Svirsky, Howard, and Berman address the U.S. Food and Drug Administration ’s oversight of tobacco products, the newest major area of regulation Congress assigned to the FDA. They discus...

Drug Safety Communications are used by the Food and Drug Administration to inform health care providers, patients, caregivers, and the general public about safety issues related to FDA-approved drugs. To assess patient knowledge of the messaging contained in DSCs related to the sleep aids zolpidem and eszopiclone, we conducted a large, cross-sectional patient survey of 1,982 commercially insured patients selected by stratified random sampling from the Optum Research Database who had filled at least two prescriptions for either zolpidem or eszopiclone (...) between July 1, 2012 and June 30, 2013. Among the 594 respondents, two-thirds reported hearing generally about drug safety information prior to starting a new drug, with the remaining one-third “rarely” or “never” hearing such information. Providers and pharmacists were primary sources of drug safety information. Two-thirds of zolpidem users and half of eszopiclone users reported having heard about the related DSC messages, ability to accurately identify the major factual messages was limited. Respondents reacted to new drug safety information about their sleep aids by reporting that they would want to learn about alternative ways to help them sleep and seek out more information about the safety of their specific sleeping pill. Opportunities may exist for the FDA to work with providers and pharmacies to help ensure the DSC information is more widely received and is more fully understood by those taking the affected medications. (shrink)

Only 19 new molecular entities and 3 biologics were approved by the Food and Drug Administration in 2007, the lowest rate in 24 years. This disappointing output occurred despite steady clinical trial and regulatory review times, the FDA maintaining high approval rates, and the pharmaceutical industry consistently reporting increasing revenues. A government report suggests that fewer new drug applications have been submitted to the FDA by the pharmaceutical industry in recent years. These data have rekindled the debate as to the (...) origins of pharmaceutical innovation and the comparative importance of public and private sources in contributing to drug discovery. The pharmaceutical industry contends that its research is responsible for most new medicines, and that the primary public institution supporting U.S. biomedical research, the National Institutes of Health, supports medical innovation “distinct from the process of drug development.”. (shrink)

Though many more patents emerge from industry sources, drug-related patents generated in the non-profit setting appear to have greater importance than patents arising from the commercial sector, which helps demonstrate the value non-profit research institutions can have in driving drug development.

The US government supports drug innovation. It is therefore crucial that it distinguish between high-value and low-value innovation in purchasing expensive prescription drugs and medical devices and ensure the continued discovery of transformative drugs and that patient and taxpayer funds are not wasted.

This special JLME symposium addresses ways that federal policy can incentivize innovation in medical therapeutics and make pharmaceuticals more financially accessible.

From the earliest application of modern randomized controlled trials in medical research, scientists and observers have deliberated the ethics of randomly allocating study participants to trial control arms. Adaptive RCT designs have been promoted as ethically advantageous over conventional RCTs because they reduce the allocation of subjects to what appear to be inferior treatments. Critical assessment of this claim is important, as adaptive designs are changing medical research, with the potential to significantly shift how clinical trials are conducted. Policy-makers are (...) swiftly moving to encourage greater use of adaptive designs. In 2016, the newly enacted 21st Century Cures Act instructed the Food and Drug Administration to help product sponsors incorporate adaptive methods into proposed clinical trial protocols and applications for investigational drugs and also biological products. In this article, we review the ethical justifications commonly offered for adaptive designs, explore these arguments in the context of actual trials, and contend that clinical equipoise is a useful standard for adaptive-trial ethics. We distinguish between theoretical and clinical equipoise and explain why ethical arguments related to adaptive trials tend to focus on the former. Yet we contend that theoretical equipoise can be an unreliable standard for adaptive ethics. While we contend that clinical equipoise is the most critical principle for the primary ethical concerns posed by adaptive trials, we suggest ethical approaches to deal with some additional concerns unique to adaptive designs. (shrink)

