American Journal of Law & Medicine

Leveraging Novel and Existing Pathways to Approve New Therapeutics to Treat Serious Drug-Resistant Infections

Accelerating the development and approval of novel therapeutics has emerged as a key public health priority given the mortality, morbidity, and economic costs associated with infections caused by drug-resistant bacteria. However, there is limited empirical evidence to guide policymaking, such as the factors that may disadvantage antibiotics compared to other classes of drugs. In this Article, we empirically examine characteristics of the key clinical trials underpinning FDA's approval of antibiotics and other drugs over the past decade. Despite perceptions that antibiotic trials are larger and more difficult to conduct, we find that antibiotic trials are no larger than those conducted for drugs approved in other disease areas with high unmet medical needs, suggesting that policymakers may need to target other levers to meaningfully stimulate innovation. We discuss the risks and benefits of harnessing new and existing regulatory pathways to speed the approval of new drugs, particularly those intended to treat patients with serious and life-threatening infections, and we evaluate ways that proposals for new regulatory pathways could be improved to better prioritize and expedite the approval of therapies with the greatest potential for patient health benefits.

     B. 505(B)(2) APPROVAL


Antimicrobial resistance is a growing public health concern. (1) The Centers for Disease Control and Prevention ("CDC") estimates that infections due to antibiotic-resistant organisms cause at least 23,000 deaths in the United States annually. (2) Antibiotic-resistant infections are more difficult and expensive to treat than antibiotic-susceptible infections, and the spread of antibiotic-resistant pathogens may disproportionately affect the global poor.' In 2014, the World Health Organization ("WHO") warned that every region had national reports of resistance to third-generation cephalosporins among E. coli and K. pneumoniae, meaning that clinicians would need to rely on costly, broad-spectrum carbapenems, which are less likely to be available in resource-poor settings, for treatment of severe infections caused by these pathogens. (4) The United Kingdom government's Review on Antimicrobial Resistance estimates that a continued rise in resistance by 2050 would lead to ten million deaths globally per year and a reduction of 2.0-3.5% in global gross domestic product, imposing a cost of $100 trillion. (5)

To address the threat of antibiotic resistance, society will need both new antibiotics and better conservation of existing (and future) antimicrobial resources. (6) Recently, legislators have focused on developing incentives to promote the development of novel antibiotics. For example, in 2012, Congress passed the Generating Antibiotic Incentives Now Act ("GAIN"), which established five years of additional market exclusivity for qualified infectious disease products, in addition to the five to seven years already guaranteed by law to all new drugs. (7) In addition, in 2012, the President's Council of Advisors on Science and Technology ("PCAST") proposed the creation of an accelerated regulatory approval process for antibiotics intended to be used in a "specific subpopulation at high risk from the disease" that would curtail the size and scope of required late-stage clinical trials. (8) PCAST also recommended that the Food and Drug Administration (FDA) use existing mechanisms to facilitate the approval of new drugs intended for patients infected with antibiotic-resistant bacteria. (9) In July 2015, the United States House of Representatives passed the 21st Century Cures Act, which included provisions that would codify this new regulatory pathway for approval of antibiotics to be used in limited patient populations. (10)

However, there is limited empirical evidence on antibiotic approvals (such as the size of antibiotic trials and their design) to inform ongoing policymaking. In addition, policymakers will need to ensure that new regulatory incentives are truly novel, and therefore additive to, existing approval mechanisms.

In this Article, we explore the risks and benefits of harnessing new and existing regulatory pathways to speed the approval of new drugs, particularly those intended to treat patients with serious and life-threatening infections, including infections caused by multidrug-resistant bacteria. We focus on the development of systemic antibacterial agents (and use the terms "antimicrobial" and "antibiotic" interchangeably here), but our results may also apply to other classes of antimicrobial agents, including antifungal and antiparasitic drugs. Part II describes the typical clinical development process for new drugs and reviews characteristics of the key trials underpinning FDA's approval of antibiotics and other drugs over the past decade. Part III discusses how existing expedited approval programs, as well as two additional pathways (505(b)(2) and the Animal Rule) that may help streamline the development of promising new antibiotics. Finally, Part IV concludes that a legislative proposal for a new regulatory pathway for antibiotics could be improved to better prioritize and expedite the approval of therapies with the greatest potential for patient health benefits.



