product met the statutory requirements for the prize, it is not clear how it advanced the legislative goal of stimulating new R&D to meet the needs of patients outside the US (rather than to motivate firms to seek US approval for old drugs that are already available elsewhere).

Using US regulatory approval as a trigger for the prize is especially odd given the aim of promoting the development of tropical disease products “for which there is no significant market in developed nations and that disproportionately affect [ … ] poor and marginalized populations.”99 A requirement of FDA approval is a costly burden to impose on a product with no significant market in developed nations. Perhaps securing US regulatory approval seemed like a reasonable marker for advancing product development to the point of being ready for clinical use, or perhaps it seemed like an easy criterion for FDA to administer. Congress may have expected developing countries with limited resources for regulating drugs to follow the decisions of agencies like FDA. On the other hand, some tropical disease products such (p. 946) as vaccines may present risks that are worth incurring in parts of the world where the disease is rampant, but not in the US where infection is less common.100 Problems in specifying ex ante the criteria for an award are a recurring challenge in designing prize systems.101

From the perspective of Congress, this prize system has the benefit of not requiring any outlay of government funds. The purchaser of the voucher pays the sponsor of the newly approved product whatever price they agree upon, and additional costs to the FDA for priority review of another application are covered by additional user fees. (Presumably these costs are ultimately borne by consumers of the product that gets to market sooner as a result of the priority review.) If Congress leaves the FDA underfunded, its backlog of pending new drug applications might increase, making priority review vouchers even more valuable, thus increasing the prize for obtaining approval of products for tropical diseases, rare pediatric diseases, and qualified infectious disease products. A further advantage of priority review vouchers is that they enlarge the period of exclusivity for an innovator without deferring generic entry, thus avoiding political opposition from the generic industry. The additional patent life comes at the front end as a result of earlier approval, rather than at the back end from extension of the term of exclusivity.

It is too soon to tell whether tradeable priority review voucher prizes will bring about more innovation in treatments for neglected diseases. The fact that Congress has already replicated the system for rare pediatric diseases may reflect the popularity of priority review vouchers with drug developing firms more than the success of the program in advancing its purported goals.

Another mechanism for promoting R&D for neglected diseases that has gained traction in recent years is advance purchase commitments (APCs) by national governments, international organizations, or private foundations to purchase a specified quantity of an as-yet undeveloped product at a certain price.102 If the purchasers are willing to make the product available for free or at a relatively low price, APCs can simultaneously mitigate both the problem of underinvestment in R&D for neglected diseases and the problem of lack of access to these products by patients living in poverty.

2.4 Non-excludable Innovations

So far, this discussion has focused primarily on pharmaceutical innovations that might be embodied in patented products such as vaccines and drugs. It is relatively easy for innovators to use patents and regulatory exclusivity to keep competitors out of the market for such innovations, although, even without competition, it may be challenging in some circumstances (discussed earlier) for innovators to capture their full social value. But for (p. 947) many innovations with considerable social value from a public health perspective, it is not possible to design effective exclusionary rights at all.103

For example, studies might indicate that widely used drugs (such as hormone replacement therapy or non-steroidal anti-inflammatory drugs) have toxic side effects and should therefore be used more sparingly.104 This is valuable information that can improve health outcomes by reducing the use of these products. But it is difficult for an innovator to use IP to capture that value. Instead, the value accrues to patients who will avoid use of harmful products and to health care payers who will avoid paying for them. Other innovations with high social value for public health that is not easily appropriable through exclusionary rights include studies of the effects of lifestyle choices (such as smoking, diet, exercise, condom use, etc.) and the effects of clinical practices (such as use of checklists by caregivers to avoid errors and prevent the spread of infections). An innovation system that relies on patents and other forms of exclusionary rights will do little to reward innovators for investments in these innovations because it is difficult to design exclusionary rights that permit owners to capture their value.

These innovations may nonetheless be attractive candidates for investment by public and private insurers seeking to reduce healthcare costs and improve outcomes.105 Certainly insurers stand to benefit from studies showing that expensive care is not worth paying for. They also stand to benefit from improvements in care that reduce future medical costs.

The increasing use of electronic health records has facilitated large observational studies in diverse patient populations that reveal differences in treatment outcomes. These records may be used for comparative effectiveness research or for personalized medicine research to help identify the best treatments for individual patients. But the results are unlikely to be excludable. For one thing, medical records typically involve treatments that are already a part of medical practice. Discovering which of these treatments is superior does not make the better treatment patentable if it is already in the prior art. The development of new algorithms for making treatment choices is also unlikely to be eligible for patent protection under recent decisions of the US Supreme Court.106 Even if these algorithms were patentable, it would be difficult to monitor infringement and enforce rights effectively. Exclusionary rights work best when they can be used to stop commercial competitors from making infringing products. They are far less effective when they must be asserted against numerous caregivers and patients whose activities are hard to monitor. Suing customers is rarely a good way to promote goodwill, especially in the context of healthcare.

Patents and other forms of exclusionary rights have been popular with pharmaceutical innovators and have been repeatedly fortified under US law and international law to (p. 948) motivate firms to perform certain kinds of innovation. But reliance on exclusionary rights fails to provide adequate incentives for certain categories of innovation that are important for public health. In the case of vaccines, positive externalities raise concerns about underinvestment, while in the case of anti-infectives, negative externalities raise concerns about overpromotion and overuse. Exclusionary rights provide inadequate incentives to address neglected diseases that primarily affect poor people, and to provide valuable information that is nonexcludable. These gaps require other strategies for promoting innovation to address important public health needs.

3. Restricted Access to Patented Health Technologies

Many public health advocates have a different criticism of patents and exclusionary rights. Even when they are effective in promoting innovation, exclusionary rights work by allowing their owners to charge higher prices, with the effect of decreasing access to lifesaving products. This is a particularly compelling version of a familiar economic criticism of patents.107 Patients and healthcare systems that would willingly pay a competitive market price sufficient to cover the marginal cost of producing a product might be unwilling or unable to pay the higher price charged by a patent holder who is protected from effective competition. From the perspective of economics, the result is dead-weight loss that does neither innovators nor consumers any good.108 From the perspective of public health advocates, it may be a humanitarian crisis and a human rights violation.109

IP advocates point to market responses that potentially mitigate these concerns. First, in some circumstances IP might facilitate price discrimination that allows owners to sell their products at lower prices to consumers who could not otherwise afford them, while still maintaining higher prices for those with more resources and willingness to pay.110 Second, in most markets individual consumers do not pay for drugs out of their own pockets, but instead rely on public or private insurance to provide additional resources to facilitate access.111

Beyond these market mechanisms, governments might facilitate access to products through price controls and through use of their national laws to limit the rights of patent (p. 949) holders (such as by authorizing compulsory licenses or threatening to do so), although they are increasingly constrained in their ability to modify patent rights by the terms of trade agreements.

