How to Rehumanize Clinical Trials: An Antibiotic Perspective

Pharmaceutical drugs are pillars of modern medicine and enshrined in the human right to health. Upholding the right to access such essential medicines requires systems that not only incentivize drug development, but that also audit new drugs for adequate safety and efficacy. In the United States, patent protection is widely recognized as a central incentive mechanism for drug-based innovation, while the Food and Drug Administration (FDA) is tasked with evaluating whether the benefits of new drugs outweigh their risks. For the FDA to approve a new drug, a designated sponsor—often, a large pharmaceutical firm—must conduct clinical trials to demonstrate that the drug is safe for human consumption and effective for a specific purpose.

Amidst a growing antibiotic resistance crisis, current approaches to both patent protection and clinical trial design are failing to adequately support new antibiotic development while upholding the human right to health. This Note argues that pharmaceutical policy proposals aimed at encouraging innovation or protecting human rights need to better consider the differences between pharmaceuticals. Using a health and human rights framework, this Note examines how antibiotic development implicates a specific set of intellectual property rights of drug developers and human rights of clinical trial participants. It then proposes refined perspectives specific to the unique landscape of antibiotic development.

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Introduction

In 1996, a severe epidemic of meningococcal meningitis occurred in Nigeria, with 109,580 reported cases and 11,717 reported deaths.[1] This acute bacterial infection is particularly severe in young children, causing inflammation of the brain and spinal cord membranes.[2] Without immediate antibiotic treatment, meningitis infections can be either fatal or leave infected individuals with permanent brain damage.[3] The meningitis outbreak was especially serious in Kano, with an estimated two-thirds of cases seen in children under the age of sixteen.[4] At the time, chloramphenicol and ceftriaxone (two types of antibiotics) were the standard of care for treating meningococcal disease.[5] Acquiring sufficient drug supplies to treat patients posed a significant challenge,[6] so Doctors Without Borders established a chloramphenicol treatment program at a field hospital in Kano.[7]

In parallel, Pfizer set up a clinical trial in two hundred infected children to test a new antibiotic drug called trovafloxacin (marketed under the brand name Trovan).[8] Prior to the Kano trial, trovafloxacin had not yet been tested in children, and it was only preliminarily tested in adults.[9] The Kano trial was “open label,” meaning that, in theory, the trial participants were not blinded and received information about their treatment.[10] Half of the participating children were given trovafloxacin.[11] The other half were given ceftriaxone as a control.[12] The recommended dose for ceftriaxone to treat meningococcal meningitis in children is between 50 and 100 mg/kg.[13] In Pfizer’s trial, the children in the control group were allegedly given ceftriaxone at 33 mg/kg.[14]

Eleven children in the trovafloxacin trial died.[15] Five had been given trovafloxacin, and six had been given ceftriaxone.[16] Participants in both treatment groups sustained severe side effects, including neurological deficits, hearing and speech impediments, paralysis, and blindness.[17] The data from the clinical trial appeared to indicate that trovafloxacin was safer and more effective than ceftriaxone.[18] Pfizer has claimed that their drug was “at least as effective as the best treatment available.”[19]

In 2000, The Washington Post began investigating Pfizer, accusing the company of carrying out a clinical trial without informed consent from the participants or their parents.[20] Eventually, investigators obtained access to a confidential report prepared by the Nigerian government.[21] The report revealed that the Nigerian government had not granted Pfizer authorization to conduct the trovafloxacin trial.[22] It also showed that there was no evidence the participants or their parents had been informed of the nature of the trial, the types of treatment they would be receiving, or that an alternative antibiotic was proximally available through Doctors Without Borders—despite the “open label” classification.[23] The Nigerian government concluded that Pfizer’s trial violated Nigerian law, the Declaration of Helsinki, and the United Nations Convention on the Rights of the Child.[24] These events triggered decades of litigation, with participants from the trial and their parents filing a series of largely unsuccessful lawsuits in U.S. and Nigerian courts against Pfizer.[25] Eventually, Pfizer settled with Kano State for approximately $75 million.[26]

The tragic events in Kano illustrate the importance of ethical conduct in clinical trials and the complexity of a trial involving antibiotic treatment of a fast-progressing, possibly lethal infection. In general, for a new drug to be approved to treat a disease or condition, researchers will sometimes test that drug in a clinical trial against a “placebo” control: a treatment that will have no impact on the disease or condition being tested.[27] Generally, a placebo-controlled clinical trial is ethically acceptable as long as there is no existing treatment option for that disease or condition.[28] If there is an existing treatment option (e.g., ceftriaxone for meningococcal meningitis), patients in the control group must receive at least the standard of care with that drug.[29] That is, from a bioethics perspective, participants in a clinical trial should not be deprived of an existing, accepted therapy for a disease or condition by virtue of their experimental placement in a control group.[30]

The issue of appropriate control groups and study design is aggravated for clinical trials designed to test new antibiotics, like trovafloxacin in Kano. Although we are now in the midst of an antibiotic resistance crisis,[31] the twentieth century saw a golden era of antibiotic discovery that supplied modern medicine with a considerable array of once-potent antibiotics.[32] Because we have so many antibiotic options—although their efficacy is dwindling—placebo-controlled trials are almost always unethical for clinical investigations of new antibiotics.[33] Participants in clinical trials who have bacterial infections should always be receiving at least the standard of care antibiotic for that infection, regardless of their placement in the control or experimental group.[34] But in Kano, the children in the control group allegedly received 33 mg/kg ceftriaxone—well below the standard of the accepted therapy to treat meningococcal meningitis.[35] Some have since suggested that Pfizer selected such a low dose to demonstrate that trovafloxacin had superior efficacy over the existing standard of care, ceftriaxone.[36] “Superiority” is an implicit requirement of the FDA approval process for many types of pharmaceutical drugs, often including antibiotics.[37]

Many human rights scholars have discussed the ethics of clinical trials, raising issues not only related to placebo controls,[38] but also with informed consent,[39] false or untrustworthy data,[40] a lack of diversity in trial participants,[41] inadequate disclosure,[42] globalization,[43] and more. Indeed, public distrust of pharmaceutical companies is growing,[44] with far too many examples of disturbing research practices.[45] Some have described the clinical trial engine as “the mild torture economy.”[46] However, much of the existing literature on this subject invokes a broad, uniform approach to the critique of clinical trial ethics, sometimes overlooking the nuances of the many different drugs and biological products under FDA evaluation.

This Note explores several ethical issues surrounding drug development and the clinical trial process, arguing that innovation- and ethics-based pharmaceutical policy proposals need to be more narrowly tailored to address differences between pharmaceutical types. Using the unique landscape of antibiotic discovery and development, this Note explains how current approaches and perspectives in both patent protection and the FDA approval process need to be refined to better promote innovation and uphold the human rights of market consumers and trial participants. Part I frames this argument against the history of the FDA; the mechanics of drug development, FDA approval, and clinical trials; the difference between “first-in-class” and “me-too” drugs in the context of antibiotics; and the difference between superiority and non-inferiority clinical studies. Part II analyzes the competing interests of parties to clinical trials: the intellectual property interests and regulatory rights of drug developers and the human rights of market consumers and clinical trial participants. Part III interrogates these issues in the specific setting of antibiotic discovery and development. It then explains how the need to incentivize antibiotic innovation must be balanced against updated perspectives on the rights of antibiotic developers; the merits of me-too drugs; the complexities of antibiotic clinical research; and the construction of efficacy, superiority, and non-inferiority.

I. How Drugs Obtain FDA Approval Through Clinical Trials

To contextualize this Note’s argument, this Part first provides a brief history of the FDA and explains the FDA approval process in the United States. It then defines two main classes of drugs that advance through the approval process, as applied to antibiotics—“first-in-class” drugs compared to “me-too” drugs. Finally, it explains the difference between “superiority” and “non-inferiority” studies to contextualize a common framework in the clinical trial process.

A.      The History of the FDA

The FDA is an agency of the Department of Health and Human Services that regulates drugs, biological products, medical devices, food, cosmetics, and radiation emitting products.[47] The current statute that authorizes the existence of the FDA requires that drugs be “shown to be effective as well as safe.”[48] However, the FDA has not always imposed these two distinct requirements. Rather, these requirements arose as the FDA evolved against a backdrop of new technologies, drug products, and biological knowledge.[49]

An initial form of the FDA originated in 1862 as the Chemical Laboratory subdivision of the U.S. Department of Agriculture.[50] In the years that followed, congressional authorization of the FDA progressed through several statutes. In 1906, Congress passed the original Federal Food and Drugs Act (termed the Pure Food and Drugs Act) to “outlaw[] states from buying and selling food, drinks, and drugs that have been mislabeled and tainted.”[51] Initially, there was no legal requirement, per the FDA or any other regulatory agency, that manufacturers test the safety of new drugs or submit safety evidence prior to public marketing.[52] But in 1937, over one hundred people in the United States were killed by elixir sulfanilamide, a form of the sulfanilamide antibiotic dissolved in diethylene glycol—a poisonous substance.[53] This formulation of sulfanilamide had not been tested for toxicity.[54] In the wake of this disaster, then-commissioner Walter Campbell stated that it was “essential . . . to public welfare that the distribution of highly potent drugs . . . be controlled,” advocating for “an adequate and comprehensive national Food and Drugs Act which will require that all medicines placed upon the market shall be safe to use under the direction for use.”[55] Thus, in 1938, Congress passed the Federal Food, Drug, and Cosmetic Act, which specified that drug manufacturers must submit evidence of the safety of new drugs prior to market entry.[56] The 1938 Act has been described as “one of the most important regulatory statutes in American and perhaps global history.”[57]

In the years after the 1938 Act, the pharmaceutical industry underwent remarkable revolutions, bringing new antibiotics, antipsychotics, steroids, cardiovascular drugs, and other small molecules into circulation.[58] But several drug-related tragedies[59] incentivized the development of good manufacturing practices, voluntary reaction reporting, and eventually, the Kefauver-Harris Drug Amendments of 1962.[60] The Kefauver-Harris Amendments are credited with “la[ying] the groundwork for the phased system of clinical trials” that are now standard practice.[61] Most notably, the Amendments added an efficacy requirement for new drugs—manufacturers were required to prove that their drug worked before the FDA would authorize market entry.[62] Thus, by the 1960s, the two key ingredients of safety and efficacy were enshrined into the FDA approval process.

It is worth noting the evolution of the Kefauver-Harris Amendments to explain two competing perspectives on efficacy that emerged in the mid-twentieth century but continue to impact drug discovery, development, and approval today.[63] One perspective—which Senator Kefauver initially proposed in response to mounting public criticism of costly prescription drugs—is that new drugs should demonstrate a therapeutic effect “significantly greater” than any predecessor drug.[64] That is, Kefauver believed that the regulatory state should assure American consumers that expensive drugs were at least undoubtedly effective, as measured by a comparison to other drugs.[65]

In light of a competing perspective, however, the Kefauver-Harris Amendments as enacted contain a more moderate construction of efficacy—one that does not inherently require a comparison.[66] In response to Kefauver’s proposal, members of the pharmaceutical industry argued that demonstrating comparative efficacy would be “completely impracticable.”[67] Others raised concerns as to the feasibility of an administrative agency conducting a comparative efficacy assessment on a new drug, over medical professionals.[68] To this end, the American Medical Association opined that “the only possible final determination as to the efficacy and ultimate use of a drug [should be] the extensive clinical use of that drug by large numbers of the medical profession over a long period of time.”[69]

Thus, the final Kefauver-Harris Amendments embraced a watered-down, noncomparative form of efficacy: A drug will not obtain FDA approval if “there is a lack of substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use.”[70] Here, “substantial evidence” is defined as “evidence consisting of adequate and well-controlled investigations . . . that allow qualified experts to fairly and responsibly conclude that the drug works for its intended purpose.”[71] The statutory “adequate and well-controlled investigations” requirement is interpreted to mean more than one randomized controlled trial, designed to show that a drug has a clinically meaningful effect.[72]

While the new efficacy standard arguably refined the U.S. pharmaceutical industry, resulting in the removal of six hundred now-ineffective drugs from the market, the Kefauver-Harris Amendments also elongated the drug approval process.[73] For a period of time, new drugs were entering European markets well before U.S. markets, creating a “drug lag” that continued to frustrate consumers.[74] Thus, in 1984, Congress passed the Drug Price Competition and Patent Term Restoration Act (also known as the Hatch-Waxman Act).[75] The 1984 Act expedited the path to market entry for generic drugs (i.e., drugs that have identical active ingredients and activity to approved, brand-name drugs), giving consumers access to certain drugs without approval delays and at relatively reduced costs.[76]

Finally, in 1997, Congress passed the Food and Drug Administration Modernization Act, which promulgated standards for the drug approval process that have persisted into the twenty-first century.[77] The 1997 Modernization Act preserved the 1938 and 1962 requirements of safety and efficacy, while adding provisions specifically tailored towards the speed of the approval process.[78] According to the 1997 Act, a drug is deemed to be “safe” for its intended use if “the benefits of the drug outweigh its risks”[79] and, again, “effective” in treating its target disease or condition if there is “substantial evidence” based on “adequate and well-controlled investigations.”[80]

B.      Basics of Drug Development and FDA Approval in the United States

Establishing the safety and efficacy of drug candidates begins well before the codified “adequate and well-controlled investigations.” When scientists are seeking to develop a new drug to treat a disease or condition, they first identify a set of promising drug candidate “hits” in the lab.[81] During an initial “preclinical” phase of development, researchers will screen these candidates in nonhuman, nonclinical settings, using medicinal chemistry strategies, structure-activity relationship studies, and cellular or animal models of disease.[82] From this early experimental evidence, many promising drug candidates will drop out of the development pipeline due to initial safety and efficacy concerns (e.g., a drug candidate will elicit too many off-target effects or will have inadequate activity against its desired target).[83] “Lead” drug candidates that survive the preclinical stage are then carried through the “clinical” phase of development.[84]

In the United States, the Center for Drug Evaluation and Research (CDER) branch of the FDA regulates the clinical development of pharmaceutical drug products.[85] CDER assesses drugs before they go on the market for consumers, using data from clinical trials to determine whether drugs meet the statutory requirements of safety and efficacy per the 1997 Modernization Act.[86] When drugs successfully complete the CDER evaluation process, they obtain “FDA approval” to be administered to treat certain diseases or conditions.[87] Some drugs are deemed eligible for unique approval routes that accelerate the path to market entry, including fast track (expedited review of drugs designed to “fill an unmet medical need”), breakthrough therapy (expedited review of drugs that “may demonstrate substantial improvement over available therap[ies]”), accelerated approval (expedited review of drugs that “fill[] an unmet medical need . . . based on a surrogate endpoint” that is typically easier to achieve), or priority review (eligible for a target application processing time of six months through the CDER).[88]