The rising cost of the opioid antagonist and overdose reversal agent naloxone is an urgent public health problem. The recent and dramatic price increase of Evzio, a naloxone auto-injector produced by Kaléo, shows how pharmaceutical manufacturers entering the naloxone marketplace rely on market exclusivity guaranteed by the patent system to charge prices at what the market can bear, which can restrict access to life-saving medication. We argue that 28 U.S.C. § 1498, a section of the federal code that allows the (...) government to use patent-protected products for its own purposes in exchange for reasonable compensation, could be used to procure generic naloxone auto-injectors, or at least bring Kaléo to the negotiating table. Precedent exists for the use of § 1498 to procure pharmaceuticals, and it could give meaning to the federal government's recent declaration of a public health emergency around the opioid epidemic, discourage new market entrants from charging exorbitant prices, and yield important public health benefits. (shrink)

Over-the-counter drugs are ubiquitous in the US. Policymakers have long debated how to modernize the system for making determinations of safety and effectiveness and addressing safety issues with OTC drugs.

The “right to repair” movement highlights opportunities to reduce health care costs and promote public health resilience through increased competition in the way in which medical devices are serviced and updated over their lifespan. We review legislative and legal facets of third-party repair of medical devices, and conclude with specific recommendations to help this market function more efficiently to the benefit of patients and health care systems.

Many hold that the so-called golden era of antibiotic discovery has passed, leaving only a limited clinical pipeline for new antibiotics. A logical conclusion of such arguments is that we need to reform the current system of antibiotic drug research—including clinical trials and regulatory requirements—to spur activity in discovery and development. The United States Congress in the past few years has debated a number of bills to address this crisis, including the 2012 Generating Antibiotic Incentives Now Act and the 2016 (...) 21st Century Cures Act. Experts have also sought to advance antibiotic development by encouraging greater use of trials with noninferiority hypotheses, which are thought to be easier to conduct. The goal underlying these proposals is to stave off the post-antibiotic era by expanding the pharmaceutical armamentarium as quickly as possible. But although new antibiotic agents are necessary to combat the long-term threat of drug-resistant disease, we argue that these research policies, which effectively lower the bar for antibiotic approval, are ethically problematic. Rather, given broader public health considerations related to the full lifecycle of antibiotic use—including development of resistance—we should reject an overly permissive approach to new antibiotic approval and instead set the bar for regulatory approval at a point that will naturally direct research resources toward the most transformative chemical or social interventions. (shrink)

We use the format of a hypothetical case study to review issues related to pharmaceutical product approval and physician prescribing practices. In this case, a new FDA-approved drug is recommended for a patient who subsequently experiences an adverse event that may or may not be related to the prescription. This case raises a number of ethical and legal considerations physicians routinely face when deciding whether to recommend such drugs for their patients. Despite the need for ongoing observation by the regulatory (...) apparatus, physicians should be cognizant of the limitations of the drug approval system and the post-approval prescription drug surveillance system. We discuss physicians’ ethical obligations when faced with a newly approved drug, including seeking out independent sources of learning, reporting adverse effects, and notifying patients about limitations in available knowledge about therapeutic recommendations. (shrink)

To improve the value of pharmaceutical spending, some manufacturers and payers have introduced outcomes-based contracts, where rebates are tied to specified outcomes. We reviewed the literature and interviewed key experts to assess these contracts' potential to slow pharmaceutical spending. We found that while outcomes-based contracts are increasingly common in the US, they are still limited by multiple factors — including the lack of meaningful outcomes data. Moreover, there is no evidence to date that they slow pharmaceutical spending or increase access. (...) Experts favored having CMS test and rigorously evaluate this model to achieve a better understanding of the implications. (shrink)

Physicians, scholars, and policymakers continue to be concerned about conflicts of interests among health care providers. At least two main types of objections to conflicts of interest exist. Conflicts of interests may be intrinsically troublesome if they violate providers’ fiduciary duties to their patients or they contribute to loss of trust in health care professionals and the health care system. Conflicts of interest may also be problematic in practice if they bias the decisions made by providers, adversely impacting patient outcomes (...) or wastefully increasing health care costs. This latter objection may be observed in differences in the prescriptions written, procedures performed, or costs billed by health care professionals who have conflicting interests, when compared to those that do not have such financial relationships. (shrink)

Legal challenges to the FDA’s approval of mifepristone have destabilized patients’ ability to access controversial medicines like medication abortion. We argue that federal courts’ receptiveness to this litigation undermines the coherence and integrity of prescription drug regulation in the U.S.

