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As vaccines are complex technologies that interact with the human body, their development is overseen by regulators in the administrative state. Countries structure the review of pharmaceutical products according to domestic rules and institutional design. As such, vaccines are reviewed as biologic products by regulatory authorities at the domestic level, such as the Therapeutic Goods Administration in Australia or the Pharmaceutical and Medical Devices Agency in Japan. The national basis of vaccine regulation inevitably leads to country-specific processes and timelines and may in some cases lead to different decisions.
The FDA’s Guidance to the Breakthrough Devices Program states the agency “may accept a greater extent of uncertainty of the benefit-risk profile for these devices if appropriate under the circumstances.” The CMS recently began providing supplemental reimbursement through New Technology Add-On Payments for “Breakthrough Devices.” CMS has waived a nearly two-decade criterion that devices receiving such payments must provide a “substantial clinical improvement” to Medicare beneficiaries. These policies will accelerate the approval and adoption into clinical practice of novel medical devices which may later be determined to not meet the statutory standard of reasonable assurance of safety and effectiveness (FDA) and/or “reasonable and necessary” (CMS). A crucial, but underutilized, regulatory authority can improve patient safety: conditional approval with withdrawal of approval when (1) clinical data demonstrate the threshold of reasonable assurance of safety and effectiveness is not met or (2) postmarket studies are not completed in a timely manner to demonstrate safety and effectiveness. It is rarely used, but there is precedent for FDA revocation of pharmaceutical approvals. In addition, payor coverage should be conditional (and proportional) on data of safety and effectiveness and withdrawn for data showing net harms or if data are not generated in a timely manner.
Attempts to modernize and speed up the FDA’s premarketing clearance and classification process for medical devices have included both new device classifications and ways of filing abbreviated applications. The FDA’s “De Novo” classification and Breakthrough Devices program allow applicants to create entirely new medical device types, with special controls and technological characteristics, including specifications on hardware and software. To encourage innovation and competition, the 21st Century Cures Act allows De Novo devices to serve as “predicates” for subsequent follow-on medical devices through the 510(k) application process, if such follow-on devices use the same controls and possess “the same” technological characteristics as the “predicate” device. This lends itself to a potentially anticompetitive strategy mediated by the interaction between IP and the 510(k) application requirements: successful De Novo applicants could use their portfolios to prevent follow-on applicants from making use of similar characteristics – potentially stymying an entire class of follow-on devices in the process. This strategy could threaten a greater diversity of new devices; may encourage an “up” classification of devices; and incentivizes technical characteristics and special controls of De Novo devices where general ones may suffice. This chapter concludes by proposing future evidence-based research in the area.
Between 2017-2018, the FDA cleared fourteen AI and ML-based software products as devices. This chapter analyzes how these products were cleared by the FDA and discusses how a lifecycle-based framework for regulating AI/ML-based software would address some of these characteristics. It is important to address the currently limited evidence for safety and effectiveness available at the time of market entry. To address the post-approval period, manufacturers and the FDA should work together to generate a list of industry-wide allowable changes and modifications that the software can employ to adapt in real-time to new data that would be subject to a “safe harbor” and thus not necessarily require premarket review by the FDA. Even anticipated changes may accumulate to generate an unanticipated divergence in the software’s eventual performance. There should be appropriate guardrails as software evolves over time. Finally, AI/ML is often criticized as a “black box” that is not well understood by or well explained to users. Given the inherent opacity of AI/ML-based software, the FDA should require a high standard of transparency to allow patients and clinicians to make informed decisions.
Relying chiefly on the combination of costly, unsystematic, and unreliable FDA monitoring and state negligence actions, the current postapproval system for controlling medical device risks falls far short of assuring optimal levels of safety. The reform proposal we advance comprehensively addresses these law enforcement deficiencies. The contemplated changes are straightforward and simple to implement yet would substantially reduce cost while increasing the effectiveness of both FDA monitoring and civil liability deterrence. Monitoring would be improved by requiring first-party insurers to investigate and report to the FDA the potential existence of a causal connection between the personal injury for which they are funding treatment and the patient’s (insured’s) use of or exposure to a medical device. The FDA would be authorized to enlist DOJ Civil Division enforcement of a federal cause-based strict liability action against the medical device manufacturer. The manufacturer would bear liability in full, with no reduction for risk contributions from the injured patient or other parties and would pay damages in total to the US Government. We explain the regulatory advantages of this new regulatory rule of cause-based strict liability relative to conventional rules of negligence and strict liability.