A drug typically enters the FDA approval process when a sponsor (e.g., a pharmaceutical company) files an Investigational New Drug Application (IND).[89] In an IND, a sponsor presents the relevant preclinical data for a drug (e.g., how active the drug is in an animal model of the target disease or condition) and proposes a study plan for human experimental testing (e.g., the population of human participants, the dosage to be tested, the relevant endpoints to be monitored, and more).[90] The first stage of clinical trial testing involves Phase I studies, where the safety of a drug is assessed in a group of twenty to one hundred healthy individuals, to determine whether it elicits any impermissible side effects.[91] Then, in Phase II studies, investigators assess the efficacy of a drug in ten to three hundred individuals who have the specific disease or condition that the drug is undergoing development to treat.[92] Phase II studies are primarily conducted to determine whether a drug has any positive impact on a target disease or condition.[93] Secondarily, Phase II studies often aim to investigate dose-responsiveness, that is, to determine an optimal dosing regimen for the drug undergoing testing (i.e., the amount, frequency, and method of administration of the drug).[94] Phase III studies implement similar experimental protocols as Phase II studies, only in hundreds to thousands of participating individuals, to gather additional safety and efficacy data in a larger human population.[95] After the successful completion of a Phase III study, a sponsor will typically file a New Drug Application (NDA), summarizing all of the preclinical and clinical data for a drug.[96] Finally, after drugs are approved, extremely large Phase IV trials may be conducted to continue collecting safety and efficacy data.[97] The design of Phase I, II, III, and IV studies; their target objectives and endpoints; and, occasionally, their preliminary results are made publicly available on ClinicalTrials.gov.[98]

Several key features must be considered when designing a clinical trial that is fair, unbiased, and will appropriately answer the research question of whether drug X is both safe and effective in treating disease Y. In addition to ensuring that sufficient data are collected on the activity of a drug, it is important that the human participants in a clinical trial are adequately protected. Indeed, the FDA identifies a “critical aspect” of its mission to be “[p]rotecting the rights, safety, and welfare of people who participate in clinical trials.”[99] To this end, the features of control groups, randomization, and blinding all comprise “good clinical practice” and are hallmarks of most clinical trials.[100] First, Phase I, II, and III studies are typically designed to include both an experimental group and a control group.[101] The experimental group will typically receive the drug undergoing testing, while the control group will receive either a “placebo” (i.e., a “sham” mimic of the substance given to the experimental group, expected to have no effect on the disease or condition being tested) or an “active comparator” (i.e., an intervention therapeutic that is known to be effective in treating the disease or condition undergoing study).[102] Second, most studies are also randomized, such that subjects are randomly assigned to participate in either the experimental group or the control group.[103] Finally, study participants—and often study assessors—are often blinded to reduce bias, such that the parties involved do not know which study group a subject is a part of.[104]

C.      Antibiotics and the Distinction Between First-in-Class and Me-Too Drugs

The processes described supra are generally applicable to all pharmaceutical classes, including antibiotics.[105] However, antibiotics are unique among pharmaceuticals. First, we are in the grips of an antibiotic resistance crisis, with so many once-potent antibiotics now rendered minimally effective against lethal bacterial infections.[106] A rapid resurgence in new antibiotic discovery and development is the only way to combat this crisis. Second, bacterial infections—the targets of antibiotics—can progress to lethality much faster than many other diseases subject to clinical trials, such as cancer.[107] This means that patients with bacterial infections must be very rapidly triaged, diagnosed, and treated. Third, the current antibiotic market is quite saturated.[108] Although the current resistance crisis begs for new antibiotic innovation, the golden era of antibiotic discovery in the twentieth century rigorously explored chemical scaffolds with antibacterial activity, yielding numerous drug options in this unique market.[109]

This third point, the saturation of the antibiotic market, bears further emphasis, as it raises the problem of “me-too” drugs—a term prevalent in the pharmaceutical literature. Put simply, most drugs can be classified as either “first-in-class” or not (“me-too”). A first-in-class drug is “one[] that use[s] a new and unique mechanism of action for treating a medical condition”—essentially, the first drug that is approved to treat a health condition with a specific type of target.[110] For example, penicillin—one of the world’s first antibiotics—is famously a first-in-class beta-lactam: a type of antibiotic that disrupts cell wall formation to kill bacteria.[111] First-in-class drugs are widely regarded as “truly innovative.”[112] And, to this end, clinical trials for first-in-class drugs can often be placebo-controlled without running afoul of bioethics principles.[113] That is, if there is no accepted therapeutic alternative for the disease or condition being studied (such that a first-in-class drug has been newly discovered), half of the participants in such a trial are assumed to be willing to receive a placebo control, foregoing the possibly effective first-in-class treatment.[114]

Most new antibiotics, however, are not first-in-class drugs. The golden era of antibiotic discovery flooded the market with a wide range of first-in-class antibiotics, occupying several different therapeutic mechanisms of action.[115] In a three-decade span of the 1900s, over twenty new antibiotic classes were discovered and developed.[116] But since then, new antibiotic classes have grown increasingly rare.[117] Many firms began developing analogs within existing antibiotic classes—for example, second- and third-generation beta-lactam antibiotics, iterating around the penicillin scaffold.[118] These types of additional compounds within existing classes are often derisively referred to as me-too drugs.

Me-too drugs are canonically defined as active pharmacological compounds that belong to the same therapeutic class as a first-in-class drug but are chemically and molecularly distinct.[119] Essentially, a first-in-class drug and its me-too counterpart will share a similar mechanism of action and have the same therapeutic purpose—but with different chemical structures and molecular features.[120] As discussed in Part I.A supra, Senator Kefauver was specifically concerned with me-too drugs in his initial proposal for the Kefauver-Harris Amendments. Kefauver initially disavowed drugs that offered mere “molecular modifications” relative to their predecessors.[121] And still today, me-too drugs are often tarnished with branding as “knock-offs” or “copycats” and the suggestion that their developers waited around for a first-in-class drug to be approved, then copied it.[122] However, despite arguments that me-too drugs provide little to no therapeutic benefit, over 60 percent of essential medicines recognized by the World Health Organization (WHO) are me-too drugs.[123] And others have shown that existing me-too drugs help combat shortages in drug supply, often show unexpected pharmacokinetic improvements in treating refined patient subpopulations,[124] are amenable to highly efficacious combination therapies,[125] have lower toxicity or higher target specificity, and reduce healthcare costs by providing price competition and reducing the length of market exclusivity periods for innovator companies.[126] While many antibiotics are me-toos (for example, cephalosporins), other notable pharmaceutical products are as well: for example, Lipitor and Crestor (me-toos of first-generation statins)[127] and Spikevax (Moderna’s SARS-CoV-2 vaccine; a me-too of Pfizer’s Comirnaty).[128] As Part III.B infra discusses further, the current criticism of me-too drugs is likely misguided—in particular, for the unique case of antibiotics.

Putting this contentious background aside, me-too drugs are in a difficult position in front of the FDA. Unlike first-in-class drugs, me-too drugs are not ethically eligible for placebo-controlled trials.[129] By definition, there is already an accepted therapeutic alternative for the disease or condition that a me-too drug is designed to test.[130] Thus, me-too drugs typically need to demonstrate adequate efficacy compared to treatment with an active comparator (e.g., the first-in-class drug for that disease or condition). And in these trials, me-too drugs must sometimes show superiority to the existing first-in-class drug (i.e., that the me-too drug is more effective than the first-in-class drug), rather than non-inferiority (i.e., that the me-too drug is “not materially worse” than the first-in-class drug).[131] This standard presents a considerable regulatory hurdle for drug developers. While existing me-too drugs are known to offer therapeutic advantages including “improved target specificity, reduced risk of off-target adverse reactions and drug-drug interactions, increased chance of benefit in some patients, and improved drug delivery and pharmacokinetics,”[132] these advantages often do not rise to the level of superior efficacy detectable in conventional trial designs.

D.     Superiority and Non-Inferiority Studies

As discussed in Part I.A supra, new drugs must demonstrate effectiveness in “adequate and well-controlled” studies (i.e., clinical trials) to receive FDA approval.[133] An inherent requirement of these studies is an experimental control group and the use of statistical comparisons to prove, essentially, that new drug X should be approved to treat condition Y.[134] While there are many different trial designs available, the FDA describes four main types: (1) showing that a drug is superior to a placebo control; (2) showing that a drug is superior to a no treatment control; (3) showing that a drug exhibits dose-responsiveness (i.e., a drug at one dose is superior to itself at a lower dose); (4) showing that a drug is superior to or not inferior to an active comparator.[135] Within these four trial design types, there are two distinct forms of comparison: superiority and non-inferiority.

Superiority studies require that a drug undergoing testing demonstrates measurably superior efficacy compared to a control—essentially showing that the new drug is better than a placebo, no treatment, a lower dose, or an active comparator preexisting drug.[136] Non-inferiority studies require that a drug undergoing testing has similar, not worsened, efficacy, compared to a previously approved drug (never a placebo)—that is, the new drug is “not [unacceptably or] materially worse” than a predecessor drug.[137] In these cases, non-inferior efficacy of the new drug is often accompanied by nonefficacy benefits.[138] Although there are no bright-line rules here, some advantages that might be captured by a non-inferiority (but not superiority) comparison include improved safety, fewer side effects, easier administration, or lower cost.[139] Non-inferiority trial designs are typically less common than superiority designs, but may be allowed by the FDA when a superiority design would be unethical (i.e., a placebo control is inappropriate) and it is otherwise not feasible to prove superiority against an active comparator.[140] Ultimately, however, even in cases where an active comparator is the only ethically appropriate control group, the gold standard—for both the FDA and prescribing clinicians—is typically superiority.[141]

Much like me-too drugs, many have heavily criticized non-inferiority studies, with some even arguing that such trials should never be conducted.[142] Indeed, non-inferiority trials are complex in design and often hard for audiences to interpret—what does it mean to be “not worse” in comparison?[143] Intuitively, patients and physicians are less likely to be compelled by a new drug that is only “not unacceptably worse” than an old drug, perhaps even preferring an older drug that at least has a longer track record of medical use. And non-inferiority studies rely on an assumption that the active comparator had its expected effect in the trial, while superiority studies typically can stand on their own and can be interpreted without any additional assumptions.[144] Part III.C infra discusses the application of non-inferiority studies in an antibiotic context and further explores this unique type of trial from a feasibility and ethical standpoint.

II. The Intellectual Property and Human Rights of Parties to Clinical Trials

The result of a successful clinical trial is, hopefully, a drug with a meaningful therapeutic effect against a disease or condition. Access to potentially lifesaving essential medicines is within the universal right to health.[145] But the clinical development process is complex. It implicates a wide range of intellectual property and human rights, stretching beyond only the fundamental right to access essential medicines. And as discussed supra, drugs must meet standards of safety and efficacy that are rooted in the history and evolution of the pharmaceutical industry, and further complicated by the realities of market competition and exclusivity. Thus, before this Note turns to where reform might be needed for the unique case of antibiotics, this Part applies a health and human rights framework to analyze the interplay of rights at stake during a clinical trial. The three Sections herein describe: (1) the intellectual property and regulatory rights of drug developers; (2) the human rights of market consumers; (3) the human rights of trial participants.

A.      Drug Developers, Patent Protection, and Market Exclusivity

A drug developer is a key party to every clinical trial and is eligible for both intellectual property protection and regulatory exclusivity as an inventor of a new drug. As discussed in Part I.B supra, drug development can be viewed as having two phases: preclinical and clinical—both of which come with distinct types of intellectual property protection. To adequately support new drug development, (i) innovation must initially be encouraged during the preclinical discovery stage (ostensibly via patent protection); then, (ii) drug approval must be regulated through the clinical development stage (accompanied by market exclusivity). Providing drug developers with a reward in the form of intellectual property protection is widely understood as necessary given the cost of drug development. From preclinical discovery to the clinical trial process, drug development is extraordinarily expensive, often necessitating the participation of large pharmaceutical firms with access to significant capital.[146] This Section elaborates on both patent protection and market exclusivity as two key parts of the clinical trial pipeline.

First, innovators have the right to seek and obtain patent protection over new drugs. A patent is a legal document issued to an inventor, conferring the right to exclude others from making, using, selling, importing, or offering to sell an invention for twenty years from the date the patent application was first filed.[147] Essentially, a patent grants a deserving applicant a temporary monopoly on an invention. In the United States, inventors submit patent applications to the Patent and Trademark Office (USPTO), laying out the scope of their inventions in the form of enumerated claims.[148] Inventions that meet several statutory criteria are deemed eligible for patent protection: The invention must comprise eligible subject matter,[149] and it must also be useful,[150] novel,[151] non-obvious,[152] enabled,[153] and adequately described.[154]

There are many different types of pharmaceutical claiming strategies. For example, patent claims might be directed to pharmaceutical compositions (e.g., new chemical structures or active ingredients with new modes of activity), chemical variations of those compositions (e.g., polymorphs or isomers), formulations of those compositions (e.g., topical forms, tablets, capsules, etc.), or methods of treating using those compositions (e.g., the use of a new drug as a therapeutic for a yet-untreated disease or condition).[155] This system is regulated by the USPTO and not the FDA. Critically, the grant of a patent does not give a sponsoring drug developer the ability to enter the market with its drug product—only a negative, exclusionary right to prevent others from making, using, or selling the patented drug product.[156]

The patent system in the United States exists to “promote the progress of science and the useful [a]rts.”[157] The granting of a patent right allows an inventor to exclude others from practicing their invention, for a limited time, as a reward for contributing that invention to society. Limited monopoly rights in the form of patent protection allow inventors to commercialize their inventions and recoup initial investment costs.[158] And in the context of pharmaceuticals—which are particularly challenging to discover, develop, and finance[159]—patent protection is embraced as an essential first step to incentivize development and market entry.[160] Many economic studies have suggested that patents are critical for pharmaceutical innovation, with the pharmaceutical industry placing a heightened emphasis on patent protection relative to other research-driven industries.[161] Again, the importance of patent protection for pharmaceuticals is a direct consequence of the “several hundred million dollars [it takes] to discover, develop, and gain regulatory approval for a new medicine.”[162] So, in theory, patents are initially essential for drug developers to recoup high research and development costs with monopoly pricing; then once those patents expire, competition from generic drugs theoretically drives down drug prices to increase access.[163]

In the drug discovery and development pipeline, patent protection is often followed by a secondary form of exclusivity, conferred by FDA approval. Not only do drug developers have the right to obtain patent protection, and resulting exclusivity, for pharmaceutical products—they also have the right to obtain market exclusivity as a byproduct of the clinical trial process. Drug developers often submit provisional patent applications shortly before, or parallel to, submitting INDs to the FDA and are granted patent protection at some point during early-stage clinical trials.[164] Therefore, the lengthy FDA approval process often overlaps with a significant portion of the twenty-year patent term.[165] Put differently, inventors often have only six to ten years of patent protection left by the time the FDA grants approval for the patented drug.[166] And if drug developers are unable to begin marketing new drugs until well within their twenty-year patent terms, they may be unable to sufficiently recoup the substantial costs of the clinical trial process. To ameliorate this term issue, the FDA attaches another form of exclusivity to drugs at the moment that they obtain approval, adding an additional temporal dimension to the initial patent monopoly.[167] This form of exclusivity through the FDA (also known as “regulatory” or “data” exclusivity) temporarily restricts the market entry of comparator generic or me-too drugs, further protecting the developers of innovator first-in-class drugs.[168] Market exclusivity is viewed as “a key element of commercial success in the drug industry.”[169]

The FDA offers several different types and time periods of exclusivity, depending on the approved drug[170]: for example, seven years for orphan drugs (drugs to treat rare diseases or conditions[171]), five years for New Chemical Entities (drugs that “contain[] no active moiety that has been [previously] approved by [the] FDA”[172]), five years for new antibiotics (termed “Generating Antibiotics Incentives Now (GAIN) Exclusivity”[173]), and three years for drugs resulting from New Clinical Investigations (clinical trials that have not yet been assessed by the FDA to show efficacy of previously approved drugs[174]). These market exclusivity periods function to further incentivize investment in drug development.[175] Considering both patent protection and market exclusivity, some have estimated that drug manufacturers enjoy a twelve- to sixteen-year window of monopoly pricing and protection from market entry of generic and me-too medicines.[176]

B.      Market Consumers and the Right to Access Affordable Essential Medicines

On the other hand, another party to every clinical trial is the end user of the to-be-approved drug product. Market consumers factor into this process with the human right to access essential medicines, codified in several sources. For example, the Universal Declaration of Human Rights (UDHR) recognizes “the right to a standard of living adequate for . . . health and well-being . . . including medical care.”[177] Further, the International Covenant on Economic, Social and Cultural Rights (ICESCR) recognizes “the right of everyone to the enjoyment of the highest attainable standard of physical and mental health.”[178] Comments interpreting the ICESCR specify an obligation for states to “provide essential drugs, as from time to time defined under the WHO Action Program[] on Essential Drugs” to satisfy this human right.[179] More specifically, the WHO Action Program provides a list of “essential medicines” that must “be available within the context of functioning health systems at all times, in adequate amounts, in the appropriate dosage forms, of assured quality, and at prices that individuals and the community can afford.”[180] To summarize: These provisions, together, describe the human right to health as inclusive of market consumers’ ability to access essential medicines at affordable prices.