Effective medical innovation is a common goal of policymakers, physicians, researchers, and patients both in the private and public sectors. With the recent slowdown in approval of new transformative prescription drugs, many have looked back to the “golden years” of the 1980s and 1990s when numerous breakthrough products emerged. We conducted a qualitative study of innovators directly involved in creation of groundbreaking drugs during that era to determine what made their work successful and how the process of conducting medical innovation (...) has changed over the past 3 decades. Transcripts were analyzed using standard coding techniques and the constant comparative method of qualitative data analysis to identify the positive features of and challenges posed by the past and present therapeutic innovation environments . Interviewees emphasized the continued central role played by individuals and the institutions they were a part of in driving innovation. In addition, respondents discussed the importance of collaboration between individuals and institutions to share resources and expertise. Strong underlying basic science was also cited to be a major contributing factor to the success of an innovation. The climate for modern-day medical innovation involves a greater emphasis on patenting in academia, difficulty negotiating the technology transfer process, and funding constraints. Regulatory demands or reimbursement concerns were not commonly cited as factors that influenced transformative innovation. This study suggests that generating future transformative innovation will require a simplification of the current technology transfer process, continued commitment to basic science research, and policy changes that promote meaningful collaboration between individuals from disparate institutions. (shrink)

The discovery and development of new therapeutics has always been central to improving health worldwide. However, there is ongoing concern regarding the current state of medical innovation. Output from the pharmaceutical industry has been criticized for not being “transformative,” that is, offering substantial improvements in patient outcomes over existing therapeutics. While the cost of drug development continues to rise, breakthrough therapies remain elusive and one half of Phase 3 studies fail. Venture capital, a traditional source of funding for new breakthrough (...) biomedical innovations, has decreased investment by 30% in the biotechnology and medical device sectors from 2007 to 2013. Stakeholders question whether the new drugs approved each year by the FDA —many criticized as marginal improvements over existing therapies — justify the enormous investment. (shrink)

In many countries, health technology assessment organizations determine the economic value of new drugs and make recommendations regarding appropriate pricing and coverage in national health systems. In the US, recent policy proposals aimed at reducing drug costs would link drug prices to six countries: Australia, Canada, France, Germany, Japan, and the UK. We reviewed these countries’ methods of HTA and guidance on price and coverage recommendations, analyzing methods and guidance documents for differences in the methodologies HTA organizations use to conduct (...) their evaluations and considerations they use when making recommendations. We found important differences in the methods, interpretations of HTA findings, and condition-specific carve-outs that HTA organizations use to conduct evaluations and make recommendations. These variations have ethical implications because they influence the recommendations of HTA organizations, which affect access to the drug through national insurance and price negotiations with manufacturers. The differences in HTA approaches result from the distinct political, social, and cultural contexts of each organization and its value judgments. New cost-containment policies in the US should consider the ethical implications of the HTA reviews that they are considering relying on to negotiate drug prices and what values should be included in US pricing policy. (shrink)

Through the Louisiana Purchase in 1803, the United States expanded its size by over 800,000 square miles. But neither President Thomas Jefferson nor Congress knew exactly what they had bought until 1806, when Meriwether Lewis and William Clark returned from their famous expedition. One of the most significant contributions of the Expedition was a better perception of the geography of the Northwest. Lewis and Clark prepared approximately 140 maps and filled in the main outlines of the previously blank map of (...) the northwestern United States. Robert I. Field has done much the same for the vast territory of U.S. health care regulation.On the front cover of Fields new book, Health Care Regulation in America: Complexity, Confrontation, and Compromise, is a picture of a giant three-dimensional labyrinth. Rarely is cover art so perfectly appropriate. (shrink)

Conflicts of Interest and the Future of Medicine: The United States, France, and Japan Content Type Journal Article Category Book Review Pages 383-386 DOI 10.1007/s11673-011-9326-y Authors Adam Licurse, Division of Internal Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA Aaron S. Kesselheim, Harvard Medical School, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, 1620 Tremont St. Suite 3030, Boston, MA, USA Journal Journal of Bioethical Inquiry Online ISSN 1872-4353 Print ISSN 1176-7529 (...) Journal Volume Volume 8 Journal Issue Volume 8, Number 4. (shrink)

Brand-name prescription drug manufacturers use various strategies to extend their market exclusivity periods by delaying generic or biosimilar competition. Recent Congressional legislation has targeted four such tactics. We analyze these proposals and assess their likely effect on competition in the U.S. drug market.