Clinical trials are essential to evidence-based drug development because they allow patients, investigators, and regulators to assess the safety and efficacy of new drags before they are used in general practice. (11) In turn, the data generated from well-designed preapproval trials help patients and clinicians weigh the risks and benefits of new treatments and, ultimately, determine whether to use a newly approved therapeutic. (12) Traditionally, investigational drugs are tested in three phases of clinical trials. (13) During Phase 1, the sponsor recruits healthy volunteers to assess the drug's pharmacokinetic and safety characteristics. (14) After demonstrating in Phase 1 some sense of how a drug is metabolized and what the right dose range might be, the sponsor carries the drug forward into Phase 2 trials, the first trials that involve a population of patients with the disease. (15) Phase 2 trials are intended to establish a proper dose for the drug, to provide information on the drug's safety profile, and potentially to provide the first signs of a drag's efficacy. (16) If the results of the Phase 2 study suggest that the drug may be safe to administer to patients and may provide clinical benefit for the intended patient population, Phase 3 trials are then organized to establish a drug's efficacy by demonstrating that an observed benefit is attributable to the drug, as well as to provide more evidence of the drug's safety profile. (17) Phase 3 trials may enroll hundreds or thousands of patients. (18)

The trial design influences the level of confidence with which investigators can assess a drug's cause-effect hypothesis. (19) Design features, including randomization, blinding, and controls, help elucidate the risk-benefit balance of a drug by isolating the specific treatment effect due to the drug from non-specific effects such as the placebo effect and the natural progression of the disease. (20) Some of the earliest randomized controlled trials were developed to evaluate treatments for infectious diseases. (21) For example, in a seminal trial of streptomycin for the treatment of tuberculosis, Marshall and colleagues noted:

   The natural course of pulmonary tuberculosis is in fact so variable
   and unpredictable that evidence of improvement or cure following
   the use of a new drug in a few cases cannot be accepted as proof of
   the effect of that drug. The history of chemotherapeutic trials in
   tuberculosis is filled with errors due to empirical evaluation of
   drugs; the exaggerated claims made for gold treatment, persisting
   over 15 years, provide a spectacular example. (22)

Thus, without adequate and rigorous data collection before these drugs are used, there is greater risk that patients may be exposed to therapies that are not effective or that are associated with serious safety issues.

The primacy of randomized controlled trials in the hierarchy of research designs is statutorily defined. By law, FDA must certify that proposed new drugs demonstrate "substantial evidence" from "adequate and well-controlled studies" evaluating the safety and efficacy of investigational agents. (23) While rigorous evidence from pivotal trials is crucial for patients, clinicians, and regulators needing to make decisions about the risks and benefits of potential treatments, conducting these pivotal trials (defined as the primary clinical studies that demonstrate safety and efficacy and that serve as the basis for regulatory approval) is also a resource-intensive process. (24) Surveys of pharmaceutical companies indicate that clinical trials comprise between 40-60% of total research and development expenditures, (25) and the results of these studies often have an immediate and material impact on financial returns. (26) The size of the pivotal trial is an important determinant of the overall cost to the developer, and previous studies found that the quality of clinical trial evidence varied widely within and between indications. (27) Additional features of clinical trial design can affect its size. For example, a non-inferiority design measures whether a treatment is no worse than another within a predetermined margin; in contrast, the better known superiority design tests whether a drug is better than a comparator. (28) Reducing the margin of non-inferiority typically results in a larger required patient population. (29)

The need to enroll large numbers of patients in pivotal trials has been noted as a cause for the declining number of antibiotic approvals. (30) In response, recent proposals to accelerate antibiotic development have centered on reducing the size and number of required preapproval trials. (31) However, there is limited empirical evidence about the size and design of antibiotic pivotal trials, crucial data points that could illuminate ways to appropriately incentivize antibiotic development. In this Part, we review characteristics of the trials underpinning FDA's approval of antibiotics over the past decade (2002-2012), and we compare the evidentiary standards for new antibiotics with those for two other categories of disease (cancer and HIV/AIDS), which are also characterized by high unmet medical need.


To shed light on the state of the regulatory environment for antibiotics, we examined the pivotal trials for all new antibiotics (antibacterials, antifungals, and antiparasitics) approved by FDA between January 1, 2002 and December 31, 2012. The names and indications of all antibiotics were identified from public domain master lists of approvals published by FDA. Reformulations, previously approved agents, and generic drugs were excluded from the study cohort.

For all new drugs, FDA publishes key information relating to the novel therapeutic on its website. (32) Each online dossier comprises the approval order, product label, and drug approval package; the latter includes summaries of the agency's medical, chemistry, pharmacology, statistical, and microbiology reviews for that particular therapeutic. (33) Using methods described previously, (34) we extracted information on the design, including number of participants, number of pivotal trials, and non-inferiority versus superiority, of the pivotal studies from the summary reviews published by FDA, which contain condensed reports of the clinical evidence submitted by the manufacturer in support of the new drug, as well as analysis by FDA reviewers. For drugs approved for more than one indication, we considered each indication separately.

We then compared the characteristics of these trials with those conducted for antiviral drugs and oncology products, two therapeutic areas characterized by unmet medical needs and high public health importance. We used the nonparametric Wilcoxon rank sum test to compare the numbers of pivotal trials and patient enrollment in antibiotic versus antiviral and antibiotic versus cancer pivotal trials. (35) We compared both the total number of patients, including those on the comparator arm(s), if any, with the number of patients exposed to active treatment (hereinafter "efficacy patients") across disease areas. Statistical analyses were performed using the Stata software package, with a two-sided [alpha] = 0. …

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