Despite the importance of adequate drug access as a human right, drug prices have skyrocketed to unsustainable levels. The United States is experiencing a drug pricing crisis, with an approximate $350 billion spent on drugs in 2020 alone.[181] Countless Americans are unable to afford prescription drugs, with many shunning the pharmaceutical industry as contributing to this problem.[182] Indeed, one recent report indicated that “[t]hree out of four American adults say prescription drug prices are unaffordable, and nearly a third admit to not taking prescribed medications due to cost.”[183] While many have proposed solutions to remedy drug access in the United States, factors such as decentralized regulation of the pharmaceutical industry, uncontrolled pricing, misaligned incentives, and complex health insurance schemes make it challenging to address this issue.[184]

In reflecting on the current drug pricing crisis in the context of clinical trials, it is imperative to consider the system of dual patent protection and market exclusivity, as discussed in Part II.A supra. As for patent protection—most of the drugs on the WHO’s essential medicines list are not patent protected and are relatively inexpensive.[185] But those drugs that are still within their patent terms are often exceptionally expensive due to the possibility of monopoly pricing.[186] These artificially inflated prices are unsustainable for many and reduce global access to essential medicines in violation of basic human rights.[187] For example, although generic manufacturers have now produced affordable copies of first-line HIV therapeutics, newer second- and third-line antiretrovirals remain under patent protection and are “prohibitively expensive” for many.[188] Multiple studies have demonstrated that patent monopolies on pharmaceutical drugs lead to increased costs and shortages for consumers and governments.[189] Thus, while patent rights of drug developers are certainly necessary to incentivize the development of essential medicines, those same patent rights can often also oppose the consumer right to access those essential medicines.

As for market exclusivity—although this concept is anchored in the need to offset regulatory delays that negate the benefits of patent protection, some have criticized the somewhat redundant nature of two layers of exclusivity as antagonizing drug access.[190] As discussed in Part I.A supra, the Hatch-Waxman Act exists in part to encourage the expedited market entry of generic drugs that ideally increase competition and prevent a prolonged pursuit of monopoly pricing by innovators.[191] The possible twelve- to sixteen-year window may result in too long of a delay for generics, and too much protection for patented brand-name drugs—perhaps even more than is necessary for innovator companies to recoup their initial investments.[192]

Overall, striking the right balance between intellectual property protection and drug affordability and access is a complex and delicate issue, and likely differs across classes of drugs, diseases, and conditions.[193] This Note does not at all purport to solve this problem at a macro level. It is exceptionally challenging—financially and otherwise—to shepherd new drugs through preclinical and clinical development. Indeed, one report estimated that approximately one in five thousand to ten thousand researched drugs obtain FDA approval, and that the approval process typically costs $3 billion and takes over a decade.[194] Part III.B infra proposes some refined perspectives on this issue in the context of antibiotic development.

C.      Clinical Trial Participants and the Rights to Bodily Integrity and Informed Consent

The participants comprise another crucial party to a clinical trial. Drug developers must conduct clinical research on trial participants to avoid the disasters of the past—elixir sulfanilamide, sulfathiazole, chloramphenicol, thalidomide, and more.[195] But testing new drugs on human subjects comes with unavoidable risks.[196] Indeed, from a strictly ethical standpoint, clinical trials are inherently morally ambiguous. Trial participants, whether healthy or sick, incur significant risk when consuming unknown drug products. And in a subset of placebo-controlled clinical trials, sick participants might be required to forgo a possibly useful treatment by virtue of their placement in the placebo group. This Section details some key human rights issues that drug sponsors and the FDA must consider when designing trials, selecting sites, and proposing study protocols.

As a threshold issue, clinical trials ask for an enormous investment on the part of trial participants. There are two main categories of participants: healthy individuals who participate in Phase I trials to collect data on drug safety, and individuals with the disease or condition undergoing testing who participate in Phase II, III, or IV trials. Healthy participants run the risk of exposure to a drug with yet-unknown, horrific side effects. For example, in 2006, a now-famous Phase I study of theralizumab (an anti-CD28 monoclonal antibody) triggered multisystem organ failure in six otherwise healthy trial participants.[197] On the other hand, individuals with the disease or condition undergoing testing might be hopeful that they will receive the possibly effective experimental drug but instead be given a placebo as part of the control group. Alternatively, these individuals may indeed receive the experimental drug, but it may have no effect—or, worse, have disease-worsening consequences. Bioethicists have recognized that modern-day trial participants engage in almost entirely altruistic behavior in choosing to expose themselves to the risks of experimental medicine in exchange for the possible outcome of understanding drug safety and efficacy.[198]

The altruistic investment on the part of trial participants both (i) implicates the human right to bodily integrity and to informed consent and (ii) obliges drug sponsors and the FDA to uphold ethical principles in trial design. As for the human rights at stake, the UDHR recognizes that “[n]o one shall be subjected to torture or to cruel, inhuman or degrading treatment” (bodily integrity).[199] The International Covenant on Civil and Political Rights (ICCPR) specifies that “no one shall be subjected without [their] free consent to medical or scientific experimentation” (informed consent).[200] The Nuremberg Code further elaborates on the importance of informed consent, requiring “voluntary consent of the human subject” wherein the subject has “the legal capacity to give consent . . . [and is] situated as to be able to exercise free power of choice, without intervention . . . and [has] sufficient knowledge and comprehension of the elements of the subject matter involved as to enable [them] to make an understanding and enlightened decision.”[201] Relatedly, the Declaration of Helsinki states that the “interest[s] of science and society should never take precedence over considerations related to the wellbeing of the subject.”[202] And finally, the Belmont Report endorses “beneficence, justice, and respect for persons” as basic principles for biomedical research.[203]

As for the obligation of drug sponsors and the FDA to uphold these human rights, recent practices in clinical research increasingly suggest failures on this front. The Kano trovafloxacin trial, for example, represents a complete failure to uphold the principles of both informed consent and bodily integrity.[204] The participants were not informed of the nature of the trial, and the deliberate low-dose control left several participants with lifelong injuries and killed others.[205] More recently, the actions of SFBC International called into question the validity of informed consent by trial participants who are receiving payment in exchange for participation. While a payment scheme is not uncommon for otherwise healthy individuals who volunteer for Phase I clinical trials, there is a high risk of coercion when payments are excessive.[206] SFBC International operated a clinical trial center in Miami that recruited undocumented immigrants and paid them to take part in Phase I clinical trials in a motel, possibly “overseen by an unlicensed medical director.”[207] The company also allegedly threatened to deport individuals who disclosed any health risks that arose during these clinical trials.[208] Similarly, it was discovered that the pharmaceutical company Eli Lilly specifically recruited unhoused individuals to participate in clinical trials in Indianapolis.[209] These events illustrate more recent instances of clinical research shirking the notion of informed consent.[210] Carl Elliott, a physician and professor focused on clinical trial ethics,[211] has stated that “[f]ew people realize how little oversight the federal government provides for the protection of subjects in privately sponsored studies.”[212]

Given the challenges of ensuring adequate regulatory oversight, the recent trend towards globalization of clinical research poses yet another risk to the human rights of trial participants. It is even more complex for the FDA to monitor clinical trials taking place outside of the United States, where there may be economically disadvantaged populations with a high susceptibility to exploitation.[213] Historically, drugs have obtained FDA approval based on clinical trials conducted in North America, Western Europe, and Oceania.[214] More recently, however, clinical research has shifted into regions of Eastern Europe, Latin America, Asia, the Middle East, and Africa.[215] Expansion into these areas has allowed drug sponsors to expand and expedite participant recruitment without incurring increased trial costs.[216] Clinical researchers have recognized that certain global sites often have “large, untested research populations who readily volunteer their involvement in clinical trials.”[217] Indeed, sometimes, it is only feasible to test a new drug in a clinical trial outside of the United States, given the rarity of some diseases in North America.[218] For example, while it is globally beneficial to discover and develop functional anti-malarial drugs, there are not enough patients with malaria in the United States to run a clinical trial to test new anti-malarial drugs.[219]

The concern here, however, is that the concept of informed consent is once again susceptible to erosion in global clinical trials. For many patients outside of the United States, participation in a clinical trial may be the only route to accessing health care.[220] And these patients might be more willing to forego a standard of care treatment option if mandated by the design of a clinical trial—even if that standard of care would be an obvious requirement in an equivalent trial taking place in the United States.[221] Thus, clinical trials in Eastern Europe and Africa have sounded warning bells to bioethicists, who are increasingly concerned about exploitative conduct on the part of drug sponsors.[222] And in the past, sponsors have skirted ethical standards and conducted placebo-controlled trials outside of the United States in situations where an active comparator was available (i.e., half of the trial participants were given a placebo instead of an available therapeutic option).[223] For example, in the 1990s, a series of clinical trials were conducted in Africa on HIV-positive individuals to test new alternatives to zidovudine, against a placebo control, rather than a zidovudine active comparator control.[224] With the Declaration of Helsinki proposing that trial participants in research should be entitled to a baseline “standard of care,” the unfair organization of a clinical trial as a placebo-controlled study when there is an acceptable treatment alternative that already exists (e.g., zidovudine) directly infringes the human right to health.[225]

Fundamentally, clinical trials are necessary to interrogate drug efficacy and safety, for the benefit of the general public, yet run the risk of ethical infractions against trial participants.[226] Trials that do not run afoul of the right to bodily integrity and to informed consent are certainly more ethically palatable. However, as discussed in this Section, the realities of participant compensation and increasing globalization have historically threatened these rights. Moreover, it is challenging to propose solutions that adequately consider the inherent differences between the many drugs and conditions currently under clinical study. To this end, Part III.C infra more narrowly focuses on these issues within the setting of antibiotic discovery and development.

III. An Antibiotic Perspective on Incentivization and Ethics in the Clinical Trial Process

Much has been written about how to best foster drug discovery and development, the reasons for and possible solutions to the drug pricing crisis, and the ethical and human rights issues surrounding clinical research. More specifically, many have argued for reform in a variety of FDA approval areas, with an emphasis on adapting to new technologies, ensuring fair subject selection, and reevaluating the ethics of placebo-controlled trials.[227] This Note applies the issues discussed in Part II in an antibiotic setting, considering: (1) the importance of incentivizing drug developer investment in antibiotic research amidst a complex and costly regulatory landscape; (2) the need to balance developer incentives against the consumer right to access essential antibiotics; and (3) the unique regulatory and ethical challenges of antibiotic-based clinical trials.

A.      Incentivizing Antibiotic Innovation

As discussed in Part II.A supra, patent protection and market exclusivity are critical components of the clinical approval process and play an important role in incentivizing drug discovery and development. For antibiotics, it is particularly important to provide incentives for new development, which is the only route to overcoming the current resistance crisis. However, it is crucial to consider how these patent and regulatory-based incentives impact the human rights discussed herein—the rights to access essential medicines, to bodily integrity, and to informed consent in clinical trial settings. This Section begins this analysis by describing the landscape of antibiotic patents and market exclusivity.

First, to be clear, antibiotic resistance is a problem because when bacteria cease to respond to existing antibiotic options, once-treatable bacterial infections become recalcitrant to treatment and possibly lethal.[228] And, to reiterate, antibiotic resistance is reaching unsustainable levels around the world.[229] Antibiotic resistance has been estimated to directly kill approximately 1.3 million people every year.[230] This health crisis has encouraged several research efforts dedicated to discovering and developing new antibiotics and nontraditional antibiotic alternatives.[231] However, current efforts are inadequate.[232] In June 2024, the WHO released an updated overview of recently approved antibiotics,[233] reporting that only thirteen new antibiotics had obtained market approval since 2017.[234] Only two of these new drugs represent new antibiotic classes (i.e., only two are first-in-class drugs).[235] And among all antibiotics under development currently, only four are active against at least one type of bacteria designated “critical” by the WHO.[236]

How, then, can greater antibiotic innovation be incentivized? World leaders and policymakers have continuously emphasized how important it is to address the dwindling antibiotic pipeline, to avoid a reversion into an era where basic surgeries are fatal due to a risk of bacterial infection.[237] But interest in new antibiotic discovery has been waning, with a decrease in antibiotic research output over the past several years.[238] Large pharmaceutical firms have been increasingly abandoning antibiotic programs in favor of other endeavors, citing a lack of profitability.[239] Some have proposed that governments and the private sector need to step in and provide financial and nonfinancial incentives to repair the market for antibiotics.[240] Many are in favor of both “push” incentives (financial, tax, and technical incentives aimed at decreasing antibiotic development costs) and “pull” incentives (mechanisms of rewarding new antibiotics by increasing market revenue).[241] One proposal, amongst pull incentives, focuses on patent term extensions.[242]

The waning antibiotic pipeline is on display in the patent landscape. In 2022, twenty times more patents were awarded for cancer drugs than antibiotics.[243] Thus, many have suggested patent-based incentives as a route to reviving antibiotic development.[244] The main proposal here is that patent terms should be elongated for antibiotics, so that antibiotic developers can enjoy a longer period of exclusivity and therefore reap greater profits on antibiotics.[245] Indeed, in theory, the possibility for greater profits may re-motivate large pharmaceutical firms towards antibiotic discovery.[246]

Regulatory challenges are also often blamed for the reduction in antibiotic development. In an attempt to address this issue, following the GAIN Act of 2012, the FDA now awards an additional five years of market exclusivity to antibiotics that are newly approved to treat priority infections.[247] However, the efficacy of this regulatory initiative is questionable, given the low number of antibiotics approved under the GAIN Act.[248]

B.      Balancing Developer Incentives Against Consumer Access: Profits and Me-Too Drugs

While many are proposing push-pull incentives to motivate antibiotic development and attract large firm investment, others are fearful that bolstering the economic rights of developers will come at the cost of access to consumers. Intellectual property and regulatory rights may indeed incentivize pharmaceutical industry engagement in antibiotic development. But if these incentives inflate drug prices, then the consumer right to access essential medicines at affordable prices is antagonized. Overall, policymakers must work towards striking an appropriate balance between these two ends. In doing so, however, they must be cautious of legal and regulatory recommendations that apply to simply “pharmaceuticals,” without paying mind to the vast differences between types of drugs. This Section explains two key issues that are specific to antibiotics, to illustrate this point.