3.1 Price Discrimination

Price discrimination could, in theory, allow patent holders to provide their products to a greater number of consumers at different prices that vary with willingness (or ability) to pay, benefiting low-income consumers as well as patent holders.112 Price discrimination thus offers a mechanism to enhance incentives for innovation while expanding the beneficiaries of innovation. In practice, however, price discrimination can be quite challenging to maintain and can lead to higher prices for some consumers, with ambiguous welfare effects.113

One challenge for patent holders is figuring out the willingness to pay of different consumers to avoid giving a price break to consumers who otherwise could and would pay more. Sometimes firms offer lower prices or rebates to NGOs or to public sector programs that provide healthcare for low-income patients, in effect relying on these purchasers to sort out which consumers are eligible for the programs.114 In the US, some pharmaceutical firms offer patient assistance programs to provide free or low-cost drugs to patients who otherwise could not afford them.115 But often, price differences in the pharmaceutical marketplace reflect differences in bargaining power rather than differences in ability to pay, with distributive consequences that seem less benign. Large payers such as pharmacy benefits managers may get better prices than retail pharmacies and their customers,116 while uninsured patients may pay considerably more than those with insurance.117

In a global marketplace, national borders might facilitate price discrimination by providing a rough proxy for willingness to pay. Drug companies typically sell their products at higher prices in wealthier nations and at lower prices in developing nations.118 But national borders are an imperfect proxy for willingness or ability to pay. There are poor people in rich nations and rich people in poor nations. Patent holders might be reluctant to sell at low prices in countries, like South Africa, with large numbers of middle class consumers (p. 950) who could otherwise pay higher prices, even though these markets also have many more poor people who could not pay those prices.119

Another challenge for patent holders is preventing purchasers who buy at low prices from reselling to those who would otherwise pay higher prices.120 Patent holders might hesitate to use differential pricing if they expect it will cause a loss of revenue on otherwise more lucrative sales. (Opportunities for arbitrage may also create public health problems if patients resell a portion of the drugs that are prescribed for them, retaining only a subtherapeutic dosage for themselves.) Drug companies may offer more favorable pricing for some large purchasers by paying them rebates that are not publicly disclosed, while maintaining nominally high prices for all consumers.121 Keeping these terms confidential reduces the risk that other buyers might demand the same price. Some buyers negotiate contracts that limit the prices they will pay based on the best price available to other buyers, making it more costly for drug companies to offer discounts. Under US law, drug companies must pay rebates to Medicaid for drug sales in an amount set by statute to give Medicaid at least the best price given to any other purchaser.122 The effect may be to drive prices higher in other parts of the market as drug companies refuse to give steeper discounts to other purchasers, knowing that they would have to give the same deal to Medicaid.

In the global market for pharmaceuticals, differential pricing may be threatened by parallel trade that allows products purchased in low-price nations to be sold in high-price nations.123 Some national patent laws, including US law prior to a recent decision of the Supreme Court, treat such imports as patent infringement on the theory that sales outside the country do not exhaust the patent right arising under that country’s laws.124 National exhaustion rules that prohibit parallel trade compromise free trade in patented goods, while their effectiveness in improving access is unclear.125 The patent laws of many developing nations permit parallel trade under a rule of international exhaustion,126 a rule that now prevails under US law following the decision of the Supreme Court in Impression Products v. Lexmark International.127 Although international exhaustion may seem contrary to the interests of nations that are otherwise likely to be beneficiaries of differential pricing, nations that lack domestic drug manufacturing capacity and depend on imports for access to drugs may prefer a rule that facilitates importation.128

(p. 951) Apart from legal protection, some drug distribution strategies may reduce the risk of arbitrage between low-price and high-price markets. For example, to prevent resale in the US market of the hepatitis C drug sofosbuvir (marketed in the US under the brand name Sovaldi), patients receiving the drug in Egypt are required to open the bottle in the presence of a pharmacist, break the seal, and take the first pill.129

Even when parallel trade may be prevented, conspicuous differences in prices for the same product in different markets may highlight the substantial profit margins of pharmaceutical products and lead to resentment, creating political pressure to bring down prices in high-price markets. Even the US Congress, which has steadfastly resisted imposing drug price controls, has nonetheless felt political pressure to allow US consumers to import drugs from Canada, where prices are lower as result of that country’s price control policies. Congress has passed legislation asking the FDA to consider whether it should permit such imports, although FDA has so far been unwilling to approve the practice as safe.130

3.2 Public and Private Insurance

The effects of insurance on access to healthcare products are complex. By subsidizing costs to consumers at the point of purchase, insurance makes consumers less sensitive to the total price of patented products, since most of the price is paid by the insurer out of the pooled premiums of all consumers.131 Insured consumers may therefore consume more patent-protected products than they would if they had to pay the full price themselves. On the other hand, insurance coverage allows patent holders to charge higher prices by making consumer purchasing decisions less sensitive to price.132 Insurers forced to pay higher prices for patent-protected products may increase the premiums they charge, leaving more consumers unable to afford insurance. As a result, although high prices for patented medical products covered by insurance may have little impact on utilization by those consumers who remain insured, by increasing the costs of insurance premiums, they may leave more consumers to pay the full costs of patent-protected products out of pocket, with resulting deadweight loss.133

In some circumstances insurers may be able to control costs through a number of strategies.134 When clinically similar competing products are available, an insurer may bargain with manufacturers to include an advantageously priced product on a preferred formulary, perhaps in exchange for a confidential rebate. The insurer may cover formulary (p. 952) products with a modest patient copay, while imposing higher cost-sharing requirements on patients or burdensome prior authorization requirements on physicians before it will pay for products that are not on the formulary. The effect may be to steer physicians and patients to choose the preferred products over equivalents. These strategies are less effective at lowering prices for unique drugs without close substitutes, although elevated cost-sharing and prior authorization requirements might nonetheless suppress utilization of expensive patented products. But suppressing utilization of healthcare products without close substitutes causes deadweight loss that is bad for public health. Public health insurance subsidies might limit the deadweight loss from underutilization, but they also allow patent holders to raise prices by suppressing the price sensitivity of consumers. These subsidies come out of the public fisc, introducing further deadweight loss from taxation.

3.3 Price Controls

Outside the US, most developed nations use a combination of public health insurance to provide access to healthcare products and price control mechanisms to limit costs.135 In single payer healthcare systems, the payer may have enough market power to bargain for favorable prices without restricting access. Some systems use internal benchmarking or external referencing to set the price of a new drug at the time of product launch. Internal benchmarking compares the price of a new drug to the price of one or more other products in the same class, sometimes in combination with reference price reimbursement that limits the amount of reimbursement to the cost of a cheaper product unless a higher price is justified by cost-effectiveness analysis. External referencing caps prices according to the price of the same drug in other markets.136 Differences in prices may reflect variations in the bargaining power of payers in different countries rather than differences in ability to pay.137 Other measures to control costs include incentives on prescribing physicians to control total expenditures.