Are Electronic Health Records Medical Devices? While statute (largely) excludes EHRs from the medical device category, commentators have struggled to offer a justification. They have argued that EHRs inform but do not replace clinical decision-making, do not directly interact with patients, and are constantly being upgraded and modified. But all these characteristics are often true of many medical devices. I argue the key aspect of EHRs that render them foreign to the FDA’s jurisdiction is their systemwide interconnectedness. The patient’s EHR affects others. EHRs must work in a certain way, for the integrity of the whole system. EHR data is used for both clinical and quality management research. Alternatively, the safety of EHRs involves greater systematic, upstream regulation – of third-party networks, data formats, and other issues that present collective action problems. This goes far beyond the mandate of the FDA that fails to consider such issues and lacks jurisdiction over many necessary third parties. I argue that the distinction between EHR functions that have a direct and primary effect on the particular patient versus those such as data format and interoperability that present these third-party and systematic considerations should determine the respective jurisdictions of the FDA and health data subagencies.
All agents approved for marketing must meet the regulatory standards of the country in which they will be marketed, and drug development programs are designed to meet these regulatory requirements. There are frequent interactions between regulators and sponsors during the development and trial process. The FDA in the USA, the EMA in Europe, the NMPA in China, and the Japanese PMDA and other national regulatory bodies communicate regularly and share information. Regulators promote drug development for serious diseases with unmet needs such as Alzheimer’s disease (AD) and can use regulatory tools to facilitate the drug development process. Regulatory agencies oversee the manufacture of treatments (drugs, monoclonal antibodies) in addition to supervising the development process through clinical trials. Regulatory science and regulatory specifications evolve in concert with new knowledge. Agencies now recognize mild cognitive impairment and preclinical AD as populations where therapeutic indications could apply. Agencies have integrated biomarkers into their concepts of drug development and have specified approaches to biomarker qualification.
Naloxone, which reverses the effects of opioids, was synthesized in 1960, though the hunt for opioid antagonists began a half-century earlier. The history of this quest reveals how cultural and medical attitudes toward opioids have been marked by a polarization of discourse that belies a keen ambivalence. From 1915 to 1960, researchers were stymied in seeking a “pure” antidote to opioids, discovering instead numerous opioid molecules of mixed or paradoxical properties. At the same time, the quest for a dominant explanatory and therapeutic model for addiction was likewise unsettled. After naloxone’s discovery, new dichotomizing language arose in the “War on Drugs,” in increasingly divergent views between addiction medicine and palliative care, and in public debates about layperson naloxone access. Naloxone, one of the emblematic drugs of our time, highlights the ambivalence latent in public and biomedical discussions of opioids as agents of risk and relief.
The recent FDA marketing authorizations granted for testing for mutations associated with hereditary breast and colon cancer, as well as pharmacogenomic susceptibilities, provide an opportunity to re-examine the medical as well as regulatory underpinnings of DTC genetic testing. In this chapter, we first examine the historical emergence of enabling technologies that have provided for the availability of DNA sequence information on a broad scale, the efforts by the medical community to incorporate these advances into models of “precision” or “personalized” medicine, and the risks and benefits of offering access to DNA germline sequence analysis outside of the traditional medical model. We then turn to the current and proposed regulatory schemes to provide oversight over DTC genetic testing, with a focus on the role of the FDA as an information regulator and guardian of public health and safety.
The rise and ease of genome-editing technologies, like CRISPR, has ushered in communities of “biohackers,” do-it-yourself enthusiasts for molecular genetics who perform experiments outside traditional institutional laboratory settings. Conventional wisdom posits that such research is beyond traditional modes of regulation or legal enforcement and that new biohacking laws are needed. This view, however, is incorrect; both public and private regulators currently possess–and in other contexts, use–many of the tools needed to regulate the safety and ethics of biohacking. The U.S. Food and Drug Administration, for example, has expansive authority over “biologics,” which includes many of the biohacking kits currently in use. Patent holders and community laboratories similarly have the power to impose ethical and safety restrictions on biohacking activities. Rather than new laws or stiffer enforcement, regulators should do what they do for other industries: actively engage with the community to educate and promote the advancement of technology.