First, new antibiotics are fundamentally less profitable than other pharmaceuticals; therefore, at least one incentivization scheme, whether patent protection, market exclusivity, or something else, is financially necessary to motivate antibiotic developers. Recommendations to enhance pharmaceutical patent protection or prolong market exclusivity are often met with concerns about drug pricing—and rightly so.[249] However, antibiotics are unique among drugs. When a new antibiotic is developed—especially a first-in-class antibiotic—it is treated as a last resort to prevent antibiotic overuse and the evolution of resistance.[250] That is, antimicrobial stewardship guidelines necessitate that a newly discovered antibiotic be rarely prescribed and only reserved for infections that are not responding to other treatment options. Worse yet, there is evidence that physicians often favor older generic antibiotics over newer options, even when those generics have diminished efficacy.[251] Because of this, antibiotic developers invariably fail to recover sufficient profit on new antibiotic candidates.[252] Given these poor financial incentives, it may be true that enhancing either patent protection, market exclusivity, or both is the only realistic way to foster new antibiotic innovation. But, to remain aligned with the need to maintain antibiotic affordability and accessibility, it may be worth turning away from the patent system and towards public funding schemes. For example, antibiotic developers might be best compensated through government-based initiatives, in a manner linked to value (considering drug resistance) rather than prescriptions and sales. An example of this model—the Pasteur Act[253]—has been introduced multiple times but remains unpassed.[254]

Second, we already have several classes of antibiotics—notwithstanding their currently diminished efficacy—meaning that it is shortsighted to not reward developers of me-too antibiotics. There are only so many druggable bacterial targets, and me-too antibiotics are simply more likely to be discovered than first-in-class ones. Given the saturation in the antibiotic market, it is not realistic to expect that developers will constantly hit upon the first-in-class standard that many consider the gold-standard of innovation.[255] And, although it is of course desirable to find more first-in-class antibiotics, expanding the list of me-too alternatives is not without merit. The literature in this area tends to frown upon the incremental innovation of me-too drugs, extolling the virtues of new classes and mechanisms of action in broad strokes.[256] But, when faced with the acute evolution of drug resistance and the rapid growth and spread of bacterial infections, it is valuable to have several different treatment options that iterate around existing antibiotic scaffolds.[257] Supplying drug classes with a diverse array of molecules (necessarily including me-toos) is a known, valuable approach against the omnipresent threat of drug resistance.[258]

Further to this point, adopting a more favorable perspective on me-too drugs in the context of antibiotic development might help in striking a more optimal balance between antibiotic patent protection and drug pricing. Me-too drugs are eligible for patent protection—a point that many criticize.[259] But the market entry of me-too drugs as competitors to first-in-class drugs may provide competition that could ameliorate issues in drug pricing—despite patent protection over both.[260] To this end, some research has shown that me-too drugs are introduced at reduced prices relative to their first-in-class counterparts, with the price differential impacted by the length of time between the market entry of the first-in-class drug and the me-too drug.[261] Other data suggest that when me-too drugs are launched sooner after first-in-class drugs (i.e., within a few years), they are “cost saving” for payers.[262] One estimate indicated that increasing from one to five patented, brand-name drugs in a class (i.e., a first-in-class drug and four me-toos) results in a 10 percent increase in the “best price discount.”[263] Taken together, these reports suggest that incentivizing the development of me-too drugs may drive down drug prices, while still granting valuable patent protection to me-too developers. Ultimately, amidst valid arguments from both critics and proponents, regulators would do well to at least recognize the possible merits of me-too drugs in an antibiotic context, considering a need for chemical diversity, treatment of resistant patient subpopulations, and drug affordability.

C.      Reframing Efficacy and Non-Inferiority for Antibiotics

Of course, antibiotics—patented, me-too, or otherwise—cannot exist without clinical trial participants. Regulatory challenges are a main impediment to robust and ethical antibiotic development, discouraging pharmaceutical firms from investing in this area.[264] As discussed in Part II.C supra, it is imperative that clinical trials interrogate drug efficacy and safety without infringing the human rights of trial participants. Ultimately, clinical trials must be carefully designed and rigorously monitored on a case-by-case basis, with an eye to the nuances of the new drug being tested, and the condition that the drug is being tested against. This Section explores some ethical issues unique to antibiotic-based clinical trials and discusses a reconstructed notion of efficacy and non-inferiority to address some of these problems.

First, antibiotic trials are more challenging than other drug trials because bacterial infections can progress to lethality much faster than other diseases.[265] This seriously complicates the design of clinical trials to study new antibiotics, because patients need to be diagnosed and treated very rapidly.[266] One major issue here is the selection of an appropriate control group in an antibiotic-based clinical trial.[267] Ethically, as a matter of the right to bodily integrity, all trial participants must have access to at least a control antibiotic with known efficacy.[268] For example, if an antibiotic-based trial is being conducted to assess new treatment options for an antibiotic-resistant infection, the trial researchers must attempt to treat the control patients to the best of their abilities, potentially even with creative combinations of existing antibiotics.[269] Even more complex is the ever-present tension between the need for clinicians to adhere to antimicrobial stewardship guidelines—and not overly prescribe antibiotics, nor overly encourage patient enrollment in antibiotic trials at risk of promoting resistance evolution—and the right for patients to access medical treatments when necessary.[270] These issues make antibiotic trials especially complex, suggesting that the FDA needs to do more by way of (1) regulatory oversight in the case of new antibiotics undergoing investigation, and (2) customization to provide antibiotic developers with unique approval pathways that are sensitive to these additional challenges.

Second, it is often very challenging to find a sufficient patient population to carry out an antibiotic trial in the United States,[271] triggering the problems with globalized clinical research discussed in Part II.C supra. For example, a clinical trial for a new antibiotic will often require that participants have not received any prior antibiotic treatment, per FDA standards.[272] However, patients in the United States who present with symptoms of a serious bacterial infection are almost always started on antibiotic treatment immediately, given the acute and rapid nature of most infections.[273] Therefore, many patients who would be otherwise eligible participants for clinical trials are almost instantly disqualified. The ample availability of antibiotics in the United States—even if older-generation and less effective—makes trial participant enrollment a significant hurdle for antibiotic developers. And even if not disqualified based on prior treatment, intuitively, many patients and clinicians simply prefer to use older, well-known antibiotics, rather than risk experimental treatment for potentially only modest gains in efficacy or safety. But, if drug developers are motivated to carry out antibiotic-based trials outside of the United States to mitigate these patient enrollment issues, the risk of ethical and human rights violations exponentially increases.[274] Worse yet, patients in and outside of the United States who are candidate antibiotic trial participants are often unable to provide informed consent at all, because they are hospitalized, in multiorgan failure, or unconscious.[275] Thus, it is imperative that policymakers consider these unique challenges, and that the FDA continue developing unique pathways for antibiotic approval[276] that ease the burden on antibiotic developers while upholding the rights of trial participants.

Third, while an ethically conducted clinical trial requires that all participants have access to an “effective” therapeutic option, defining “efficacy” for an antibiotic in a largely resistant landscape is much more complex than for the average new drug. Recall Senator Kefauver’s initial efficacy proposal made in response to the escalating costs of prescription drugs in the late 1950s.[277] Kefauver proposed a heightened efficacy standard—that new drugs should have “significantly greater” therapeutic effects than predecessor drugs, to discourage the development of allegedly useless me-too drugs.[278] Although a more neutral efficacy requirement was ultimately codified into the Kefauver-Harris Amendments,[279] the prevalence of and preference for superiority clinical trials has essentially resurrected Kefauver’s comparative efficacy requirement for most drugs under clinical evaluation today. This is problematic for two reasons: (1) the landscape of drug discovery and development is not the same today as in the 1950s, when the Kefauver-Harris Amendments were developed—at the time, far fewer classes of drugs had been discovered, and (2) in the case of antibiotics, this standard is overly harsh in a way that fails to encourage antibiotic innovation and ultimately infringes the right to access essential medicines. To expand upon this second reason: amidst an antibiotic resistance crisis, what “effective” means for an antibiotic should be construed much more broadly than for other drugs. For example, it is valuable to have a nearly identical me-too antibiotic that, due to slight chemical differences, requires a shorter period of administration, presents fewer side effects, or simply is active against just one patient who happens to be resistant to its first-in-class counterpart.[280] While these benefits do not rise to the level of complete superior efficacy, they are far from worthless. Therefore, it is worth reframing existing legal and policy perspectives on efficacy in light of the differences across pharmaceutical types, with antibiotics as one leading example.[281]

Further to this point, a shifted perspective on what efficacy means for an antibiotic should be accompanied by a renewed appreciation for non-inferiority trials. The FDA has elevated approval requirements for many antibiotics and me-too drugs, from non-inferiority to superiority.[282] And even when not strictly required, non-inferiority trials are disfavored among regulators, clinicians, and ethicists.[283] As discussed in Part I.D supra, superiority studies are appreciated for their standalone nature and statistical power, while non-inferiority studies require an assumption that the control group is adequately efficacious.[284] But, it is extraordinarily difficult to demonstrate superior efficacy for many antibiotics and many me-too drugs.[285] And, again, in cases where discovery is focused specifically on overcoming drug resistance, similar and not superior efficacy may be the only route to resupplying existing drug classes with adequate chemical diversity.[286]

Reconstructing how efficacy is assessed for antibiotics also addresses some ethical concerns with non-inferiority studies in this setting. Antibiotics that might be only non-inferior in their canonical efficacy are not useless to trial participants when those antibiotics offer benefits in the form of mitigating present and future antibiotic resistance.[287] Worth noting, too, is that a focus on non-inferiority over superiority would constitute an “easier” approval standard[288] that may incentivize development and disincentivize exploitative conduct without risking the safety and clinical outcomes of trial participants. In the Kano trials, for example, if trovafloxacin were subject to a non-inferiority standard, low-dosing the control ciprofloxacin group would not have been necessary to demonstrate efficacy at that threshold.[289] Taken together, if non-inferiority studies were more widely accepted for antibiotics and perhaps other me-too drugs, drug developers might be (1) incentivized to continue developing antibiotics and other drugs, whether they end up as me-toos or not, and (2) able to re-allocate some resources to the pursuit of higher-risk drug discovery and development, for which the reward might be a true end to the resistance crisis.

Conclusion

Rigorous drug development is essential to upholding the human right to health, but complex to incentivize and carry out without running afoul of that human right. This Note asserts that pharmaceutical policy proposals aimed at fostering innovation or protecting human rights need to be more narrowly tailored to consider the unique challenges faced by different pharmaceuticals. Using antibiotics as a case study for this point, this Note explains how fostering antibiotic development may require intellectual property-based incentives; a refined perspective on the merits of me-too drugs; and a reformed outlook on drug efficacy, superiority, and non-inferiority. Future research should quantitatively interrogate clinical trial protocols, ethical violations, and resulting drug approvals to better understand how these ideas feature in both antibiotic and other pharmaceutical settings. As is always true for scientific progress and development, the best drugs have yet to be discovered—and hopefully will be found without the “mild torture economy” engine.

Copyright © 2025 Caressa N. Tsai, Ph.D., McMaster University, Department of Biochemistry and Biomedical Sciences, 2021; J.D., University of California, Berkeley, School of Law, 2024. I am especially grateful to Rohini Haar and Eric Stover for their guidance, encouragement, and support in preparing this Note. I would also like to thank John Rex for advice on non-inferiority trial designs and considerable thought leadership on fostering antibiotic development. Special thanks to Sara Shnider, the participants of the Fall 2023 Health and Human Rights class, and the editors of the California Law Review.

          [1].     1996 – Niger, World Health Org., https://www.who.int/emergencies/disease-outbreak-news/item/1996_03_01b-en [https://perma.cc/65Q3-9Q2X] (last visited Aug. 27, 2024); Idris Mohammed, Abdussalam Nasidi, A.S. Alkali, M.A. Garbati, E.K. Ajayi-Obe, Kudi A. Audu, Abdulmumini Usman & Suleiman Abdullahi, A Severe Epidemic of Meningococcal Meningitis in Nigeria, 1996, 94 Transactions Royal Soc’y Tropical Med. & Hygiene 265, 265 (2000).

          [2].     Meningitis, World Health Org. (Apr. 17, 2023), https://www.who.int/news-room/fact-sheets/detail/meningitis [https://perma.cc/8XQ3-RGZB]; Sarah Mbaeyi, Jonathan Duffy & Lucy A. McNamara, Meningococcal Disease, Ctrs. Disease Control & Prevention (Apr. 25, 2024), https://www.cdc.gov/pinkbook/hcp/table-of-contents/chapter-14-meningococcal-disease.html?CDC_AAref_Val=https://www.cdc.gov/vaccines/pubs/pinkbook/mening.html [https://perma.cc/D5KZ-46B3].

          [3].     Meningitis, World Health Org., supra note 2; Meningitis, Nat’l Inst. Neurological Disorders & Stroke, https://www.ninds.nih.gov/health-information/disorders/meningitis#:~:text=In%20more%20serious%20cases%2C%20the,%2C%20medication%2C%20and%20supportive%20care [https://perma.cc/Q888-BVHZ] (last updated July 19, 2024).

          [4].     C. L. Ejembi, E. P. Renne & H.A. Adamu, The Politics of the 1996 Cerebrospinal Meningitis Epidemic in Nigeria, 68 Africa: J. Int’l African Inst. 118, 120 (1998).

          [5].     Semeeh Akinwale Omoleke & Kehinde Kazeem Kanmodi, Seasonal Meningococcal Meningitis Outbreaks in Nigeria: A Need for an Accelerated Introduction of a Conjugated Meningococcal Vaccine into the National Routine Immunization Schedule, 9 Int’l J. Med. Rsch. & Health Scis. 31, 32 (2020).

          [6].     See Ejemi et al., supra note 4, at 121.

          [7].     Belinda Archibong & Francis Annan, What do Pfizer’s 1996 Drug Trials in Nigeria Teach Us About Vaccine Hesitancy?, Brookings (Dec. 3, 2021), https://www.brookings.edu/articles/what-do-pfizers-1996-drug-trials-in-nigeria-teach-us-about-vaccine-hesitancy/ [https://perma.cc/TTX6-PWDH].

          [8].     Id.; see Trovafloxacin, Nat’l Libr. Med., https://pubchem.ncbi.nlm.nih.gov/compound/Trovafloxacin [https://perma.cc/7RF9-4RH2] (last visited Nov. 4, 2024).

          [9].     See Ctr. For Drug Evaluation & Rsch., Approval Package for Application Number: 020759/020760 1 (1997) (providing the FDA approval letter for trovafloxacin, sponsored by Pfizer, as of Dec. 18, 1997); see also Archibong & Annan, supra note 7 (describing the Kano trial).

        [10].     Jacqui Wise, Pfizer Accused of Testing New Drug Without Ethical Approval, 322 BMJ 194, 194 (2001); NCI Dictionary of Cancer Terms, open label study, Nat’l Cancer Inst., https://www.cancer.gov/publications/dictionaries/cancer-terms/def/open-label-study [https://perma.cc/JPJ2-386B] (last visited Oct. 22, 2023) (defining an “open label” clinical study).