The power of government payers to insist on price breaks may be constrained by political pressure to address public health needs. Some patients and public health advocates have brought successful legal challenges to government policies that limit provision of costly treatments as violating rights to health protections under national laws or international agreements.138 Governments threatened with such lawsuits may find it challenging to (p. 953) bargain hard with a patent holder for a product without clinical substitutes. When payers are required by law to provide coverage of expensive drugs, their bargaining position is weakened.

Drug manufacturers may also encounter considerable political pressure to provide affordable access to their products, especially in the face of conspicuous public health crises. This became apparent in a very public battle between the South African government and the pharmaceutical industry over access to treatments for HIV during the 1990s.139 The Pharmaceutical Association of South Africa sued the South African government in an effort to block implementation of legislation authorizing parallel imports and compulsory licensing to bring down the cost of patented drugs. The pharmaceutical industry initially enjoyed the support of the US government, which threatened the South African government with trade sanctions and withdrawals of aid.140 But sustained media attention brought about a dramatic shift in the position of the Clinton administration and Congress. The litigation became a public relations disaster for the industry and was eventually settled, leading to the provision of drugs at sharply discounted prices.141 This episode revealed limits to the power of patent holders to hold out for high prices and focused the attention of the public health community on the IP provisions of international trade agreements as an obstacle to access to medications.

3.4 Restrictions on Patents

Patents are national in scope, and national patent laws may differ in important ways, leaving inventions that are patentable in some countries ineligible for protection in others. Variation among national patent laws was greater prior to the 1994 TRIPS Agreement, which binds members of the World Trade Organization (WTO) to implement patent laws meeting certain minimum standards. Of particular importance to the pharmaceutical industry, the TRIPS Agreement requires that

patents shall be available for any inventions, whether products or processes, in all fields of technology, provided that they are new, involve an inventive step and are capable of industrial application. … patents shall be available and patent rights enjoyable without discrimination as to the place of invention, the field of technology and whether products are imported or locally produced.142

The drafting history of this provision reflects a clear goal of requiring all Member States to provide protection for pharmaceutical products as well as processes.143 Prior to that time, approximately 50 nations did not allow patents for pharmaceuticals, while some (such as India) allowed patents only on pharmaceutical manufacturing methods, but not on the drugs themselves.144

(p. 954) The TRIPS Agreement initially allowed extra time for developing countries and least-developed countries to bring their national laws into compliance.145 The extensions for developing countries to extend patent protection to drugs expired in 2005, making new drugs eligible for patent protection in countries such as India that had previously been important exporters of generic drugs. The WTO TRIPS Council has extended the transition period for least developed countries until 2033.146 Forty-eight countries, including 34 members of the WTO, are on the United Nations list of least developed countries.147

The TRIPS Agreement allows some latitude for members to address public health considerations within their patent laws. Notably, they may “adopt measures necessary to protect public health and nutrition … provided that such measures are consistent with the provisions of this Agreement.”148 In addition to applying their own laws to determine whether inventions are “new, involve an inventive step and are capable of industrial application,”149 members may exclude from patentability “diagnostic, therapeutic and surgical methods for the treatment of humans or animals,”150 they “may provide limited exceptions to the exclusive rights conferred by a patent, provided that such exceptions do not unreasonably conflict with a normal exploitation of the patent and do not unreasonably prejudice the legitimate interests of the patent owner, taking account of the legitimate interests of third parties,”151 and they may choose their own rule concerning exhaustion of patent rights to permit imports of patented goods following a first sale in another country.152 They may even authorize compulsory licenses to use a patented product or process, without the patent owner’s consent, subject to a list of restrictions, including (initially) that the use be “predominantly for the supply of the domestic market of the Member authorizing such use” and subject to payment of “adequate remuneration … taking into account the economic value of the authorization.”153 The “domestic market” limitation was problematic for countries that did not have the capacity to manufacture pharmaceuticals domestically. Governments that sought to make use of these TRIPS flexibilities, such as South Africa, Brazil, and Thailand, faced aggressive countermeasures from the pharmaceutical industry and from industry-friendly governments such as the US and the EU.154

Developing nations organized effectively and successfully pushed back against the IP advocates in the 2001 WTO meeting in Doha, Qatar, leading to a ministerial declaration clarifying that the TRIPS Agreement “can and should be interpreted and implemented in a manner supportive of WTO members' right to protect public health and, in particular, to promote access to medicines for all.”155 The Doha Declaration explicitly recognized (p. 955) “that WTO members with insufficient or no manufacturing capacities in the pharmaceutical sector could face difficulties in making effective use of compulsory licensing under the TRIPS Agreement” and instructed the Council for TRIPS “to find an expeditious solution to this problem.”156 The TRIPS Council responded by implementing a temporary waiver of the “domestic market” limitation and proposing a new TRIPS Article 31bis as a formal amendment to the TRIPS Agreement to allow waiver of the “domestic market” limitation on compulsory licensing. The new waiver regime, which entered into force in 2017 after two-thirds of the WTO members accepted it, requires that both the exporting and importing members issue compulsory licenses and requires the exporting country to pay remuneration to the patent holder.157 Despite these and other burdensome provisions, some compulsory licenses have been implemented under this process,158 although compulsory licensing activity appears to have declined in recent years.159

Countries that have used compulsory licensing have drawn sharp criticism from foreign governments as well as retaliatory measures from pharmaceutical firms.160 When Thailand used compulsory licensing to get cheaper access to Abbott’s combination lopinavir/ritonavir antiretroviral product, Abbott withdrew seven pending applications for registration of new medicines from the Thai Food and Drug Administration, temporarily withholding these drugs from patients in Thailand.161 India and Brazil have submitted complaints to the WTO against the EU for seizing shipments of generic drugs in transit from India to other developing countries when they go through customs in European ports, allegedly on suspicion of IP infringement.162 These tactics may have discouraged developing nations from exercising their rights under TRIPS. On the other hand, Australia recently adopted legislation and regulations to authorize domestic drug manufacturers to produce generic drugs for export to countries exercising their compulsory licensing rights.163

The recent decline in compulsory licensing activity may also be due to more restrictive provisions of subsequent regional and bilateral free trade agreements, known as “TRIPS-plus agreements,” which impose additional requirements for IP beyond the minimum (p. 956) requirements of the TRIPS Agreement.164 To the extent that TRIPS-plus agreements negotiated by the US and the EU impose requirements that undo some of the affirmative requirements for flexibility set forth in the TRIPS Agreement, they may contravene the TRIPS Agreement itself, which provides in its introductory principles that:

Members may, but shall not be obliged to, implement in their law more extensive protection than is required by this Agreement, provided that such protection does not contravene the provisions of this Agreement.165

This language plainly contemplates that more extensive protection might sometimes contravene the provisions of the TRIPS Agreement.166

One area in which post-TRIPS agreements curtail the flexibilities of members to protect public health is requirements to provide protection against unfair commercial use or disclosure of confidential data submitted in support of applications for regulatory approval to sell drugs.167 While TRIPS leaves members flexibility to determine when use or disclosure is unfair, subsequent agreements restrict this flexibility and require data protection that provides an additional source of patent-like regulatory exclusivity before competitors may get marketing approval for a generic version of the same drug. These TRIPS-plus requirements arguably contravene the requirements of TRIPS by limiting the ability of members to use compulsory licensing to provide access to drugs to meet public health needs.168

The result is an uneven patchwork of uncertain legal protection around the globe that creates risks for countries that bypass the asserted rights of patent holders in order to promote public health. In countries where a healthcare product is not under patent or covered by regulatory exclusivity, other firms might, in theory, compete to provide it at lower prices, although it may be unclear just what rights are in effect in different countries. Even when they believe their rights are clear, developing countries may lack the political and economic resources to keep up the fight.

On the other hand, there are reasons to be more optimistic about long-term prospects for reconciling the priorities of public health advocates with the goals of IP advocates. Conspicuous controversies have led to more cooperation among the WHO, WTO, and World Intellectual Property Organization to establish priorities and shared goals.169 These collaborations have provided useful resources to help nations understand their rights and (p. 957) obligations.170 At the same time, unprecedented collaborative efforts have brought together public and private resources to pursue innovation to address the health needs of the developing world.171 These alliances offer hope for improved understanding of the relationship between IP, innovation, and public health.

4. Conclusion

Innovation offers the promise of continuing improvements to public health in the face of changing and expanding needs. But innovation is costly, and public health budgets are limited. Private sector innovators have been very effective in securing requirements for provision of legal exclusionary rights for new healthcare products throughout the world in the terms of trade agreements. These exclusionary rights leave important gaps in incentives for public health innovation, requiring other measures to meet public health needs for vaccines, anti-infectives, neglected diseases, and non-excludable innovations. At the same time, exclusionary rights permit innovators to charge higher prices, thereby threatening to limit access to new technologies to the detriment of public health. Although patents eventually expire, permitting access to older technologies at competitive prices, the social costs of delayed access to treatments can be devastating. Public health considerations provide a powerful argument for giving governments flexibility in the implementation of exclusionary rights to new medical technologies.

Notes:

(*) Rebecca S Eisenberg has asserted her moral right to be identified as the author of this contribution. All websites were last accessed in February 2018, unless otherwise specified.

(1) Panel Report, “Canada—Patent Protection of Pharmaceutical Products” WT/DS/114/R (17 March 2000); RC Dreyfuss and C Rodriguez-Garavito, Balancing wealth and health: the battle over intellectual property and access to medicines in Latin America (OUP 2014).

(2) M Kaminski, “The Capture of International Intellectual Property Law Through the U.S. Trade Regime” (2014) 87 Southern California Law Review 977.

(3) WHO Commission on Intellectual Property Rights, Innovation and Public Health, Public health innovation and intellectual property rights (2006).

(4) DJ Hemel and LL Ouellette, “Beyond the Patents-Prizes Debate” (2013) 92 Texas Law Review 303.

(5) W Cohen et al, “Protecting Their Intellectual Assets: Appropriability Conditions and Why U.S. Manufacturing Firms Patent (Or Not)” (2000) NBER Working Paper 7551, 2, 12.

(6) A Kapzcynski and T Syed, “The Continuum of Excludability and the Limits of Patents” (2013) 122 Yale LJ 1900; RE Sachs, “Prizing Reimbursement: Prescription Drug Reimbursement as Innovation Incentive” (2016) 30 Harvard J. Law & Tech 153.

(7) P Lydon, PL Beyai, I Chaudhri, N Cakmak, A Satoulou, and L Dumolard, “Government financing for health and specific national budget lines: The case of vaccines and immunization” (2008) 26(51) Vaccine 6727.

(8) FA Sloan, “The Economics of Vaccines,” in PM Danzon and S Nicholson (eds), The Oxford Handbook of the Economics of the Biopharmaceutical Industry (OUP 2012) 524.

(9) See President’s Council of Advisors on Science and Technology, “Report to the President on Reengineering the Influenza Vaccine Production Enterprise to Meet the Challenges of Pandemic Influenza” <https://obamawhitehouse.archives.gov/sites/default/files/microsites/ostp/Vaccinology-Backgrounder.pdf>, 9–10.

(10) A Kapczynski, “Order Without Intellectual Property Law? A Case Study in Influenza” (2017) 102 Cornell L. Rev. 1539.

(11) WD Bradford and A Mandlich, “Some State Vaccination Laws Contribute to Greater Exemption Rates and Disease Outbreaks in the United States” (2015) 34(8) Health Affairs 1383.

(13) SK Parker, B Schwartz, J Todd, and LK Pickering, “Thimerosal-containing vaccines and autistic spectrum disorder: a critical review of published original data” (2004) 114(3) Pediatrics 793; F DeStefano, CS Price, and ES Weintraub, “Increasing Exposure to Antibody-Stimulating Proteins and Polysaccharides in Vaccines Is Not Associated with Risk of Autism” (2013) 163(2) Journal of Pediatrics 561.

(14) W Parmet, “Pandemics, Populism and the Role of Law in the H1N1 Vaccine Campaign” (2010) 4 St. Louis University Journal of Health Law & Policy 113; JG Hodge Jr and LO Gostin, “School Vaccination Requirements: Historical, Social, and Legal Perspectives” (2001-02) 90 Kentucky Law Journal 831.

(15) The Immunization Action Coalition maintains a summary of vaccine mandates in the United States at <http://www.immunize.org/laws/>.

(16) See Parmet (n 14) 140; Network for Public Health Law (2012) <http://www.networkforphl.org/_asset/80p3y7/MSEHPA-States-Table-022812.pdf>.

(17) Patient Protection and Affordable Care Act, Pub L 111-148, § 1001, 124 Stat 119, 131 (codified as amended at 42 USC 300gg-13 (2010)); see also ibid § 4104, 124 Stat 557 (extending similar benefits to Medicare beneficiaries) and ibid § 4106, 124 Stat 559-60 (codified as amended at 42 USC § 1396d(b)) (providing additional funding to states that agree to provide similar coverage to Medicaid beneficiaries).