Egilman et al. review the current data sharing practices of three global regulatory agencies — Health Canada, the European Medicines Agency and the Food and Drug Agency. While there has been progress towards increasing transparency over the past decade, progress has been slow.
The advent of recombinant DNA technology in the 1970s led to general concerns about the use of novel biotechnologies and the potential effects on public health and the environment. To assuage those concerns, the Reagan Administration created the Coordinated Framework for the Regulation of Biotechnology. This 1986 policy document avowed that existing health and safety laws could provide adequate regulatory oversight for biotechnology products under a products-based, rather than a process-based, approach and assigned broad federal jurisdiction to the FDA, EPA, and USDA. This chapter examines how novel genome-editing technologies will test the limits of the Coordinated Framework, which is largely limited in scope by older genetic-engineering methods. The chapter analyzes the regulatory status of gene-edited crops and how, under specific circumstances, these crops can escape regulatory oversight due to the Coordinated Framework’s focus on the use of transgenic DNA to carry out the intended genetic manipulations. The chapter explores current regulatory gaps and argues that, in the near future, it will likely be increasingly cumbersome to distinguish between genome-edited crops and naturally occurring crops. The technology, therefore, is likely to challenge the very essence of what constitutes a GMO and extends opportunities to help allay controversies surrounding genetically modified crops.
This essay examines certain epistemic problems facing administrative states’ efforts to draft efficient regulations for their societies. I argue that a basic feature of the administrative state’s authority, namely its monopoly over the production of legally binding rules for all members of a geographically defined society, creates epistemic problems that impede efficient rule-making. Specifically, the administrative state’s monopoly over the production of legally binding rules prevents multiple public policies from being simultaneously implemented and compared. The resulting singularity of administrative states’ regulatory decisions prevents observation of the counterfactual effects of policies that were possible but which were not implemented. The absence of observable policy counterfactuals frustrates efforts to assess the efficiency of administrative states’ decisions, as it is impossible to determine whether different policies would have generated greater benefits at lower cost than the policy the state implemented. As these epistemic problems are derived from the singularity of administrative states’ decisions, they exist independently of principal agent problems, suboptimal incentives, or the preferences and capabilities of administrative personnel.
Employers and governments are interested in the use of serological (antibody) testing to allow people to return to work before there is a vaccine for SARS-CoV-2. We articulate the preconditions needed for the implementation of antibody testing, including the role of the U.S. Food & Drug Administration.
Availability of trained professionals to assist researchers navigating regulatory pathways for new drug and device development is limited within academic institutions. We created ReGARDD (Regulatory Guidance for Academic Research of Drugs and Devices), a regional forum initially involving regulatory professionals from four Clinical and Translational Science Award (CTSA)-funded institutions, to build and capitalize on local expertise and to develop a regulatory guidance website geared toward academic researchers. Since 2015, members organized 15 forums covering topics such as FDA premarket submissions, gene therapy, and intellectual property for devices and therapeutics. Through user feedback, targeted surveys, and ongoing iterative processes, we refined and maintained a shared regulatory website, which reached 6000+ users in 2019. Website updates improved navigation to drug versus device topic areas, provided new educational content and videos to address commonly asked questions, and created a portal for posting upcoming training opportunities. Survey respondents rated the website favorably and endorsed expanding ReGARDD as a centralized resource. ReGARDD strengthened the regional regulatory workforce, increased regulatory efficiency, and promulgated best organizational and operational practices. Broad-scale deployment of the ReGARDD model across the CTSA consortium may facilitate the creation of a network of regional forums and reduce gaps in access to regulatory support.
The US Food and Drug Administration (FDA) is responsible for assessing safety (risks) and effectiveness (benefits) of new drug products using the data provided in a Sponsor’s new drug product marketing application before they can be marketed. The FDA forms cross-disciplinary review teams to conduct these assessments. Recently, the FDA began implementing more interdisciplinary approaches to its assessments, reducing redundancy in review processes and documentation by increasing team integration around review issues.