        [11].     Id.

        [12].     Id.

        [13].     CEFTRIAXONE Injectable, Medecins Sans Frontieres, https://medicalguidelines.msf.org/en/viewport/EssDr/english/ceftriaxone-injectable-16682532.html [https://perma.cc/BY4V-4X7Y] (last visited Jan. 17, 2025).

        [14].     Jeanne Lenzer, Nigeria Files Criminal Charges Against Pfizer, 334 Brit. Med. J. 1181 (2007) (“Pfizer acknowledged to the BMJ that it used a low dose of ceftriaxone—33 mg/kg. When asked why a low dose was chosen, Pfizer’s spokesperson, Bryant Haskins said that full dose shots were too ‘painful’ for the children and made it hard for them to walk.”); see also Pfizer, Trovan Fact Sheet, https://cdn.pfizer.com/pfizercom/news/trovan_fact_sheet_final.pdf [https://perma.cc/VAT7-G49A] (last visited Aug. 29, 2024).

        [15].     Wise, supra note 10, at 194.

        [16].     Id.

        [17].     Izza Choudhry, Origins of Vaccine Hesitancy: The 1996 Pfizer Drug Trials in Nigeria, Hist. Vaccines (Dec. 12, 2022), https://historyofvaccines.org/blog/origins-vaccine-hesitancy-1996-pfizer-drug-trials-nigeria [https://perma.cc/57Z6-DD49].

        [18].     See Pfizer, supra note 14.

        [19].     Id.

        [20].     See Joe Stephens, Panel Faults Pfizer in ‘96 Clinical Trial in Nigeria, Wash. Post (May 7, 2006), https://www.washingtonpost.com/wp-dyn/content/article/2006/05/06/AR2006050601338.html [https://perma.cc/D3MJ-94QU]; Archibong & Annan, supra note 7.

        [21].     Stephens, supra note 20.

        [22].     Id.

        [23].     See id.; Y. Tony Yang, Brian Chen & Charles L. Bennett, Offshore Pharmaceutical Trials: Evidence, Economics, and Ethics, 2 Mayo Clinic Procs.: Innovations, Quality & Outcomes 226, 226 (2018).

        [24].     Stephens, supra note 20.

        [25].     See, e.g., David Smith, Pfizer Pays Out to Nigerian Families of Meningitis Drug Trial Victims, Guardian (Aug. 12, 2011), https://www.theguardian.com/world/2011/aug/11/pfizer-nigeria-meningitis-drug-compensation [https://perma.cc/9Z98-8T57] (describing the events following the Kano trial); Jeanne Lenzer, Secret Report Surfaces Showing that Pfizer was at Fault in Nigerian Drug Tests, 332 Brit. Med. J. 1233 (2006) (discussing the Nigerian government report following the Kano trial).

        [26].     Pfizer, Kano State Reach Settlement of Trovan Cases, Pfizer (July 29, 2009), https://www.pfizer.com/news/press-release/press-release-detail/pfizer_kano_state_reach_settlement_of_trovan_cases [https://perma.cc/YDU9-XG8J]; Camillus Eboh, Pfizer, Nigeria Sign $75 Mln Trovan Settlement, Reuters (July 30, 2009), https://www.reuters.com/article/world/africa/pfizer-nigeria-sign-75-mln-trovan-settlement-idUSLU52274/ [https://perma.cc/VAT7-G49A].

        [27].     Ethical Use of Placebo Controls in Research, AMA Code Med. Ethics, https://code-medical-ethics.ama-assn.org/ethics-opinions/ethical-use-placebo-controls-research [https://perma.cc/XZ3D-PY3T] (last visited Aug. 29, 2024).

        [28].     See id.

        [29].     See id.; see generally Joseph Millum & Christine Grady, The Ethics of Placebo-Controlled Trials: Methodological Justifications, 36 Contemp. Clinical Trials 510 (2014) (describing ethical concerns associated with placebo-controlled clinical trials).

        [30].     See Ethical Use of Placebo Controls in Research, supra note 27; see also Franklin G. Miller & Howard Brody, What Makes Placebo-Controlled Trials Unethical?, 2 Am. J. Bioethics 3 (2002) (describing ethical concerns associated with placebo-controlled clinical trials).

        [31].     See, e.g., Antimicrobial Resistance, World Health Org. (Nov. 21, 2023), https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance [https://perma.cc/K2LY-NW9V].

        [32].     See, e.g., Eric D. Brown & Gerard D. Wright, Antibacterial Drug Discovery in the Resistance Era, 529 Nature 336, 336 (2016) (describing the golden era of antibiotic discovery).

        [33].     For more discussion on the ethics of placebo-controlled trials, see Richard Bax, Flic Gabbay & Ian Phillips, Antibiotic Clinical Trials—The Witley Park Symposium, 5 Clinical Microbiology & Infection 774, 778 (1999).

        [34].     See id.

        [35].     See Lenzer, supra note 14; CEFTRIAXONE Injectable, supra note 13.

        [36].     See, e.g., Abdullahi v. Pfizer, Inc. (Abdullahi I), No. 01 Civ. 8118, 2002 U.S. Dist. LEXIS 17436, at *4–7 (S.D.N.Y. Sept. 16, 2002) (providing the allegations regarding superiority in the Pfizer trial).

        [37].     See id.; see also, e.g., Kristen A. Stafford, Mallory Boutin, Scott R. Evans & Anthony D. Harris, Difficulties in Demonstrating Superiority of an Antibiotic for Multidrug-Resistant Bacteria in Nonrandomized Studies, 59 Clinical Infectious Diseases 1142 (2014) (describing issues relating to superiority trials for antibiotics).

        [38].     See, e.g., Benjamin Freedman, Charles Weijer & Kathleen Cranley Glass, Placebo Orthodoxy in Clinical Research I: Empirical and Methodological Myths, 24 J.L. Med. & Ethics 243 (1996) (describing ethical concerns associated with placebo-controlled clinical trials).

        [39].     See, e.g., Chéna Farhat, Enforcing Ethical Informed Consent Practices to Protect Human Rights in the Pursuit of Clinical Research Globalization, 45 Suffolk Transnat’l L. Rev. 47 (2022) (discussing issues with informed consent in clinical research).

        [40].     See, e.g., Ton J. Cleophas & Aeilko H. Zwinderman, Clinical Trials are Often False Positive: A Review of Simple Methods to Control This Problem, 1 Current Clinical Pharmacology 1 (2006) (describing issues with statistical hypothesis testing in clinical trials); Sanaa Al-Marzouki, Stephen Evans, Tom Marshall & Ian Roberts, Are These Data Real? Statistical Methods for the Detection of Data Fabrication in Clinical Trials, 331 Brit. Med. J. 267 (2005) (discussing issues with data fabrication in clinical trials).

        [41].     See, e.g., Sarah Thompson Schick & Kirsten Axelsen, Considering Modifications to Existing FDA Regulatory Incentives to Achieve Greater Racial and Ethnic Diversity in Pivotal Clinical Trials for Drug Approvals, 77 Food & Drug L.J. 246 (2022) (discussing issues with clinical trial diversity); Joseph Liss, David Peloquin, Mark Barnes & Barbara E. Bierer, Applying Civil Rights Law to Clinical Research: Title VI’s Equal Access Mandate, 50 J.L. Med. & Ethics 101 (2022) (discussing discriminatory practices in clinical research).

        [42].     See, e.g., Katherine Cohen, Joseph W. Cormier & Mahnu V. Davar, Predictable Materiality: A Need for Common Criteria Governing the Disclosure of Clinical Trial Results by Publicly-Traded Pharmaceutical Companies, 29 J. Contemp. Health L. & Pol’y 201 (2013) (discussing public disclosure of clinical trial data); Matthew Herder, Toward a Jurisprudence of Drug Regulation, 42 J.L. Med. & Ethics 244 (2014) (discussing a need for greater transparency in clinical research).

        [43].     See, e.g., Bobbi M. Bittker, The Ethical Implications of Clinical Trials in Low- and Middle-Income Countries, 46 Hum. Rts. 6 (2021) (describing issues associated with clinical trial globalization); Breanne M. Schuster, For the Love of Drugs: Using Pharmaceutical Clinical Trials Abroad to Profit off the Poor, 13 Seattle J. for Soc. Just. 1015 (2015) (same).

        [44].     See, e.g., Yashaswini Singh, Matthew D. Eisenberg & Neeraj Sood, Factors Associated with Public Trust in Pharmaceutical Manufacturers, 2023 JAMA Network Open e233002 (2023) (discussing consumer trust in pharmaceutical firms); Christopher Robertson, Introduction, in FDA in the Twenty-First Century: The Challenges of Regulating Drugs and New Technologies 109 (Holly Fernandez Lynch & I. Glenn Cohen eds., 2015) (“[T]here is one great problem that seriously challenges the ability of America’s research-based pharmaceutical companies to . . . research and develop new cures and treatments. In a word, it is trust.”).

        [45].     See, e.g., David Adam, How a Data Detective Exposed Suspicious Medical Trials, Nature (July 23, 2019), https://www.nature.com/articles/d41586-019-02241-z [https://perma.cc/5QJB-P2V5] (discussing problematic practices in clinical trials); Richard Van Noorden, Medicine is Plagued by Untrustworthy Clinical Trials. How Many Studies are Faked or Flawed?, Nature (July 18, 2023), https://www.nature.com/articles/d41586-023-02299-w [https://perma.cc/9NHH-BW8W] (same); Derek Lowe, Too Many Bad Clinical Trials, Science (July 25, 2023), https://www.science.org/content/blog-post/too-many-bad-clinical-trials [https://perma.cc/5S92-M8WU] (same).

        [46].     See Carl Elliott, The Mild Torture Economy, London Rev. Books (Sept. 23, 2010), https://www.lrb.co.uk/the-paper/v32/n18/carl-elliott/the-mild-torture-economy [https://perma.cc/4KBY-GTZZ].

        [47].     Food & Drug Administration, U.S. Dep’t Health & Hum. Servs., https://www.hhs.gov/ohrp/regulations-and-policy/regulations/fda/index.html [https://perma.cc/5CAW-XRUM] (last visited Jan. 19, 2025); What We Do, U.S. Food & Drug Admin., https://www.fda.gov/about-fda/what-we-do#:~:text=Information%20for%20Consumers-,FDA%20Mission,and%20products%20that%20emit%20radiation [https://perma.cc/9TP4-ZWY7] (last visited Aug. 27, 2024).

        [48].     U.S. Dep’t Health & Hum. Servs., Demonstrating Substantial Evidence of Effectiveness With One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence 1 (2023) [hereinafter Demonstrating Substantial Evidence] (providing draft guidance for administrative comment purposes) (emphasis added).

        [49].     See Holly Fernandez Lynch & I. Glenn Cohen, Introduction, in FDA in the Twenty-First Century: The Challenges of Regulating Drugs and New Technologies 2 (Holly Fernandez Lynch & I. Glenn Cohen eds., 2015).

        [50].     Peter Barton Hutt, Historical Themes and Developments at FDA over the Past Fifty Years, in FDA in the Twenty-First Century: The Challenges of Regulating Drugs and New Technologies 17–18 (Holly Fernandez Lynch & I. Glenn Cohen eds., 2015).

        [51].     U.S. Food & Drug Admin., A History of the FDA and Drug Regulation in the United States 1 (2006) [hereinafter A History of the FDA]; accord Theodore W. Ruger, After the FDA: A Twentieth-Century Agency in a Postmodern World, in FDA in the Twenty-First Century: The Challenges of Regulating Drugs and New Technologies 78 (Holly Fernandez Lynch & I. Glenn Cohen eds., 2015).

        [52].     See Carol Ballentine, Sulfanilamide Disaster, U.S. Food & Drug Admin. 2 (1981); Clinton Lam & Preeti Patel, Food, Drug, and Cosmetic Act, in StatPearls (2023).

        [53].     Ballentine, supra note 52, at 1; Part II: 1938, Food, Drug, Cosmetic Act, U.S. Food & Drug Admin. (Nov. 27, 2018), https://www.fda.gov/about-fda/changes-science-law-and-regulatory-authorities/part-ii-1938-food-drug-cosmetic-act#:~:text=The%20new%20law%20brought%20cosmetics,before%20it%20could%20be%20sold [https://perma.cc/BT27-7U3C].

        [54].     See Ballentine, supra note 52, at 2.

        [55].     Id. at 4–5 (emphasis added).

        [56].     A History of the FDA, supra note 51, at 2; Lam & Patel, supra note 52.

        [57].     Daniel Carpenter, Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA 73 (2010).

        [58].     Jeremy A. Greene & Scott H. Podolsky, Reform, Regulation, and Pharmaceuticals – The Kefauver-Harris Amendments at 50, 367 New Eng. J. Med. 1481, 1481 (2012); see generally Franco Malerba & Luigi Orsenigo, The Evolution of the Pharmaceutical Industry, 57 Bus. Hist. 664 (2015) (tracing the evolution of the pharmaceutical industry and describing main eras of drug discovery and development).

        [59].     The distribution of sulfathiazole (an antibiotic) accidentally tainted with phenobarbital caused approximately three hundred deaths and injuries, chloramphenicol (also an antibiotic) was revealed to have caused approximately 180 cases of blood diseases, and thalidomide (an antinauseant) caused severe birth defects in thousands of infants. See A History of the FDA, supra note 51, at 2.

        [60].     See id. at 2–3.

        [61].     Greene & Podolsky, supra note 58, at 1481.

        [62].     A History of the FDA, supra note 51, at 3.

        [63].     See infra Part III.C.

        [64].     See Greene & Podolsky, supra note 58, at 1481–82.

        [65].     See id.

        [66].     See id. at 1482.

        [67].     Id.

        [68].     See id.

        [69].     Id.

        [70].     Aaron S. Kesselheim & Jerry Avorn, The Food and Drug Administration Has the Legal Basis to Restrict Promotion of Flawed Comparative Effectiveness Research, 31 Health Affs. 2200, 2200 (2012).

        [71].     Id. (internal quotation marks removed).

        [72].     Id. at 2200–01; see also Demonstrating Substantial Evidence, supra note 48, at 8, 16 (explaining the “adequate and well-controlled investigations” standard).

        [73].     See Greene & Podolsky, supra note 58, at 1482.

        [74].     Id.

        [75].     Elizabeth Stotland Weiswasser & Scott D. Danzis, The Hatch-Waxman Act: History, Structure, and Legacy, 71 Antitrust L.J. 585, 585 (2003).

        [76].     See id.; Rafael Alfonso-Cristancho, Tatiana Andia, Tatiana Barbosa & Jonathan H. Watanabe, Definition and Classification of Generic Drugs Across the World, 13 Applied Health Econ. & Health Pol’y S5 (2015); Generic Drugs: Questions & Answers, U.S. Food & Drug Admin. (Mar. 16, 2021), https://www.fda.gov/drugs/frequently-asked-questions-popular-topics/generic-drugs-questions-answers#:~:text=Generic%20medicines%20and%20brand%2Dname,generic%20medicine%2C%20may%20be%20different [https://perma.cc/Q4DG-HHZ7].

        [77].     See Christopher-Paul Milne, The Food and Drug Administration Modernization Act and the Food and Drug Administration: Metamorphosis or Makeover?, 34 Drug Info. J. 681, 681 (2000).

        [78].     See id.