(18) Committee on the Evaluation of Vaccine Purchase Financing in the US, Institute of Medicine, “Financing Vaccines in the 21st Century: Assuring Access and Availability 47” (2003).

(19) ibid 116; FA Sloan, “The Economics of Vaccines” in Danzon and Nicholson (n 8) 525.

(20) JA Keith, LA Bigger, PA Arthur, E Maes, and R Daems, “Delivering the promise of the Decade of Vaccines: Opportunities and challenges in the development of high quality new vaccines” (2013) 31S Vaccine 184.

(21) Financing Vaccines (n 18) 111–116; PCAST Influenza Vaccine Report (n 9) 17.

(22) M Kremer and CM Snyder, “Why Are Drugs More Profitable Than Vaccines?” (2003) NBER Working Paper No. 9833 <http://www.nber.org/papers/w9833.pdf>.

(23) Parmet (n 14) 114 (estimating that over 60 million out of 124 million doses of H1N1 vaccine that had been distributed in the United States by January 2010 in anticipation of an influenza were unused, with much of that total destined to be destroyed).

(25) Parmet (n 14).

(26) RE Sachs (n 6) 14; ME Halloran, IM Longini, and CJ Struchiner, Design and Analysis of Vaccine Studies (Springer 2010).

(27) See Food and Drug Administration, “Guidance for Industry: Clinical Data Needed to Support the Licensure of Pandemic Influenza Vaccines” (May 2007) <http://fda.gov/cber/guidelines.htm>.

(28) Parmet (n 14) 130–132.

(29) JB Apolinsky and JA Van Detta, “Rethinking Liability for Vaccine Injury” (2010) Cornell Journal of Law and Public Policy 537, 546–563; Bruesewitz v Wyeth 562 US 223 (2011).

(30) Parmet (n 14) 144.

(31) RS Eisenberg, “Patents and Regulatory Exclusivity” in Danzon and Nicholson (n 8) 167.

(32) RS Eisenberg, “Pharma’s Nonobviousness Problem” (2008) 12 Lewis & Clark Law Review 375.

(33) 35 US Code § 156. The remaining patent life after extension may not exceed 14 years beyond the date of FDA approval. 35 US Code § 156(c), (g)(1)(B), (g)(6). The period of extension includes one-half of the time spent in clinical trials and all of the time between submission and approval of the NDA, 35 US Code § 156(c)(2), reduced by any time attributable to an applicant’s lack of diligence: 35 US Code § 156(c)(1).

(34) Keith et al (n 20) B187; cf M Bregu, SJ Draper, AVS Hill, and BM Greenwood, “Accelerating vaccine development and deployment: Report of a Royal Society satellite meeting” (2011) 366 Philosophical Transactions of the Royal Society B 2841 (“The development of a human vaccine from concept to licensure currently takes at least 15 years.”).

(35) For empirical evidence that firms invest fewer resources in developing pharmaceutical products that require more time to develop, see E Budish, BN Roin, and H Williams, “Do Fixed Patent Terms Distort Innovation?” (2013) Chicago-Booth Research Paper No. 13-79 <http://papers.ssrn.com/sol3/papers.cfm?abstract_id=2353471>.

(36) Pub L No 78-410, 58 Stat 682 (1944), codified as amended at 42 US Code § 201 et seq.

(37) Pub L No 75-717, 52 Stat 1040 (1938), codified as amended at 21 US Code § 301 et seq.

(38) Pub L No 98-417, 98 Stat 1585 (1984), codified as amended at 21 US Code §§ 355, 360cc; 35 US Code §§ 156, 271.

(39) 21 US Code § 355(j).

(40) 21 US Code § 355(j)(2).

(41) 21 US Code § 355(j)(5)(B)(ii).

(42) RS Eisenberg and DA Crane, “Patent Punting: How FDA and Antitrust Courts Undermine the Hatch-Waxman Act to Avoid Dealing with Patents” (2015) 21 Michigan Telecommunications and Technology Law Review 197.

(43) The stay of ANDA approval may be terminated sooner if a court determines that the patent is invalid or not infringed: 21 US Code § 355(j)(5)(B)(ii).

(44) The Biologics Price Competition and Innovation Act of 2009, signed into law as Title VII, Subtitle A, §§ 7001-03 of the Patient Protection and Affordable Care Act, Pub L No 111-148 (HR 3590) (2010), permits the use of an abbreviated pathway for a biological product that is “biosimilar” to a previously licensed biological product after a 12-year period following initial approval of the reference product.

(45) AB Engelberg et al, “Balancing Innovation, Access, & Profits—Market Exclusivity for Biologics” (2009) 361 New England Journal of Medicine 1917; Federal Trade Commission “Authorized Generics: An Interim Report” (2009) <http://www.ftc.gov/os/2009/06/P062105authorizedgenericsreport.pdf>.

(46) H Grabowski, “Follow-on Biologics: Data Exclusivity and the Balance between Innovation and Competition” (2008) 7 Nature Reviews Drug Discovery 479.

(47) An applicant must demonstrate that its product is “biosimilar to a reference product” based upon data derived from analytical studies, animal studies, and one or more clinical studies “that are sufficient to demonstrate safety, purity, and potency” in a use for which the reference product is licensed, unless the FDA determines that one of these elements is unnecessary. Patient Protection and Affordable Care Act (n 37) § 7002 (a)(2), codified at 42 US Code § 262(k)(2)(A)(i), (ii).

(48) A determination of interchangeability requires information showing that the biosimilar product “can be expected to produce the same clinical result as the reference product in any given patient,” and for products administered more than once, that “the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.” ibid codified at 42 US Code § 262(k)(2)(B), (k)(4).

(49) W Kingston, “Antibiotics, Invention and Innovation” (2000) 29 Research Policy 679.

(50) GD Wright and H Poinar, “Antibiotic resistance is ancient: implications for drug discovery” (2012) 20(4) Trends in Microbiology 157; GD Wright, “Antibiotics: A New Hope” (2012) 19 Chemistry & Biology 3.

(51) M Alekshun and SB Levy, “Molecular Mechanisms of Antibacterial Multidrug Resistance” (2007) 128 Cell 1037.

(52) Resistance may also impose costs on the treated individual. For example, a subtherapeutic dosage of an anti-infective agent may fail to cure the infection, leaving the patient with an infection that is more difficult to treat because the surviving microbes are resistant to the previously used treatment. Even effective treatment of an infection may leave the individual with resistant strains of microbes in her system that could migrate to another part of her body where they cause an infection that is resistant to treatment, such as resistant E. coli causing a bladder infection.

(53) K Outterson, “The Vanishing Public Domain: Antibiotic Resistance, Pharmaceutical Innovation and Intellectual Property Law” (2005) 67 University of Pittsburgh Law Review 67.