Through a phenomenological descriptive comparative case study, the impact of FDA’s new interdisciplinary approach on review team integration was compared with its traditional multidisciplinary review approach.
We identified collaborative integration occurring in one FDA review team using the new interdisciplinary review and another team using the traditional review and then modeled and analyzed the collaborative, cross-disciplinary integration in each case using an input-process-output (IPO) model drawn from the Science-of-Team-Science (SciTS).
This study provides a systematic method for understanding and visualizing integration in each type of review previously and presently used at FDA and illustrates how the new interdisciplinary approach can ensure more integration than more traditional approaches previously used. In addition, our study suggests that an IPO model of integration can characterize how effectively FDA review teams are integrating around issues and assist in the evaluation of differences in integration between FDA’s new interdisciplinary review and the existing multidisciplinary approach. The approach used here is a new application of SciTS scholarship in a unique sector, and it also serves as an example for measuring review team effectiveness.
After millennia of use as a folk remedy, the National Academies of Sciences, Engineering and Medicine declared there is conclusive or substantial evidence that cannabinoids are effective for the treatment of chronic pain in adults, nausea and vomiting due to chemotherapy and for improving the spasticity of multiple sclerosis. The Academies’ statement contradicts the FDA’s placing marijuana on Schedule I as a dangerous drug with no medical use. Considerable basic research also establishes its potential medical use for bone fractures, osteoporosis, head trauma, stroke, MI, cancer, stress related disease such as PTSD, inflammation, and neurodegenerative disease. Understanding the potential value of cannabinoid-based medications requires understand the function of our natural endocannabinoid system and the unique properties of CBD separate from THC. CBD produces many of marijuana’s medical benefits by altering how cannabinoid receptors respond to endocannabinoids and THC. CBD’s modulation of THC is particularly evident in its reduction of psychotic reactions to THC and possible value in treatment resistant schizophrenia. CBD has a high safety profile, may be useful for anxiety, insomnia, and has FDA approval for severe childhood epilepsy. Unfortunately, intensive marketing has made CBD a fad without rigorous scientific proofs of its often exaggerated benefits.
Maju et al. provided clarifications on important and controversial issues related to esketamine clinical trial data, in response to a vivid debate triggered by the marketing authorisation recently granted by this new medicine. In this commentary, we reply to their comments attempting to critically discuss the evidence base needed to obtain regulatory approval.
As the pace of biomedical innovation rapidly evolves, there is a need to train researchers to understand regulatory science challenges associated with clinical translation. We describe a pilot course aimed at addressing this need delivered jointly through the Mayo Clinic Center for Clinical and Translational Science and the Yale-Mayo Center for Excellence in Regulatory Science and Innovation. Course design was informed by the Association for Clinical and Translational Science’s Regulatory Science Working Group’s competencies. The course used didactic, case-, and problem-based learning sessions to expose students to regulatory science concepts. Course evaluation focused on student satisfaction and learning. A total of 25 students enrolled in the first two course deliveries. Students represented several disciplines and career stages, from predoctoral to faculty. Students reported learning “an incredible amount” (7/19, 36.8%) or “a lot” (9/19, 47.4%); this was reflected in individual coursework and their course evaluations. Qualitative feedback indicated that assignments that challenged them to apply the content to their own research were appreciated. The heterogeneity of students enrolled, coupled with assessments and course evaluations, supports the statement that there is a growing need and desire for regulatory science-focused curricula. Future research will determine the long-term impact.
In March 2019, the US Food and Drug Administration (FDA) approved a nasal spray formulation of esketamine for the treatment of resistant depression in adults. Esketamine is the S-enantiomer of ketamine, an FDA-approved anaesthetic, known to cause dissociation and, occasionally, hallucinations. While ketamine has not been approved for depression in the USA or in any other country, it has been used off-label in cases of severe depression. This commentary critically reviewed the evidence on esketamine submitted to the FDA, aiming to draw implications for clinical practice, research and regulatory science.