        [79].     Demonstrating Substantial Evidence, supra note 48, at 3.

        [80].     Id. at 2–3. The FDA is still in the process of optimizing its own “substantial evidence” requirement. See id.

        [81].     See Allen D. Roses, Pharmacogenetics in Drug Discovery and Development: A Translational Perspective, 7 Nature Revs. Drug Discovery 807, 807–08 (2008); Exploring the Five Phases of Drug Development, ThermoFisher Sci. (Oct. 23, 2023), https://www.patheon.com/us/en/insights-resources/blog/drug-development-phases.html [https://perma.cc/2453-8NS6].

        [82].     Id.

        [83].     See, e.g., Richard D. Taylor, Malcolm MacCoss & Alastair D. G. Lawson, Rings in Drugs, 57 J. Med. Chemistry 5845, 5845 (2014) (providing one example of toxicity based on chemical structure).

        [84].     Roses, supra note 81, at 807–08.

        [85].     See Development & Approval Process | Drugs, U.S. Food & Drug Admin., https://www.fda.gov/drugs/development-approval-process-drugs [https://perma.cc/P5VK-4FS7] (last visited Aug. 29, 2024).

        [86].     Id.

        [87].     Id.

        [88].     Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review, U.S. Food & Drug Admin., https://www.fda.gov/patients/learn-about-drug-and-device-approvals/fast-track-breakthrough-therapy-accelerated-approval-priority-review [https://perma.cc/FW3W-5FNU] (last visited Aug. 29, 2024).

        [89].     The FDA’s Drug Review Process: Ensuring Drugs Are Safe and Effective, U.S. Food & Drug Admin., https://www.fda.gov/drugs/information-consumers-and-patients-drugs/fdas-drug-review-process-ensuring-drugs-are-safe-and-effective [https://perma.cc/2UNA-BBPK] (last visited Oct. 9, 2023) [hereinafter The FDA’s Drug Review Process].

        [90].     Id.

        [91].     Id.; Clinical Trial Phases Defined, Univ. Cin. Coll. Med., https://med.uc.edu/depart/psychiatry/research/clinical-research/crm/trial-phases-1-2-3-defined [https://perma.cc/4C3P-7P8R] (last visited Aug. 29, 2024).

        [92].     The FDA’s Drug Review Process, supra note 89.

        [93].     Clinical Trial Phases Defined, supra note 91.

        [94].     Id.

        [95].     Id.

        [96].     Id.

        [97].     See Scott R. Evans, Fundamentals of Clinical Trial Design, 3 J. Experimental Stroke Translational Med. 19 (2010).

        [98].     FDA’s Role: ClinicalTrials.gov Information, U.S. Food & Drug Admin., https://www.fda.gov/science-research/clinical-trials-and-human-subject-protection/fdas-role-clinicaltrialsgov-information [https://perma.cc/L69C-LEPS] (last visited Aug. 29, 2024).

        [99].     Clinical Trials and Human Subject Protection, U.S. Food & Drug Admin., https://www.fda.gov/science-research/science-and-research-special-topics/clinical-trials-and-human-subject-protection [https://perma.cc/XKJ8-F9EL] (last visited Nov. 10, 2023).

      [100].     Id.; see also Evans, supra note 97 (outlining important elements in clinical design to reduce errors).

      [101].     Evans, supra note 97, at 22–23.

      [102].     Id.; ClinicalTrials.gov Glossary Terms, Nat’l Libr. Med., https://clinicaltrials.gov/study-basics/glossary [https://perma.cc/N75G-Q8CJ] (last visited Nov. 4, 2024) (defining the “active comparator” arm of a clinical study).

      [103].     See Evans, supra note 97, at 21–23.

      [104].     See id.

      [105].     The FDA has introduced some guidelines specific to antibiotics. See, e.g., New Drug and Antibiotic Regulations, U.S. Food & Drug Admin. (Feb. 22, 1985), https://www.fda.gov/science-research/clinical-trials-and-human-subject-protection/new-drug-and-antibiotic-regulations [https://perma.cc/9VBK-2ZNM].

      [106].     See generally, e.g., Brown & Wright, supra note 32 (discussing the antibiotic resistance crisis). Antibiotic resistance develops when bacteria become capable of surviving antibiotics that previously would have killed them. Belma Skender, The Demise of the Antibiotic Pipeline: The Bayer Case, 11 Humanities & Soc. Scis. Commc’ns 1, 2 (2024).

      [107].     See, e.g., Carly Deusenbery, Yingying Wang & Anita Shukla, Recent Innovations in Bacterial Infection Detection and Treatment, 7 ACS Infectious Diseases 1 (2021) (noting the rapidly progressing nature of bacterial infections).

      [108].     See generally Richard J. Fair & Yitzhak Tor, Antibiotics and Bacterial Resistance in the 21st Century, 6 Persps. in Med. Chemistry 25 (2014) (summarizing the state of antibiotic use and resistance in the modern era).

      [109].     See generally Brown & Wright, supra note 32 (describing the antibiotic resistance crisis).

      [110].     Joel Lexchin, How Safe and Innovative Are First-in-Class Drugs Approved by Health Canada: A Cohort Study, 12 Healthcare Pol’y 65, 66 (2016).

      [111].     Karen Bush & Patricia A. Bradford, β-Lactams and β-Lactamase Inhibitors: An Overview, 6 Cold Spring Harbor Persps. Med. A025247 (2016).

      [112].     See Nicholas Downing, Promoting Innovation in Drug Development, Yale Inst. Soc. & Pol’y Stud. (Feb. 2014), https://isps.yale.edu/news/blog/2014/02/promoting-innovation-in-drug-development [https://perma.cc/HJN7-YNK5].

      [113].     See Millum & Grady, supra note 29, at 510 (2013).

      [114].     See id.

      [115].     See, e.g., Anthony R.M. Coates, Gerry Halls & Yanmin Hu, Novel Classes of Antibiotics or More of the Same?, 163 Brit. J. Pharmacology 184 (2011) (discussing antibiotic classes and the antibiotic discovery pipeline).

      [116].     Id. at 184.

      [117].     Id.

      [118].     See id.

      [119].     Jeffrey K. Aronson & A. Richard Green, Me-Too Pharmaceutical Products: History, Definitions, Examples, and Relevance to Drug Shortages and Essential Medicines Lists, 86 Brit. J. Clinical Pharmacology 2114, 2114 (2020) (defining me-too drugs as “pharmacologically active compound[s] that [are] structurally related to a first-in-class compound, regarded as belonging to the same therapeutic class as the original compound, and used for the same therapeutic purposes, but which may differ in some respects, such as specificity of pharmacological action, adverse reactions profile, or drug-drug interactions”).

      [120].     Note that me-too drugs are distinct from generic drugs, and the difference between brand-name and generic drugs is not the same as the difference between first-in-class and me-too drugs. As discussed in Section I.A supra, the Hatch-Waxman Act operates to facilitate the market entry of generic drugs, which are identical to existing, brand-name drugs in “dosage form, safety, strength, route of administration, quality, performance characteristics, and intended use.” Generic Drugs: Questions & Answers, supra note 76. Essentially, there are no meaningful differences between a brand-name drug and its generic counterpart, aside from who developed each and when. A me-too drug, on the other hand, is not identical to a first-in-class drug—both are in the same overall therapeutic class and have similar activity, but each has a different chemical structure and molecular features.

      [121].     See Greene & Podolsky, supra note 58, at 1482.

      [122].     Derek Lowe, Those Me-Too Drugs, Science (Jan. 26, 2011), https://www.science.org/content/blog-post/those-me-too-drugs [https://perma.cc/4WNJ-RQTH]. Despite copycat accusations, data suggest that much of the development of me-too drugs overlaps in timing with the development of a first-in-class drug. Id. That is, developers are not waiting around to copy a first-in-class drug with a me-too, but rather, several developers will all work towards being the first to obtain FDA approval for a new drug, with one first-in-class winner being granted approval before the remaining candidates, all to be shafted to me-too status. Joseph A. DiMasi & Laura B. Faden, Competitiveness in Follow-On Drug R&D: A Race or Imitation?, 10 Nature Revs. Drug Discovery 23, 27 (2011).

      [123].     Aronson & Green, supra note 119, at 2114; see generally World Health Org., The Selection and Use of Essential Medicines 2023 (2023) (describing essential medicines for different therapeutic areas).

      [124].     Peter Kolchinsky, Why Wait for Generics? In Praise of Me-Too Drugs, Medium (Mar. 24, 2018), https://medium.com/the-biotech-social-contract/the-biotech-social-contract-kolchinsky-tbsc-4-470443a6da69 [https://perma.cc/YM86-HGA8].

      [125].     Id. (analogizing to cocktail therapies comprising multiple anti-viral drugs that might be me-toos of each other).

      [126].     See Aronson & Green, supra note 119, at 2116; Anupam B. Jena, John E. Calfee, Edward C. Mansley & Tomas J. Philipson, ‘Me-Too’ Innovation in Pharmaceutical Markets, 12 F. Health Econ. & Pol’y 1, 1 (2009).

      [127].     Aronson & Green, supra note 119, at 2119 (listing first-in-class and me-too statins in Table 5).

      [128].     John LaMattina, Even Me-Too Drugs Matter when it Comes to New Medicines, STAT (Sept. 24, 2021), https://www.statnews.com/2021/09/24/me-too-drugs-matter-when-it-comes-to-new-medicines/ [https://perma.cc/MPZ8-WER8].

      [129].     Ethical Use of Placebo Controls in Research, supra note 27.

      [130].     See Aronson & Green, supra note 119; Jena et al., supra note 126.

      [131].     U.S. Food & Drug Admin., Non-Inferiority Clinical Trials to Establish Effectiveness 2 (2016) [hereinafter Non-Inferiority Clinical Trials]. Superiority and non-inferiority designs are not the only options for clinical trials; for example, another option is an equivalence study. However, for the purpose of the instant discussion and proposal, this Note will only focus on superiority and non-inferiority.

      [132].     Aronson & Green, supra note 119, at 2121.

      [133].     See Demonstrating Substantial Evidence, supra note 48, at 1; see also 21 C.F.R. § 314.126 (describing “adequate and well-controlled” studies).

      [134].     See Demonstrating Substantial Evidence, supra note 48, at 5.

      [135].     Non-Inferiority Clinical Trials, supra note 131, at 2.

      [136].     See, e.g., John Rex, In Praise of Non-Inferiority, AMR.Solutions (Sept. 19, 2020), https://amr.solutions/2020/09/19/in-praise-of-non-inferiority/ [https://perma.cc/N29K-ZT3G].

      [137].     Id.; Non-Inferiority Clinical Trials, supra note 131, at 2; Stuart J. Head, Sanjay Kaul, Ad J.J.C. Bogers & A. Pieter Kappetein, Non-Inferiority Study Design: Lessons to be Learned from Cardiovascular Trials, 33 Eur. Heart J. 1318, 1318 (2012).

      [138].     Peter Doshi, Peter Hur, Mark Jones, Husam Albarmawi, Tom Jefferson, Daniel J. Morgan, Patricia A. Spears & John H. Powers III, Informed Consent to Study Purpose in Randomized Clinical Trials of Antibiotics, 1991 Through 2011, 177 JAMA Internal Med. 1452, 1452 (2017).

      [139].     See David J. Cohen, Non-Inferiority Trials: What Are They and Why Are They So Difficult? 5 (2009); accord David Shaywitz, ‘Non-Inferior’ Doesn’t Mean ‘Me-Too’ -- Except When It Does, Forbes (June 26, 2013), https://www.forbes.com/sites/davidshaywitz/2013/06/26/non-inferior-doesnt-mean-me-too-except-when-it-does/ [https://perma.cc/M6LZ-V7SP].

      [140].     Non-Inferiority Clinical Trials, supra note 131, at 1, 7. There are several unique situations in which a non-inferiority trial design is the only adequate option. For example, Coumadin (warfarin) is an anticoagulant therapy that has been used to treat and prevent blood clots for decades. Head et al., supra note 137, at 1319. While Coumadin is considered a standard treatment option for many patients, it elicits unfavorable side effects in certain patient subpopulations. Id. Over time, researchers developed “me-too” versions of Coumadin that were better tolerated in these subpopulations. Id. Importantly, these me-too variants are “effective” just to the same extent as Coumadin, without the side effects. However, reduced side effects are not typically considered in the assessment of traditional “efficacy.” Id. Thus, these me-too Coumadins would fail a traditional superiority study, but would meet the standards of a non-inferiority study. So, for subpopulations that do not respond well to traditional Coumadin, the existence of a non-inferiority design standard is essential.

      [141].     Non-Inferiority Clinical Trials, supra note 131, at 1, 7; Stefano Ricci, What Does ‘Non-Inferior to’ Really Mean?: A Clinician Thinking Out Loud, 29 Cerebrovascular Diseases 607, 608 (2010).

      [142].     Head et al., supra note 137, at 1318; Thomas R. Fleming, Current Issues in Non-Inferiority Trials, 27 Stat. Med. 317, 317 (2008) (“In clinical practice, considerable uncertainty remains regarding when such trials should be conducted, how they should be designed, what standards for quality of trial conduct must be achieved, and how results should be interpreted.”).

      [143].     Head et al., supra note 137, at 1318. Essentially, the non-inferiority question in such a trial is answered with a statistical analysis that varies on a case-by-case basis. More information on how the non-inferiority margin is defined and assessed across clinical trials is summarized, in one example, here. See, e.g., Turki A. Althunian, Anthonius de Boer, Olaf H. Klungel, Widya N. Insani & Rolf H. H. Groenwold, Methods of Defining the Non-Inferiority Margin in Randomized, Double-Blind Controlled Trials: A Systematic Review, 18 Trials 1 (2017).

      [144].     Non-Inferiority Clinical Trials, supra note 131, at 2.

      [145].     Expert Committee on Selection and Use of Essential Medicines, World Health Org., https://www.who.int/groups/expert-committee-on-selection-and-use-of-essential-medicines [https://perma.cc/HSE9-FA6B] (last visited Aug. 31, 2024); see Access to Medicines and the Right to Health, United Nations Hum. Rts. Off. High Comm’r, https://www.ohchr.org/en/special-procedures/sr-health/access-medicines-and-right-health#:~:text=About%20special%20procedures,-About%20special%20procedures&text=The%20issue%20of%20access%20to,appropriate%20access%20to%20quality%20medicines [https://perma.cc/45YR-LTER] (last visited Feb. 10, 2025).

      [146].     See Michael Schlander, Karla Hernandez-Villafuerte, Chih-Yuan Cheng, Jorge Mestre-Ferrandiz & Michael Baumann, How Much Does It Cost to Research and Develop a New Drug? A Systematic Review and Assessment, 39 Pharmacoeconomics 1243, 1244 (2021); Bernard Munos, Lessons From 60 Years of Pharmaceutical Innovation, 8 Nature Revs. Drug Discovery 959, 967 (2009).

      [147].     Robert Cook-Deegan & Christopher Heaney, Patents in Genomics and Human Genetics, 11 Ann. Rev. Genomics & Hum. Genetics 383, 384 (2010); Small Business Assistance: Frequently Asked Questions on the Patent Term Restoration Program, U.S. Food & Drug Admin., https://www.fda.gov/drugs/cder-small-business-industry-assistance-sbia/small-business-assistance-frequently-asked-questions-patent-term-restoration-program [https://perma.cc/SAT3-NAA2] (last visited Jan. 18, 2025).