(54) SE Cosgrove, “The Relationship between Antimicrobial Resistance and Patient Outcomes: Mortality, Length of Hospital Stay, and Health Care Costs” (2006) 42 (Suppl 2) Clinical Infectious Diseases S82, <http://cid.oxfordjournals.org/content/42/Supplement_2/S82.full.pdf+html>.

(55) R Laxminarayan and A Malani, Extending the Cure: Policy responses to the growing threat of antibiotic resistance (Resources for the Future 2007); Infectious Diseases Society of America, “Bad Bugs, No Drugs” (July 2004) <http://www.idsociety.org/uploadedFiles/IDSA/Policy_and_Advocacy/Current_Topics_and_Issues/Advancing_Product_Research_and_Development/Bad_Bugs_No_Drugs/Statements/As%20Antibiotic%20Discovery%20Stagnates%20A%20Public%20Health%20Crisis%20Brews.pdf>; Council of the European Union, “Council Conclusions on innovative incentives for effective antibiotics” (1 December 2009) <http://www.consilium.europa.eu/uedocs/cms_data/docs/pressdata/en/lsa/111608.pdf>.

(56) See, eg, World Health Organization, “Global Action Plan on Antimicrobial Resistance” (2015) <http://apps.who.int/iris/bitstream/10665/193736/1/9789241509763_eng.pdf?ua=1>; US Congress, Office of Technology Assessment, “Impacts of Antibiotic-Resistant Bacteria” OTA-H-629 (US Government Printing Office 1995); DL Heymann, “Resistance to Anti-Infective Drugs and the Threat to Public Health” (2006) 124 Cell 671; C Fox, “Resisting Antibiotic Resistance: Legal Strategies to Maintain Man’s Dominion Over Microbes” (2011) 12 Houston Journal of Health Law & Policy 35.

(57) J Avorn and DH Solomon, “Cultural and Economic Factors That (Mis)Shape Antibiotic Use: The Nonpharmacologic Basis of Therapeutics” (2000) 133 Annals of Internal Medicine 128.

(58) K Outterson, “The Legal Ecology of Resistance: The Role of Antibiotic Resistance in Pharmaceutical Innovation” (2010) 31 Cardozo Law Review 613.

(59) E Kades, “Preserving a Precious Resource: Rationalizing the Use of Antibiotics” (2005) 99 Northwestern University Law Review 611.

(60) ibid 653–659.

(61) B Roin, “Intellectual Property versus Prizes: Reframing the Debate” (2014) 81 University of Chicago Law Review 999; AK Rai, “The Information Revolution Reaches Pharmaceuticals: Balancing Innovation Incentives, Cost and Access in the Post-Genomics Era” (2001) University of Illinois Law Review 173.

(62) B Roin (n 61) 1052–1053.

(63) TRIPS Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) (opened for signature 15 December 1993, entered into force 1 January 1995) 1869 UNTS 299 (hereafter TRIPS) art 31.

(64) Kades (n 59) 657–658.

(65) Outterson (n 53) 87.

(66) AS Kesselheim and K Outterson, “Fighting Antibiotic Resistance: Marrying New Financial Incentives to Meeting Public Health Goals” (2010) 29(9) Health Affairs 1.

(67) K Outterson, “New Business Models for Sustainable Antibiotics” (2014) Centre on Global Health Security Working Group Papers, Working Groups on Antimicrobial Resistance, Paper No. 1, <http://www.chathamhouse.org/sites/files/chathamhouse/public/Research/Global%20Health/0214SustainableAntibiotics.pdf>.

(68) 35 US Code § 156.

(69) Eisenberg (n 31).

(70) 21 US Code § 355(j)(5)(F)(ii).

(71) 42 US Code § 262(k)(7)(A), (B).

(72) Orphan Drug Act of 1983, Pub L No 97-414, 96 Stat 2049, codified as amended at 21 US Code § 527.

(73) 21 US Code § 355a.

(74) This legislation was enacted as Title VIII of the Food and Drug Administration Safety and Innovation Act of 2012, Pub L No 112-144, 126 Stat 993, and is codified at 21 US Code §§ 355, 355f, 356, 360a-1, and 360n-1.

(75) 21 US Code § 355f.

(76) ibid § 360n-1.

(77) ibid § 356.

(78) The Pew Charitable Trusts, “GAIN: How a New Law is Stimulating the Development of Antibiotics” (2013) <http://www.pewtrusts.org/en/research-and-analysis/issue-briefs/2013/11/07/gain-how-a-new-law-is-stimulating-the-development-of-antibiotics>.

(79) President’s Council of Advisors for Science and Technology, “Report to the President on Combating Antibiotic Resistance” (2014).

(80) M Kremer, “Pharmaceuticals and the Developing World” (2002) 16(4) Journal of Economic Perspectives 67.

(81) WHO, “Neglected Tropical Diseases” (2014) <http://www.who.int/neglected_diseases/diseases/en/>.

(82) International Federation of Pharmaceutical Manufacturers & Associations, “Pharmaceutical R&D Projects to Prevent and Control Neglected Conditions” (2014) <http://www.ifpma.org/fileadmin/content/Publication/2015/IFPMA_2014_Status_Report_NTDs_FINAL.pdf>, 5.

(83) M Kremer and R Glennerster, Strong Medicine: Creating Incentives for Pharmaceutical Research on Neglected Diseases (Princeton University Press 2004).

(84) F Mueller-Langer, “Neglected infectious diseases: are push and pull incentive mechanisms suitable for promoting drug development research?” (2013) 8 Health Economics, Policy and Law 185.

(85) S Villa, A Compagni, and MR Reich, “Orphan drug legislation: lessons for neglected tropical diseases” (2008) 24 International Journal of Health Planning and Management 27.

(86) 21 US Code §§ 360aa-360ff. For a summary of other orphan drug laws, see S Villa et al (n 85).

(88) Villa et al (n 85) 33–34.

(89) ibid 34.

(90) A Côté and B Keating, “What is Wrong with Orphan Drug Policies?” (2012) 15 Value in Health 1185; O Wellman-Labadie and Y Zhou, “The U.S. Orphan Drug Act: Rare disease research stimulator or commercial opportunity?” (2010) 95 Health Policy 216.

(91) GF Andersen, “Spurring New Research for Neglected Diseases” (2009) 28(6) Health Affairs 1750 (reporting that as of July 2002 only 12 of 238 market approvals for orphan indications in the United States were for neglected diseases).

(92) This incentive was initially passed as part of the Food and Drug Administration Amendments Act of 2007, Pub L No 110-85, 121 Stat 823, § 1102, codified as amended at 21 US Code § 360n.

