Source: https://journalofethics.ama-assn.org/article/regulating-nanomedicine-food-and-drug-administration/2019-04
Timestamp: 2019-04-19 06:20:55+00:00

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The US Food and Drug Administration (FDA) oversees safety and efficacy of a broad spectrum of medical products (ie, drugs, biologics, and devices) under the auspices of federal legislation and agency regulations and policy. Complex and emerging nanoscale products challenge this regulatory framework and illuminate its shortcomings for combination products that integrate multiple mechanisms of therapeutic action. This article surveys current FDA regulatory structures and nanotechnology-specific guidance, discusses relevant nanomedicine products, and identifies regulatory challenges.
Cutting-edge nanomedicine applications often integrate chemical, mechanical, and biological properties to enable and enhance detection, diagnostic capabilities, and therapeutic modes of action. In the near future, it will be possible for a single nanomedicine product, once deployed in a patient’s body, to be programmed to target specific organs and tissues, create images, measure vital signs, diagnose in real time, and subsequently provide tailored therapeutics.
The US Food and Drug Administration (FDA), as a gatekeeper of health care products, plays a vital role in assessing nanomedicine products. However, its decades-old classifications to distinguish product domains for purposes of review and approval prove challenging for nanomedicine products due to their novel characteristics and cross-category features. In addition, nanoscale particles and materials have different risk profiles given their decreased size, increased biological activity, and unique properties. These risk profiles, which are largely unknown, create novel legal and ethical challenges for clinical trials, patient use, and public health.
The FDA is tasked with protecting public health and promoting innovations and striking a balance between the two when evaluating products generated by science and emerging technologies. The FDA regulates products under 2 primary statutes: the Food, Drug, and Cosmetic Act (FDCA), which addresses chemically synthesized drugs as well as devices; and the Public Health Service Act (PHSA), which addresses biologically derived therapeutic products.4 The FDA must characterize products under definitions provided by Congress in both the FDCA and the PHSA. Fundamentally, these definitions and supplemental FDA policies distinguish among 3 product areas based on whether the product has a chemical mode of action (drug), a mechanical mode of action (device), or a biological source. The Table provides statutory definitions for each of the 3 product domains. Nanotechnology products span all 3 regulated domains, and many products’ mechanisms of action span 2 or more of these domains.
Drug Generally, a drug is any chemically synthesized product intended for use in the “diagnosis, cure, mitigation, treatment, or prevention of disease”; products “intended to affect the structure or any function of the body”; and components.a New drugs are those “not generally recognized” by qualified experts “as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling thereof”b and must undergo clinical trials as a requirement for approval.
The approval process for both new drugs and biological products is subject to 3 phases of clinical trials. Each phase includes laboratory and manufacturing controls; protections for human subjects; review and approval procedures; and requirements for labeling, adverse event disclosure, reporting and tracking, and postmarket surveillance, including ongoing assessment to ensure safety and efficacy using a risk-benefit approach tailored to a product’s intended use.4,9 Products developed to address an unmet health need or to treat a serious or life-threatening disease may qualify for abbreviated review and approval under breakthrough therapy status and other accelerated mechanisms.10 There are also abbreviated routes to market for drugs and biologics through the generic11 and biosimilar12 pathways based on comparisons to reference innovator products already approved by the FDA. These routes to market do not require full-scale clinical trials but only a showing of bioequivalence (for generics) and biosimilarity (for biosimilars).
The FDA’s Office of Combination Products (OCP) assesses emerging technologies at the interface of the 3 product domains.16 A combination product is one containing a drug and a device; a drug and a biologic; a device and a biologic; or all 3 types of products. A combination product is categorized and reviewed according to its primary mode of action, which is the mode of action by which the product achieves its primary therapeutic effect—whether chemical, biological, or mechanical.17 Once the primary mode of action is determined, the FDA evaluates the product according to applicable statutory and regulatory requirements. For example, if the product’s primary mode of action is chemical, the FDA will apply drug requirements. The FDA can also adjust or combine regulatory requirements to address novel issues arising with combination products.
The combination product process has been subject to criticism for its shortcomings in classifying products that integrate chemical, biological, and mechanical elements; for a general lack of transparency; and for inconsistency in applying and making decisions about the requirements.18 Notably, the 21st Century Cures Act, enacted in December 2016, contains provisions for transparency and consistency in FDA procedures for classifying and evaluating combination products and for the conduct of collaborative product assessment.19 While not changing the FDCA in substance, the act served to nudge the agency on these issues. The FDA routinely classifies nanotechnology-derived products as combination products, assigning a primary regulatory route (ie, drug, device, or biologic) and supplementing with ad hoc requirements as necessary to assure safety and efficacy.
The FDA faces numerous challenges as nanomedicine progresses, and 3 core challenges stand out. The first is the adequacy of the regulatory framework itself; nanomedicine highlights the rigidity of product domains that dictate product approval requirements. At the nanoscale, decades-old definitions of chemical and mechanical action may not be suitable to characterize products with novel mechanisms of action and properties. For the purpose of evaluating such products, traditional definitional distinctions and accompanying legal requirements for review, approval, and postmarket surveillance and assessment may not be ideal. Current regulatory structures and processes may work for existing products, but the increasing complexity of nanotechnology and its convergence with other fields (eg, neurotechnologies and genetics) will likely strain their limits. Ongoing deliberations, stakeholder input, and agency policy must assess whether and to what extent current regulations are adaptable to newly emerging nanomedicine products or whether implementation of new frameworks is necessary to ensure safety and efficacy.
A second challenge has to do with the potential for novel risks, which raise questions about traditional safety and efficacy requirements’ appropriateness. Questions persist about whether nanoscale properties alter established risk-benefit measures and assessments of clinical trials and research protocols; whether and when abbreviated review of nanomedicine products is appropriate; and whether and when postmarket assessments should be tailored to address nano-specific toxicology and exposure concerns. As nanotechnology advances, particularly in the realm of human health, ample attention to scientific developments should also be paid to characterizing, assessing, and reporting adverse events. As part of the National Nanotechnology Initiative and other federal agency collaborations, large-scale research efforts are underway to characterize nanoscale materials and quantify their impact for purposes of developing toxicological assessment and testing tools.32 Information obtained from this research should be integrated into FDA review and approval processes as appropriate.
A third challenge has to do with whether labeling of nanomedicine products for consumers is sufficient to inform them that products contain nanotechnology or nanomaterials. This is not to say that explicit labeling should be a requirement; however, the FDA must contemplate whether increased patient and consumer education and consumer engagement is warranted and whether FDA policy on labeling requirements for nanoproducts responds well to public sentiment and the public’s health literacy needs. For these efforts to succeed—similar to consumer awareness campaigns and advocacy efforts in the realm of genetically modified food and biotechnology—positive perceptions and understanding of applications is essential.
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Jordan Paradise, JD is Georgia Reithal Professor of Law at the Loyola University Chicago School of Law in Illinois, where she is also a faculty member in the Beazley Institute for Health Law and Policy. She previously served as a co-principal investigator on a National Science Foundation grant titled “NIRT: Evaluating Oversight Models for Active Nanostructures and Nanosystems: Learning from Past Technologies in a Societal Context.’’ Her scholarship explores legal and policy issues that arise with emerging medical products and technologies such as nanotechnology, synthetic biology, gene editing, and biosimilars.

References: §351
 §262
 §505
 §355
 §505
 §355
 §513
 §360