      [148].     Cook-Deegan & Heaney, supra note 147, at 383–84.

      [149].     35 U.S.C. § 101.

      [150].     Id.

      [151].     Id. § 102.

      [152].     Id. § 103.

      [153].     Id. § 112.

      [154].     Id.

      [155].     Amy Kapczynski, Chan Park & Bhaven Sampat, Polymorphs and Prodrugs and Salts (Oh My!): An Empirical Analysis of “Secondary” Pharmaceutical Patents, 7 PLoS One 1, 1 (2012).

      [156].     Daniel J. Nam, Patent & Regulatory Exclusivities: The Two Keys Driving Generic and Follow-on Market Availability, 41 U.S. Pharmacist 6 (2016).

      [157].     U.S. Const. art. 1, § 8, cl. 8 (providing the Intellectual Property Clause of the U.S. Constitution).

      [158].     See Rachel E. Sachs, The Uneasy Case for Patent Law, 117 Mich. L. Rev. 499, 503 (2018).

      [159].     See generally Schlander et al., supra note 146 (reviewing literature to estimate total research and development costs for drugs).

      [160].     Cynthia M. Ho, Drugged Out: How Cognitive Bias Hurts Drug Innovation, 51 San Diego L. Rev. 419, 421 & n.6 (2014).

      [161].     See, e.g., Henry Grabowski, Patents, Innovation and Access to New Pharmaceuticals, 5 J. Int’l Econ. L. 849, 850–51 (2002) (describing studies supporting the importance of patents for increasing pharmaceutical innovation).

      [162].     Id. at 851.

      [163].     Kapczynski, Park & Sampat, supra note 155, at 1.

      [164].     Michael K. Dunn, Timing of Patent Filing and Market Exclusivity, 10 Nature Revs. Drug Discovery 487, 488 (2011); Small Business Assistance: Frequently Asked Questions on the Patent Term Restoration Program, supra note 147.

      [165].     See Dunn, supra note 164, at 488; Small Business Assistance: Frequently Asked Questions on the Patent Term Restoration Program, supra note 147.

      [166].     Leticia Monjas-Gómez, Data & Market Exclusivity as Incentives in Drug Development, Scendea, https://www.scendea.com/data-market-exclusivity-as-incentives-in-drug-development [https://perma.cc/4WYH-YYMA] (last visited Aug. 31, 2024).

      [167].     Frequently Asked Questions on Patents and Exclusivity, U.S. Food & Drug Admin. (Feb. 5, 2020), https://www.fda.gov/drugs/development-approval-process-drugs/frequently-asked-questions-patents-and-exclusivity [https://perma.cc/QA3X-246G].

      [168].     Id.; see generally Bo Peng & Marta Cavero Tomas, A Cheat Sheet to Navigate the Complex Maze of Exclusivities in the United States, 3 Pharm. Pat. Analyst 339 (2014) (explaining regulatory and other pharmaceutical exclusivities).

      [169].     Dunn, supra note 164, at 487.

      [170].     Id.

      [171].     Rare Diseases at FDA, U.S. Food & Drug Admin., https://www.fda.gov/patients/rare-diseases-fda#:~:text=Back%20to%20top-,What%20is%20an%20orphan%20drug%3F,drug%20development%20for%20rare%20diseases [https://perma.cc/7XCT-NGFN] (last visited Jan. 18, 2025).

      [172].     Small Business Assistance: Frequently Asked Questions for New Drug Product Exclusivity, U.S. Food & Drug Admin. (Feb. 11, 2016), https://www.fda.gov/drugs/cder-small-business-industry-assistance-sbia/small-business-assistance-frequently-asked-questions-new-drug-product-exclusivity [https://perma.cc/QA3X-246G]; Frequently Asked Questions on Patents and Exclusivity, supra note 167.

      [173].     Frequently Asked Questions on Patents and Exclusivity, supra note 167.

      [174].     Small Business Assistance: Frequently Asked Questions for New Drug Product Exclusivity, supra note 172.

      [175].     Monjas-Gómez, supra note 166.

      [176].     See, e.g., Aaron S. Kesselheim, Michael. S. Sinha & Jerry Avorn, Determinants of Market Exclusivity for Prescription Drugs in the United States, 177 JAMA Internal Med. 1658, 1658 (2017) (noting that “most new drugs receive about 12 to 16 years of market exclusivity from both kinds of monopoly protection combined.”).

      [177].     Universal Declaration of Human Rights, G.A. Res. 217A (III) (1948), Art. 25.

      [178].     International Covenant on Economic, Social and Cultural Rights, G.A. Res. 2200A (XXI) (1966), Art. 12.

      [179].     Joseph Millum, Are Pharmaceutical Patents Protected by Human Rights?, 34 J. Med. Ethics 25, 25 (2008).

      [180].     Expert Committee on Selection and Use of Essential Medicines, World Health Org., https://www.who.int/groups/expert-committee-on-selection-and-use-of-essential-medicines [https://perma.cc/HSE9-FA6B] (last visited Aug. 31, 2024).

      [181].     S. Vincent Rajkumar, The High Cost of Prescription Drugs: Causes and Solutions, 10 Blood Cancer J. 1, 1 (2020).

      [182].     See, e.g., Ashoka, How to Fix The Drug Pricing Crisis—And The Patent Problem Fueling It, Forbes (Mar. 23, 2022), https://www.forbes.com/sites/ashoka/2022/03/23/how-to-fix-the-drug-pricing-crisis-and-the-patent-problem-fueling-it/?sh=4b8ac2dd1048 [https://perma.cc/P9VX-X6QX].

      [183].     Laurie Flynn, What is Behind the Legal Drug Crisis in the US?, Stan. Med. Scope (Oct. 6, 2023), https://scopeblog.stanford.edu/2023/10/06/pharmaceuticals-pricing-generics-medicare/ [https://perma.cc/2HYC-PKG8].

      [184].     See id.; Rebecca Robbins & Christina Jewett, Six Reasons Drug Prices Are So High in the U.S., N.Y. Times (Jan. 17, 2024), https://www.nytimes.com/2024/01/17/health/us-drug-prices.html [https://perma.cc/G665-24TQ].

      [185].     Grabowski, supra note 161, at 856.

      [186].     Id.

      [187].     See Millum, supra note 179, at 26.

      [188].     Id.

      [189].     See, e.g., Brigitte Tenni, Hazel V. J. Moir, Belinda Townsend, Burcu Kilic, Anne-Maree Farrell, Tessa Keegel & Deborah Gleeson, What is the Impact of Intellectual Property Rules on Access to Medicines? A Systematic Review, 18 Globalization & Health 1 (2022) (discussing the impact of intellectual property protection on drug pricing and access).

      [190].     Cf. Angélique McCall & Gene Quinn, The FDA Process, Patents and Market Exclusivity, IPWatchdog (Mar. 12, 2017), https://ipwatchdog.com/2017/03/12/fda-process-patents-market-exclusivity/id=79305/ [https://perma.cc/39Q2-F3MV] (describing the function of the FDA in the drug approval process and explaining different types of exclusivity).

      [191].     See generally Weiswasser & Danzis, supra note 75 (describing the Hatch-Waxman Act and its goals); see, e.g., Patents, Market Exclusivity, and Generic Drugs, Friends Cancer Rsch., https://friendsofcancerresearch.org/glossary-term/patents-market-exclusivity-and-generic-drugs/ [https://perma.cc/9U7R-C64B] (last visited Aug. 31, 2024).

      [192].     Again, note that the distinction between brand-name drugs and generic drugs is entirely separate from the distinction between first-in-class and me-too drugs. See supra note 120 and accompanying text.

      [193].     See, e.g., Nam, supra note 156 (providing an example of the difficulties in balancing the need to incentivize innovation with the need to maintain equitable access to medicines).

      [194].     See McCall & Quinn, supra note 190; see also Duxin Sun, Wei Gao, Hongxiang Hu & Simon Zhou, Why 90% of Clinical Drug Development Fails and How to Improve It?, 12 Acta Pharmaceutica Sinica B 3049, 3050 (2022) (asserting that 90 percent of drugs fail out of the clinical development pipeline).

      [195].     See supra Part I.A.

      [196].     See, e.g., Scott D. Halpern, Jason H. T. Karlawish & Jesse A. Berlin, The Continuing Unethical Conduct of Underpowered Clinical Trials, 288 JAMA 358, 358 (2002) (discussing ethical issues in clinical trials).

      [197].     See Matt Lamkin & Carl Elliott, Avoiding Exploitation in Phase I Clinical Trials: More than (Un)Just Compensation, 46 J.L. Med. Ethics 52, 53 (2018) (noting the TGN1412 study at Northwick Park Hospital in England).

      [198].     See David F. Horrobin, Are Large Clinical Trials in Rapidly Lethal Diseases Usually Unethical?, 361 Lancet 695, 695 (2003).

      [199].     Universal Declaration of Human Rights, supra note 177.

      [200].     International Covenant on Civil and Political Rights, G.A. Res. 2200A (XXI) (1966), Art. 7.

      [201].     George J. Annas, Bodily Integrity and Informed Choice in Times of War and Terror, A.B.A (Apr. 1, 2003), https://www.americanbar.org/groups/crsj/publications/human_rights_magazine_home/human_rights_vol30_2003/spring2003/hr_spring03_intro/#:~:text=The%201948%20Universal%20Declaration%20of,course%2C%20do%20not%20view%20human [https://perma.cc/M9U8-MG3R].

      [202].     Andrés Constantin, Human Subject Research: International and Regional Human Rights Standards, Health & Hum. Rts. J. (Dec. 4, 2018), https://www.hhrjournal.org/2018/12/human-subject-research-international-and-regional-human-rights-standards/#_edn15 [https://perma.cc/SA2C-M2VD].

      [203].     June Smith-Tyler, Informed Consent, Confidentiality, and Subject Rights in Clinical Trials, 4 Procs. Am. Thoracic Soc’y 189, 189 (2007).

      [204].     See supra Introduction.

      [205].     Id.

      [206].     See generally Emily A. Largent & Holly Fernandez Lynch, Paying Research Participants: Regulatory Uncertainty, Conceptual Confusion, and a Path Forward, 17 Yale J. Health Pol’y L. Ethics 61 (2017) (describing this phenomenon). Acknowledging that excessively high payments run the risk of unduly influencing trial participants to undergo experimentation that they would otherwise not, the FDA has supported minimal payments to subjects as compensation for their participation in clinical trials. See Lamkin & Elliott, supra note 197.

      [207].     Carl Elliott & Trudo Lemmens, Ethics for Sale, SLATE (Dec. 13, 2005), https://slate.com/technology/2005/12/ethics-for-sale.html [https://perma.cc/DT6J-8YRV]; see Elliott, supra note 46.

      [208].     David Evans & Michael Smith, Three Drug Testers Claim SFBC Threatened Them, Seattle Times (Nov. 20, 2005), https://www.seattletimes.com/business/three-drug-testers-claim-sfbc-threatened-them/ [https://perma.cc/X7W6-EQJ2].

      [209].     Elliott & Lemmens, supra note 207.

      [210].     See Cecilia Nardini, The Ethics of Clinical Trials, 8 ecancer Med. Sci. 387, 388–89 (2014).

      [211].     Carl Elliott, U. Minn., https://cla.umn.edu/about/directory/profile/ellio023 [https://perma.cc/N4UR-H8DY] (last visited Aug. 27, 2024).

      [212].     Lisa Chedekel, The Dark Side of Drug Trials, BU Today (Mar. 7, 2012), https://www.bu.edu/articles/2012/the-dark-side-of-drug-trials/ [https://perma.cc/BU77-SF54].

      [213].     Trudie Lang & Sisira Siribaddana, Clinical Trials Have Gone Global: Is This a Good Thing?, 9 PLoS Med. 1, 2, 4 (2012); see generally Yang et al., supra note 23 (describing the challenges of globalized clinical trials and highlighting problems with regulatory oversight for offshore testing).

      [214].     Sohyun Jeong, Minji Sohn, Jae Hyun Kim, Minoh Ko, Hee-won Seo, Yun-Kyoung Song, Boyoon Choi, Nayoung Han, Han-Sung Na, Jong Gu Lee, In-Wha Kim, Jung Mi Oh & Euni Lee, Current Globalization of Drug Interventional Clinical Trials: Characteristics and Associated Factors, 2011-2013, 18 Trials 1, 1 (2017).

      [215].     Id.

      [216].     Id. at 2. One study reported that sponsors completed Phase III trials approximately six to seven months earlier in non-American, non-European settings. Id. Another stated that sponsors prefer to conduct Phase II and III trials in China, India, and South America, given the potential “cost saving[]” benefits of those locations. Id.

      [217].     Id. at 5.

      [218].     Katrin Weigmann, The Ethics of Global Clinical Trials, 16 EMBO Reps. 566, 566 (2015).

      [219].     Id.

      [220].     Id.

      [221].     Fabio A. Thiers, Anthony J. Sinskey & Ernst R. Berndt, Trends in the Globalization of Clinical Trials, 7 Nature Revs. Drug Discovery 13, 13 (2008).

      [222].     Alexander Simmonds, Ethics of Placebo-Controlled Trials in Developing Countries: The Search for Standards and Solutions, 7 Morningside Rev. 45, 45 (2020). It is worth noting that there are some benefits to globalized trials; for example, diversified participant populations might lead to more accurate clinical data that better reflects diversity in consumers. Thiers, Sinskey & Brendt, supra note 221. It is, of course, important that drug products are tested in a wide range of populations—and for many years, significant subpopulations have remained under-represented in clinical research and medicine. Lang & Siribaddana, supra note 213, at 1.

      [223].     Simmonds, supra note 222, at 45.

      [224].     Id. at 46–47.

      [225].     Id. at 46.

      [226].     Vasantha Muthuswamy, Ethical Issues in Clinical Research, 4 Persps. Clinical Rsch. 9, 10 (2013).

      [227].     See generally FDA in the Twenty-First Century: The Challenges of Regulating Drugs and New Technologies (Holly Fernandez Lynch & I. Glenn Cohen eds., 2015) (describing, among other topics, the history of the FDA, its evolution through changes in drug development, and regulatory challenges for adapting to new technological areas).

      [228].     WHO Releases Report on State of Development of Antibacterials, World Health Org. (June 14, 2024), https://www.who.int/news/item/14-06-2024-who-releases-report-on-state-of-development-of-antibacterials [https://perma.cc/M36A-D38L].

      [229].     See generally, e.g., Brown & Wright, supra note 32 (describing the problem of antibiotic resistance).

      [230].     Gary Humphreys, John Rex: The Case for Investment in Antimicrobials, 101 Bull. World Health Org. 369, 369 (2023).

      [231].     Id.

      [232].     See, e.g., Anne J. Manning, Paving the Way for a New Class of Antibiotics, Harv. Gazette (Mar. 5, 2024), https://hms.harvard.edu/news/paving-way-new-class-antibiotics [https://perma.cc/G4FS-K2PX] (“No new antibiotics have been introduced for [G]ram-negative bacteria in more than 50 years, and the WHO has declared that development of new antibiotics remains ‘inadequate’ to address the global threat of antibiotic resistance.”).

      [233].     World Health Org., 2023 Antibacterial Agents in Clinical and Preclinical Development: An Overview and Analysis (2024).