(93) DB Ridley, HG Grabowski, and J Moe, “Developing Drugs for Developing Countries” (2006) 25(2) Health Affairs 313.

(94) The statutory list of eligible diseases includes tuberculosis, malaria, blinding trachoma, buruli ulcer, cholera, dengue/dengue haemorrhagic fever, dracunculiasis (guinea-worm disease), fascioliasis, human African trypanosomiasis, leishmaniasis, leprosy, lymphatic filariasis, onchocerciasis, schistosomiasis, soil transmitted helmithiasis, yaws, filoviruses [including Ebola], and any other infectious disease for which there is no significant market in developed nations and that disproportionately affects poor and marginalized populations: 21 US Code § 360n(a)(3).

(95) 21 US Code § 360n(c). For the 2016 fiscal year, the FDA set the fee at $2,727,000: 80 Federal Register 55121–55123 (14 September 2015). This amount is in addition to the standard fee for nonpriority review of a new drug application requiring clinical data, which the FDA has set at $2,374,220 for the 2016 fiscal year: 80 Federal Register 46028–46032 (3 August 2015).

(96) Food and Drug Administration Safety and Innovation Act of 2012 § 908, Pub L No 112-144, 126 Stat 993, 1094–1098, codified as amended at 21 US Code § 360ff.

(97) AS Kesselheim, LR Maggs, and A Sarpatwari, “Experience with the Priority Review Voucher Program for Drug Development” (2015) 314(16) The Journal of the American Medical Association 1687.

(98) T Anderson, “Novartis under fire for accepting new reward for old drug” (2009) 373 Lancet 1414.

(99) 21 US Code § 360n(a)(3)(R).

(100) M Kremer (n 80) 72–73.

(101) M Kremer and H Williams, “Incentivizing Innovation: Adding to the Tool Kit” (2010) 10(1) Innovation Policy and the Economy 1.

(102) O Barder, M Kremer, and H Williams, “Advance Market commitments: A Policy to Stimulate Investment in Vaccines for Neglected Diseases” (2006) Economists’ Voice <http://economics.mit.edu/files/6809>.

(103) A Kapczynski and T Syed, “The Continuum of Excludability and the Limits of Patents” (2013) 122 Yale Law Journal 1900.

(104) Writing Group for the Women’s Health Initiative Investigators, “Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women’s Health Initiative Randomized Controlled Trial” (2002) 288(3) The Journal of the American Medical Association 321; J Graham et al, “Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclooxygenase-2 selective and nonselective non-steroidal anti-inflammatory drugs: nested case-control study” (2005) 365 Lancet 475.

(105) RS Eisenberg and WN Price, “Promoting Healthcare Innovation on the Demand Side” (2017) 4(1) Journal of Law and the Biosciences 3.

(106) Mayo Collaborative Services v Prometheus Laboratories, Inc 566 US 66 (2012).

(107) JE Stiglitz, “Economic Foundations of Intellectual Property Rights” (2008) 57 Duke Law Journal 1693, 1701.

(108) S Scotchmer, Innovation and Incentives (MIT Press 2004) 36–37.

(109) LR Helfer and GW Austin, Human Rights and Intellectual Property: Mapping the Global Interface (CUP 2011) 90–170; AS Godoy, Of Medicines and Markets: Intellectual Property and Human Rights in the Free Trade Era (Stanford University Press 2013). See also the chapter by Laurence Helfer, this volume.

(110) PM Danzon and A Towse, “Differential Pricing for Pharmaceuticals: Reconciling Access, R&D & Patents” (2003) 3 International Journal of Health Care Finance and Economics 183.

(111) BN Roin, “Intellectual Property versus Prizes: Reframing the Debate” (2014) 61 University of Chicago Law Review 999, 1048–1050.

(112) FR Lichtenberg, “Pharmaceutical Companies’ Variation of Drug Prices Within and Among Countries Can Improve Long-Term Social Well-Being” (2011) 30 Health Affairs 1539.

(113) PM Danzon, “Price Discrimination for Pharmaceuticals: Welfare Effects in the US and the EU” (1997) 4 International Journal of the Economics of Business 301; HR Varian, “Price discrimination and social welfare” (1985) 75 American Economic Review 870.

(114) A Towse, E Keuffel, HE Kettler, and DB Ridley, “Drugs and Vaccines for Developing Countries” (2012) in Danzon and Nicholson (n 8) 302.

(115) Rx Assist Patient Assistance Program Center <http://www.rxassist.org/patients>.

(116) Cash & Henderson Drugs v Johnson & Johnson 799 F3d 202 (2nd Circuit 2015).

(117) ER Berndt and JP Newhouse, “Pricing and Reimbursement in US Pharmaceutical Markets” in Danzon and Nicholson (n 8) 201, 220–221.

(118) Lichtenberg (n 112); European Commission, Directorate-General for Trade, “Working Document: Tiered Pricing for Medicines Exported to Developing Countries Measures to Prevent Their Re-Importation into the EC Market and Tariffs in Developing Countries” (22 April 2002) <http://trade.ec.europa.eu/doclib/docs/2005/april/tradoc_122196.pdf>.

(119) “Hard Pills to Swallow” The Economist (New York, 4 January 2014) <http://www.economist.com/node/21592655/print>.

(120) K Outterson, “Pharmaceutical Arbitrage: Balancing Access and Innovation in International Prescription Drug Markets” (2005) 5 Yale Journal of Health Policy, Law, and Ethics 193.

(121) PM Danzon, “Pricing and Reimbursement of Biopharmaceuticals and Medical Devices in the USA” (2014) 3 Encyclopedia of Health Economics 127.

(122) 42 US Code § 1396r-8(c)(1)(B)(i)(VI).

(124) Lexmark International v Impression Products 816 F3d 721 (Federal Circuit 2016), reversed sub nom Impression Products v Lexmark International, 137 S Ct 1523 (2017).

(125) SW Rajec, “Free Trade in Patented Goods: International Exhaustion for Patents” (2014) 29 Berkeley Technology Law Journal 317, 361–367.

(126) Nick Gallus, “The Mystery of Pharmaceutical Parallel Trade and Developing Countries” (2002) 7 The Journal of World Intellectual Property 169.

(127) 137 S Ct 1723 (2017).

(128) DJ Hemel and LL Ouellette, “Trade and Tradeoffs: The Case of International Patent Exhaustion” (2016) 116(17) Columbia Law Review Sidebar <http://papers.ssrn.com/sol3/papers.cfm?abstract_id=2667338>.

(129) DG McNeil Jr, “Curing Hepatitis C, in an Experiment the Size of Egypt” New York Times (New York, 16 December 2015) <http://www.nytimes.com/2015/12/16/health/hepatitis-c-treatment-egypt.html>.