New research and a government investigation have shed light on an anticompetitive practice called “Product Hopping” and specifically how it was employed in the case of the multiple sclerosis treatment glatiramer acetate beginning in 2014, which cost payers billions of dollars. We examine this case as well as a separate, impending instance of product hopping.

Biomarkers can be powerful tools to guide diagnosis, treatment, and research. However, prudent use of biomarkers requires formal validation efforts. Although the data needed for biomarker validation has traditionally been hard to access, new research initiatives can ease this process.

The European Commission’s proposal to address antimicrobial resistance using transferable exclusivity vouchers (TEVs) is fundamentally flawed. European policymakers and regulators should consider alternatives, such as better funding for basic and clinical research, use of advance market commitments funded by a pay-or-play tax, or enacting an EU Fund for Antibiotic Development.

The FDA's new table of surrogate endpoints used for drug approvals is an important step forward for overseeing the use of biomarkers in clinical trials. Nevertheless, we present several ways in which the table can be improved.

Gene therapies to treat sickle cell disease are in development and are expected to have high costs. The large eligible population size — by far, the largest for a gene therapy — poses daunting budget challenges and threatens to exacerbate health disparities for Black patients, who make up the vast majority of American sickle cell patients.

Key messages The research environment has changed since clinical equipoise was first proposed 30 years ago New trial designs—such as umbrella and basket trials, adaptive platform trials, and cluster randomised trials—raise new ethical challenges for evaluating the state of scientific uncertainty and communicating about risks with patients and participants Clinical equipoise needs to evolve We propose the design of specific guidelines to provide ethics committees and trialists with instructions for how to evaluate equipoise in the context of new designs and (...) biomarkers and how to optimise communication with participants. (shrink)

Numerous reports have noted decreasing numbers of antibiotic approvals. To determine the context for this decline, we examined all new molecule entities (NMEs) and new biologic licenses (NBLs) approved by the FDA from 1980–2009, and compared approval rates of the 61 approved antibiotics to trends in other drug classes. We also tracked withdrawals of approved drugs and found more withdrawals for antibiotics than other drug classes. After adjusting for drugs subsequently withdrawn, the record for antibiotic innovation is less dire than (...) previously reported. We also report problems with the quality of the approved antibiotics studied. Future policies providing incentives for new antibiotic development should not be based on simple numerical targets and key provisions should ensure appropriate quality as well as quantity of antibiotic drug innovation. (shrink)

Antibiotic use triggers evolutionary and ecological responses from bacteria, leading to antibiotic resistance and harmful patient outcomes. Two complementary strategies support long-term antibiotic effectiveness: conservation of existing therapies and production of novel antibiotics. Conservation encompasses infection control, antibiotic stewardship, and other public health interventions to prevent infection, which reduce antibiotic demand. Production of new antibiotics allows physicians to replace existing drugs rendered less effective by resistance.In recent years, physicians and policymakers have raised concerns about the pipeline for new antibiotics, pointing (...) to a decline in the number of antibiotics approved since the 1980s. This trend has been attributed to high research and development costs, low reimbursement for antibiotics, and regulatory standards for review and approval. Professional societies and researchers around the world have called for renewed emphasis on antimicrobial stewardship, while also supporting antibiotic research and development through grants, changes to intellectual property laws to extend market exclusivity periods, and modification of premarket testing regulations to reduce antibiotic development time and expenses. (shrink)

BackgroundThe U.S. Food and Drug Administration traditionally has kept confidential significant amounts of information relevant to the approval or non-approval of specific drugs, devices, and biologics and about the regulatory status of such medical products in FDA’s pipeline.ObjectiveTo develop practical recommendations for FDA to improve its transparency to the public that FDA could implement by rulemaking or other regulatory processes without further congressional authorization. These recommendations would build on the work of FDA’s Transparency Task Force in 2010.MethodsIn 2016-2017, we convened (...) a team of academic faculty from Harvard Medical School, Brigham and Women’s Hospital, Yale Medical School, Yale Law School, and Johns Hopkins Bloomberg School of Public Health to develop recommendations through an iterative process of reviewing FDA’s practices, considering the legal and policy constraints on FDA in expanding transparency, and obtaining insights from independent observers of FDA.ResultsThe team developed 18 specific recommendations for improving FDA’s transparency to the public. FDA could adopt all these recommendations without further congressional action.FundingThe development of the Blueprint for Transparency at the U.S. Food and Drug Administration was funded by the Laura and John Arnold Foundation. (shrink)