      [234].     WHO Releases Report on State of Development of Antibacterials, supra note 228.

      [235].     Id.

      [236].     Id.

      [237].     2023 Antibacterial Agents in Clinical and Preclinical Development, supra note 233, at 68; see generally Brown & Wright, supra note 32 (emphasizing the importance of adequate antibiotics to modern medicine).

      [238].     See Chris Dall, Report Warns of ‘Brain Drain’ from Antibiotic Research and Development, CIDRAP (Feb. 8, 2024), https://www.cidrap.umn.edu/antimicrobial-stewardship/report-warns-brain-drain-antibiotic-research-and-development [https://perma.cc/36CG-Y7XA] (highlighting the “steady decline in [antimicrobial resistance] researchers”).

      [239].     Id.; see also Chris Dall, Achaogen Bankruptcy Raises Worry Over Antibiotic Pipeline, CIDRAP (Apr. 16, 2019), https://www.cidrap.umn.edu/antimicrobial-stewardship/achaogen-bankruptcy-raises-worry-over-antibiotic-pipeline [https://perma.cc/6BRB-SKZQ] (providing an example of an antibiotic developer that filed for bankruptcy due to insufficient profits from their lead antibiotic candidate).

      [240].     Dall, Achaogen, supra note 239.

      [241].     See, e.g., Ilinca A. Dutescu & Sean A. Hillier, Encouraging the Development of New Antibiotics: Are Financial Incentives the Right Way Forward? A Systematic Review and Case Study, 14 Infection & Drug Resistance 415, 419–23 (2021); Push and Pull Incentives, GARDP, https://revive.gardp.org/resource/push-and-pull-incentives/?cf=encyclopaedia [https://perma.cc/R5PQ-23YK] (last visited Nov. 4, 2024).

      [242].     Dutescu & Hillier, supra note 241, at 419.

      [243].     Dall, Report, supra note 238.

      [244].     Dutescu & Hillier, supra note 241, at 419.

      [245].     Id.

      [246].     See id.

      [247].     GAIN: How a New Law is Stimulating the Development of Antibiotics, Pew (Nov. 7, 2013), https://www.pewtrusts.org/en/research-and-analysis/issue-briefs/2013/11/07/gain-how-a-new-law-is-stimulating-the-development-of-antibiotics#:~:text=GAIN%20grants%20an%20additional%20five,of%20market%20protection%20is%20in [https://perma.cc/S95M-SDJG].

      [248].     Tarishi Gupta, Gain Exclusivity, IQVIA (Jan. 7, 2021), https://www.iqvia.com/blogs/2021/01/gain-exclusivity [https://perma.cc/LML4-TTZG].

      [249].     See supra Part II.B.

      [250].     Ryan Chapman, Why is it so Hard to Develop New Antibiotics?, Wellcome (Jan. 21, 2020), https://wellcome.org/news/why-is-it-so-hard-develop-new-antibiotics#why-is-it-so-difficult-to-develop-new-antibiotics?-ad17 [https://perma.cc/H4QR-7VRK].

      [251].     Rowan Walrath, New Antibiotics are Hard to Come By. Red Tape is Making the Problem Worse, Chem. & Eng’g News (May 31, 2024), https://cen.acs.org/pharmaceuticals/antibiotics/New-antibiotics-hard-come-Red-tape-making-the-problem-worse/102/i17 [https://perma.cc/Q4AD-XZG8].

      [252].     Id.; cf. Few Antibiotics Under Development, ReAct, https://www.reactgroup.org/toolbox/understand/how-did-we-end-up-here/few-antibiotics-under-development/ [https://perma.cc/58XD-XCK3] (last visited Nov. 4, 2024) (discussing financial barriers and unclear regulatory requirements as contributing to abandonment); Skender, supra note 106, at 4.

      [253].     S. 1355, 118th Cong. (2023) (providing the PASTEUR Act of 2023, a bill to authorize the Department of Health and Human Services to enter into subscription contracts for antibiotics).

      [254].     Walrath, supra note 251; John Parkinson & Amanda Jezek, An Update on the Pasteur Act, ContagionLive (Sep. 5, 2024), https://www.contagionlive.com/view/an-update-on-the-pasteur-act [https://perma.cc/AYL5-N959].

      [255].     Scholars sometimes approximate pharmaceutical innovation by tracking the number of FDA approvals of New Molecular Entities (NMEs). See, e.g., Kapczynski, Park & Sampat, supra note 155, at 3, 5. The FDA defines NMEs as “novel drugs,” or “products [that] contain active moieties that [the] FDA had not previously approved.” Novel Drug Approvals at FDA, U.S. Food & Drug Admin. (Apr. 8, 2024), https://www.fda.gov/drugs/development-approval-process-drugs/novel-drug-approvals-fda [https://perma.cc/D4KK-RLUS].

[256]    See supra Part I.C.

      [257].     See Razelle Kurzrock, The Argument in Favor of ‘Me-Too’ Drug Approvals for Cancer Care, ASCO Daily News (June 16, 2021), https://dailynews.ascopubs.org/do/argument-favor-me-too-drug-approvals-cancer-care [https://perma.cc/J2QE-6FR4]; Mark J. DiNubile, Noninferior Antibiotics: When Is “Not Bad” “Good Enough”?, 3 Open F. Infectious Diseases 1 (2016).

      [258].     See, e.g., Richard Bergström, Recognising the Value of the “Me-Too”, Eur. Fed’n Pharm. Indus. & Ass’ns (Aug. 1, 2014), https://efpia.eu/news-events/the-efpia-view/blog-articles/140108-recognising-the-value-of-the-me-too/ [https://perma.cc/U4PL-P9XM] (“The value of me-too’s lies largely in the minute differences that set them apart from their predecessors. This is especially true when we look at the escalating war against viruses and resistant bacteria. We need more variants to combat the development of resistance, a growing concern at global level.”).

      [259].     See supra Part I.C.

      [260].     See Aidan Hollis, Me-Too Drugs: Is There A Problem? 1 (2005).

      [261].     Stephane Régnier, What is the Value of ‘Me-Too’ Drugs?, 16 Health Care Mgmt. Sci. 300, 312 (2013).

      [262].     Id.

      [263].     Joshua J. Gagne & Niteesh K. Choudhry, How Many “Me-Too” Drugs Is Too Many?, 305 JAMA 711, 711 (2011) (where “best price discount” means “the difference between the average price paid by pharmacies and the lowest price paid by any private purchaser in the United States”). To be sure, more economic research is certainly required to fully understand the substantial market impact of me-too drugs. As some have noted, the alleged “free market” of prescription drugs is likely a fallacy, with “the assumptions underlying a well-functioning market imply[ing] that consumers have complete and accurate knowledge of the efficacy, safety, and side effects of an array of drugs”—and they do not. David S. Guzick, The ‘Invisible Hand’ Doesn’t Work for Prescription Drugs, 136 Am. J. Med. 333, 333 (2023) (“The depiction of how Adam Smith’s invisible hand guides the price and utilization of prescription drugs under a free market is so far from reality as to be fantastical.”). For example, consumers are not well-positioned to make rational choices based on cost-benefit analyses of acceptable drug prices, and demand for pharmaceuticals is largely independent from the manufacturers who supply them. See id. at 333–34 (providing a list of assumptions of well-functioning markets that do not apply in the case of pharmaceutical drugs).

      [264].     Fair & Tor, supra note 108, at 26 (“Regulatory hurdles have also muted the interest of major pharmaceutical companies.”).

      [265].     See, e.g., John H. Rex, George H. Talbot, Mark J. Goldberger, Barry I. Eisenstein, Roger M. Echols, John F. Tomayko, Michael N. Dudley & Aaron Dane, Progress in the Fight Against Multidrug-Resistant Bacteria 2005–2016: Modern Noninferiority Trial Designs Enable Antibiotic Development in Advance of Epidemic Bacterial Resistance, 65 Clinical Infectious Diseases 141, 141 (2017) (describing this “paradox”); John H. Rex, Holly Fernandez Lynch, I. Glenn Cohen, Jonathan J. Darrow & Kevin Outterson, Designing Development Programs for Non-Traditional Antibacterial Agents, 10 Nature Commc’ns 1, 4 (2019) (“Unlike rare genetic disease or tumors where there is time to refer to a specialty center, acute infections progress to produce substantial morbidity and mortality over hours to a few days.”).

      [266].     Id.

      [267].     See generally Brad Spellberg, Roger J. Lewis, Helen W. Boucher & Eric P. Brass, Design of Clinical Trials of Antibacterial Agents for Community-Acquired Bacterial Pneumonia, 1 Clinical Investigations 19 (2011) (discussing ethical challenges associated with clinical trials of new antibiotics against community-acquired bacterial pneumonia, highlighting issues with control group selection).

      [268].     See supra Part II.C.

      [269].     See Rex et al., Progress in the Fight, supra note 265, at 141.

      [270].     See Bax, Gabbay & Phillips, supra note 33.

      [271].     See Mical Paul, Yael Dishon-Benattar, Yaakov Dickstein & Dafna Yahav, Optimizing Patient Recruitment into Clinical Trials of Antimicrobial-Resistant Pathogens, 27 JAC-Antimicrobial Resistance 1, 2 (2023).

      [272].     See Ed Miseta, The (Almost) Insurmountable Recruitment Challenges of Antibiotic Clinical Trials, Clinical Leader (May 7, 2020), https://www.clinicalleader.com/doc/the-almost-insurmountable-recruitment-challenges-of-antibiotic-clinical-trials-0001 [https://perma.cc/NC45-3CDE].

      [273].     Id.

      [274].     See supra Part II.C (discussing the issues of globalized clinical research).

      [275].     Paul et al., supra note 271, at 1–2.

      [276].     See, e.g., David M. Shlaes, Dan Sahm, Carol Opiela & Brad Spellberg, The FDA Reboot of Antibiotic Development, 57 Antimicrobial Agents & Chemotherapy 4605, 4606–07 (2013).

      [277].     See Greene & Podolsky, supra note 58, at 1482.

      [278].     See id. at 1481–82.

      [279].     See supra Part I.A, describing the codified standard that there must be substantial evidence consisting of adequate and well-controlled investigations demonstrating that a new drug has the effect it purports to have under the advertised conditions of use.

      [280].     See Rex, supra note 136. John Rex, Scott Evans, and others have also proposed expanding the notion of efficacy and using alternative metrics to assess the outcomes of clinical trials. Id.; see also, e.g., Scott R. Evans, Daniel Rubin, Dean Follman, Gene Pennello, W. Charles Huskins, John H. Powers, David Schoenfeld, Christy Chuang-Stein, Sara E. Cosgrove, Vance G. Fowler, Jr., Ebbing Lautenbach & Henry F. Chambers, Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of Antibiotic Risk (RADAR), 61 Clinical Infectious Diseases 800 (2015) (describing a new paradigm for evaluating drug benefits and harm, considering overall clinical outcome). A central idea here is that new drug products might be better evaluated based on holistic clinical outcomes, more comprehensively considering adverse effects, complications, and patient symptom experiences. Id.; see also Desirability of Outcome Ranking (DOOR), Antibacterial Resistance Leadership Grp., https://arlg.org/desirability-of-outcome-ranking-door/ [https://perma.cc/5LN8-FKZY] (last visited Nov. 19, 2024) (noting new methods for clinical trial analysis based on overall clinical outcome and a more expansive assessment of patient experience).

      [281].     To be sure, this problem is extraordinarily complex, and adequate solutions will require input from both regulators and medical professionals with clinical research expertise.

      [282].     Fair & Tor, supra note 108, at 26 (“Approval requirements during clinical trials have escalated in most cases from demonstration of noninferiority to superiority, and at times a lack of clear trial guidelines for antibiotics, in particular, have stifled development.”). Similarly, more recently the FDA explicitly suggested a preference for superiority over non-inferiority for even non-traditional antibiotic agents. Ursula Theuretzbacher & Laura J.V. Piddock, Non-Traditional Antibacterial Therapeutic Options and Challenges, 26 Cell Host & Microbe 61, 69 (2019).

      [283].     See Rex et al., Designing Development Programs, supra note 265, at 4, 6; Sunita Rehal, Tim P. Morris, Katherine Fielding, James R. Carpenter & Patrick P. J. Phillips, Non-Inferiority Trials: Are They Inferior? A Systematic Review of Reporting in Major Medical Journals, 6 Brit. Med. J. 1 (2016).

      [284].     Aaron Dane, John H. Rex, Paul Newell & Nigel Stallard, The Value of the Information That Can Be Generated: Optimizing Study Design to Enable the Study of Treatments Addressing an Unmet Need for Rare Pathogens, 9 Open F. Infectious Diseases 1, 1–2 (2022).

      [285].     Dane et al., supra note 284, at 6; Rex et al., Designing Development Programs, supra note 265, at 4 (“While superiority trials provide stronger evidence of efficacy, in many infection settings the only plausible trial design is non-inferiority.”); Matteo Quartagno, A. Sarah Walker, James R. Carpenter, Patrick P. J. Phillipsm & Mahesh K. B. Parmar, Rethinking Non-Inferiority: A Practical Trial Design for Optimising Treatment Duration, 15 Soc’y Clinical Trials 477, 477–78 (2018).

      [286].     See DiNubile, supra note 257.

      [287].     See Rex et al., Designing Development Programs, supra note 265, at 6–7. Note, however, that this ethical construction still does require a considerable degree of altruism on the part of trial participants.

      [288].     See, e.g., Theuretzbacher & Piddock, supra note 282, at 63; see generally Rex et al., Designing Development Programs, supra note 265 (describing the complexities of clinical research for “non-traditional” antibacterial agents and discussing non-inferiority and superiority trial designs).

      [289].     Of course, this proposal is not a suggestion that the FDA should require no showing of efficacy for me-too drugs, nor that the current FDA approval standard should be uniformly lowered across drug classes. Indeed, excessive leniency on the part of the FDA can lead to disastrous consequences. Take, for example, the regulatory lapses that catalyzed the opioid crisis. See Andrew Kolodny, How FDA Failures Contributed to the Opioid Crisis, 22 AMA J. Ethics 743, 744–45 (2020); Timeline of Selected FDA Activities and Significant Events Addressing Substance Use and Overdose Prevention, U.S. Food & Drug Admin. (Oct. 4, 2024), https://www.fda.gov/drugs/food-and-drug-administration-overdose-prevention-framework/timeline-selected-fda-activities-and-significant-events-addressing-substance-use-and-overdose#:~:text=FDA%20had%20worked%20with%20sponsors,abuse%2C%20addiction%2C%20and%20overdose [https://perma.cc/2QJW-NMAT]. Or the case of aducanumab (marketed under the brand name Aduhelm), a first-in-class drug intended to treat Alzheimer’s disease by targeting beta-amyloid accumulation. Rebecca Robbins, Biogen Abandons Its Controversial Alzheimer’s Drug Aduhelm, N.Y. Times (Jan. 31, 2024), https://nytimes.com/2024/01/31/business/biogen-alzheimers-aduhelm.html [https://perma.cc/FPY8-XA7N]. Described as “perhaps ‘the worst approval decision’” of the FDA, Aduhelm’s approval process featured unusual protocols and possibly fraudulent collaboration between the sponsoring company (Biogen) and the FDA. Id. In November 2024, Biogen lost market rights for Aduhelm in the United States, due to its insufficient efficacy in treating Alzheimer’s disease. Id.