(130) HHS Task Force on Drug Importation, “Report on Prescription Drug Importation” (2004) <http://archive.hhs.gov/importtaskforce/Report1220.pdf>.

(131) ER Berndt and JP Newhouse, “Pricing and Reimbursement in US Pharmaceutical Markets” in Danzon and Nicholson (n 8) 201.

(132) PM Danzon, “Regulation of Price and Reimbursement for Pharmaceuticals” in Danzon and Nicholson (n 8) 266.

(133) D Lakdawalla and N Sood, “Health insurance as a two-part pricing contract” (2013) 102 Journal of Public Economics 1.

(134) PM Danzon, “Pricing and Reimbursement of Biopharmaceuticals and Medical Devices in the USA” (2014) 3 Encyclopedia of Health Economics 127.

(135) OECD, “Pharmaceutical Pricing Policies in a Global Market” (2008) <http://www.oecd.org/els/pharmaceutical-pricing-policies-in-a-global-market.htm>; US Department of Commerce’s International Trade Administration, “Pharmaceutical Price Controls in OECD Countries: Implications for U.S. Consumers, Pricing, Research and Development and Innovation” (2004) <http://trade.gov/td/health/DrugPricingStudy.pdf>.

(136) Danzon (n 131) 276–284.

(138) UNAIDS, “Courting Rights: Case Studies in Litigating the Human Rights of People Living With AIDS” (March 2006) UN Doc UNAIDS/06.01E; S Gloppen, “Litigation as a Strategy to Hold Governments Accountable for Implementing the Right to Health” (2008) 10 Health and Human Rights 21; HV Hogerzeil et al, “Is Access to Essential Medicines as Part of the Fulfillment of the Right to Health Enforceable Through the Courts?” (2006) 368 Lancet 305.

(139) WW Fisher III and CP Rigamonti, “The South Africa AIDS Controversy: A Case Study in Patent Law and Policy” (2005) <http://cyber.law.harvard.edu/people/tfisher/South%20Africa.pdf>.

(140) ibid 6–8.

(141) ibid 8–10.

(142) TRIPS art 27(1).

(143) D Gervais, The TRIPS Agreement: Drafting History and Analysis (2nd edn, OUP 2003) 218–219.

(144) Helfer and Austin (n 109) 119–120.

(145) TRIPS, arts 65, 66.

(146) WTO Council for Trade-Related Aspects of Intellectual Property Rights, “Extension of the Transition Period Under Article 66.1 of the TRIPS Agreement for Least Developed Country Members for Certain Obligations with respect to Pharmaceutical Products” (6 November 2015) <http://docs.wto.org/dol2f3/Pages/SS/directdoc.aspx?filename=q:/IP/C/73.pdf>.

(147) United Nations Department of Economic and Social Affairs, Development Policy and Analysis Division, Committee for Development Policy, “List of Least Developed Countries” (as of 16 February 2016) <http://www.un.org/en/development/desa/policy/cdp/ldc/ldc_list.pdf>.

(148) TRIPS, art 8(1).

(149) ibid art 27(1).

(150) ibid art 27(3)(a).

(151) ibid art 30.

(152) ibid art 6.

(153) ibid art 31(f), (h).

(154) EFM ’t Hoen, The Global Politics of Pharmaceutical Monopoly Power (AMB Publishers 2009) 21–25.

(155) Doha Ministerial Declaration on the TRIPS Agreement and Public Health 20 November 2001 WT/MIN(01)/DEC/2, <www.wto.org/english/thewto_e/minist_e/min01_e/mindecl_trips_e.htm>.

(156) ibid s 6.

(157) FM Abbott and JH Reichman, “Doha Round’s Public Health Legacy: Strategies for the Production and Diffusion of Patented Medicines Under the Amended TRIPS Provisions” (2007) Journal of International Economic Law 921, 940.

(158) Helfer and Austin (n 109) 127–134.

(159) R Beall and R Kuhn, “Trends in Compulsory Licensing of Pharmaceuticals Since the Doha Round: A Database Analysis” (2012) 9(1) PLOS Medicine 1.

(160) AD So and R Sachs, “Making Intellectual Property Work for Global Health” (2012) 53 Harvard International Law Journal 107, 113–114.

(161) K Alcorn, “Abbott to withhold new drugs from Thailand in retaliation for Kaletra compulsory license” (2007) <http://www.aidsmap.com/Abbott-to-withhold-new-drugs-from-Thailand-in-retaliation-for-iKaletrai-compulsory-license/page/1426590/>.

(162) WTO Dispute Settlement 408, European Union and a Member State—Seizure of Generic Drugs in Transit (2010) <http://www.wto.org/english/tratop_e/dispu_e/cases_e/ds408_e.htm>; WTO Dispute Settlement 409, European Union and a Member State—Seizure of Generic Drugs in Transit (2010) <http://www.wto.org/english/tratop_e/dispu_e/cases_e/ds409_e.htm>.

(163) Intellectual Property Laws Amendment Act 2015, <http://www.legislation.gov.au/Details/C2015A00008>; Intellectual Property Legislation Amendment (TRIPS Protocol and Other Measures) Regulation 2015, <http://www.legislation.gov.au/Details/F2015L00852/Html/Text#_Toc419884669>.

(164) CM Ho, “A New World Order for Addressing Patent Rights and Public Health” (2007) 82 Chicago-Kent Law Review 1469, 1495–1505; Abbott and Reichman (n 156) 963.

(165) TRIPS, art 1(1).

(166) GB Dinwoodie and RC Dreyfuss, A Neofederalist Vision of TRIPS (OUP 2012) 150–151.

(167) TRIPS, art 39(3).

(168) CM Correa, “Bilateralism in Intellectual Property: Defeating the WTO System for Access to Medicines” (2004) 36 Case Western Reserve Journal of International Law 79; FM Abbott, “Toward a New Era of Objective Assessment in the Field of TRIPS and Variable Geometry for the Preservation of Multilateralism” (2005) 8 Journal of International Economic Law 77, 89–91.

(169) WHO, WIPO, and WTO, “Promoting Access to Medical Technologies and Innovation: Intersections between public health, intellectual property and trade” (2012); L Pedraza-Farina, “Competition and Coordination in Shared Regulatory Space: WHO, WTO, and Access to Medicines Policies” (2015 draft on file with author).

(170) R Smith et al (eds), “Trade and Health: Towards building a National Strategy” (WHO 2015).

(171) RM Taylor et al, “The Role of Public-Private Partnerships in Health Systems Strengthening: Workshop Summary” (National Academies Press 2016); WHO Department of Control of Neglected Tropical Diseases, “Accelerating Work to Overcome the Global Impact of Neglected Tropical Diseases: A Roadmap for Implementation” (WHO 2012).