The 21st Century Cures Act is a major act of legislation that contains numerous changes to drug and device regulation. The House of Representatives passed the Act after considerable interest group lobbying, but the bill and the key changes made during its drafting remain controversial. Using publicly disclosed records of written comments on the bill, we reviewed the key areas of lobbying activity and the compromises made in the final text. We focused on legislative provisions relating to management of the (...) National Institutes of Health, incentives for medical product development, and approval standards for new drugs and devices. By the end of the first comment period, the Committee received 118 comments. Most respondents were patient organizations, professional societies, and pharmaceutical and device companies. Overall, the majority of public comments were positive, although public health and consumer organizations were underrepresented in the number of submitted comments. As the legislative process continued, the draft bill underwent several changes relating to NIH funding, market exclusivity provisions, and scrutiny of regulatory evidentiary standards. Understanding the key statutory provisions and how they have evolved could help patients, researchers, and advocates make more informed comments on the bill and future health care legislation. (shrink)

The Covid‐19 pandemic highlighted the need to examine public trust in the U.S. Food and Drug Administration (FDA) vaccine approval process and the role of political influence in the FDA's decisions. Ensuring that the FDA is itself trustworthy is important for justifying public trust in its actions, like vaccine approvals, thereby promoting public health. We propose five conditions of trustworthiness that the FDA should meet when it reviews vaccines, even during emergencies: consistency with rules, proper expert or political decision‐makers, proper (...) decision‐making and noninterference, connection to public preference, and transparency of both reasons and procedures. The five conditions provide a road map of procedural and substantive requirements, which the FDA has variably implemented, focused on ensuring appropriate influence of political interests. While being a trustworthy agency cannot guarantee the public's trust, implementing these conditions builds a groundwork for public trust. (shrink)

Since the 1980s, developed countries, led by the United States and the countries of the European Union, have sought to incorporate intellectual property rights provisions into global trade agreements. These countries successfully negotiated the World Trade Organization's 1994 Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS), which required developing countries to adopt intellectual property provisions comparable to developed countries. In this manuscript, we review the policy controversy surrounding TRIPS and examine the two main ethical arguments articulated in its support (...) — a theory of natural rights and a utilitarian argument. We contend that these theories provide insufficient bases for an intellectual property rights regime that compromises access to essential medicines in the developing world. While the policy community has engaged in active debate around the policy effects of TRIPS, scholars have not thoroughly considered the full ethical underpinnings of those policy arguments. We believe that a more robust understanding of the ethical implications of the agreement should inform policy discussions in the future. (shrink)

In recent decades, advances in information technology have given rise to a post-industrial society in which emphasis on the manufacture of material goods has been supplanted by the creation of intellectual property. Indeed, this new “knowledge economy” can be tracked by the exponential growth in patented products across a range of sectors since the 1980s. According to the United States Patent and Trademark Office, the number of annual patent applications submitted grew from 112,379 to 520,277 over the past three decades, (...) a 464% increase.The transformation in the industrial markets has been accompanied by the rise of a new, global institution for coordinating intellectual property rights : the World Trade Organization. (shrink)

In recent months, pharmaceutical manufacturers have brought legal challenges to a provision of the 2022 Inflation Reduction Act (IRA) empowering the federal government to negotiate the prices Medicare pays for certain prescription medications. One key argument made in these filings is that price negotiation is a “taking” of property and violates the Takings Clause of the US Constitution. Through original case law and health policy analysis, we show that government price negotiation and even price regulation of goods and services, including (...) patented goods, are constitutional under the Takings Clause. Finding that the IRA violates the Takings Clause would radically upend settled constitutional law and jeopardize the US’s most important state and federal health care programs. (shrink)