The consolidation of nanomedicine (Report)

The Policy

What it does

Analyzes lack of innovation in nanomedicine and recommends policy changes to encourage more development.

Synopsis

“The consolidation of nanomedicine” is an academic review articles that uses U.S. patent data to examine trends and developments in nanomedicine since the Food and Drug Administration (FDA) approved the first nanotherapeutic product in 1995. Others had previously asserted that the growth of nanomedicine was stunted by complex safety, ethical, and regulatory issues, making the pharmaceutical industry more likely to improve existing technology than risk investing in new areas of nanomedicine. This leads to incremental developments rather than the sweeping advances expected from nanomedicine.

This article aimed to investigate this claim by considering U.S. patent data since 1974. Because it is critical to disclose and cite prior related technology in patent applications, the authors use citations in patents to indicate how much new discoveries rely on existing technology. They create patent citation networks to examine how closely linked nanomedicine patents are. Additionally, they consider other trends in patent data, such as rate of nanomedicine patents granted and the novelty of those patents. Their main findings include:

  • The early stages of nanomedicine research from 1974 to 1990 saw developments in several distinct areas.
  • Since 1990, nanomedicine has increasingly consolidated, with nearly all patents linked to each other.
  • The number of nanomedicine patents filed has remained mostly constant since 1996.
  • The majority of the top-cited nanomedicine patents involve new formulations of existing drugs rather than new, independent products.

Based on this analysis, the authors assert that research in nanomedicine has indeed consolidated and left many advances untapped. This article does not analyze the reasons for this consolidation but does suggest that safety, regulatory, and ethical uncertainties have contributed. To remedy this, they suggest several avenues for regulatory agencies to reduce the uncertainty surrounding innovations in nanomedicine:

  • Establish standardized regulatory definitions for terms related to nanomedicine (e.g. “nanomaterial”).
  • Establish specific, enforceable regulations and protocols for pre-clinical assessment and safety of nanomedicine instead of issuing guidance documents.
  • Develop a centralized database containing safety information for nanomedicine products and provide incentive for manufacturers to voluntarily submit data prior to going to market.

Further, the authors suggest that public funding agencies have a unique role to play in reducing the uncertainty of nanomedicine. By funding targeted initiatives in unexplored areas (e.g. the National Cancer Institute’s Alliance for Nanotechnology in Cancer), agencies can identify promising research paths and reduce risk for the private sector in pursuing those areas.

Context

Nanomedicine products are currently subject to the same FDA regulatory process as traditional products. The FDA regulates drugs and medical devices under the Food, Drug, and Cosmetic Act (FDCA) and biologically-derived products under the Public Health Service Act (PHSA). New medical products require pre-market review by the FDA’s Center for Drug Evaluation and Research, where manufacturers must submit data on product safety and effectiveness. Each product is considered on an individual basis, and the FDA can request additional safety data if nanomaterials are used in the product. However, there are currently no nano-product specific regulations by the FDA or standardized testing criteria. Additionally, nanomedicine products often categorized as a combination of drug, device, or biologic, presenting further regulatory obstacles. The FDA Office of Combination Products is responsible for categorizing and regulating combination products and has been criticized for subjecting products to additional and inconsistent requirements.

In 2013, the FDA launched the Nanotechnology Regulatory Science Research Plan designed to establish regulatory standards for emerging nanomaterials. Despite the lack of binding regulations, it has issued two guidance documents on nanotechnology in medical products since then. The 2014 guidance document Considering Whether an FDA-regulated Product Involves the Application of Nanotechnology discusses that the FDA will use two key definitions to determine if a product contains nanomaterials:

  1. A material engineered to have at least one dimension under approximately 100 nm (including any internal structures).
  2. A material which exhibits novel properties attributable to its dimensions with features up to 1000 nm.

These are not enforceable regulatory definitions but instead are frameworks intended to guide industry in determining if products contain nanomaterials and additional testing that may be necessary to as a result. This guidance also distinguishes nanomaterials from biological products (e.g. gene therapy or vaccines), unless deliberately engineered to have dimensions or properties that could classify them as nanomaterials. The 2017 Drug Products, Including Biological Products, that Contain Nanotechnology: Guidance for Industry guidance document provides suggestions for toxicity testing methods and potential risk factors of nanomedicine products.

Many of the challenges associated with understanding risks and regulating nanomedicine arise from the lack of established, cost-effective methods to reliably test the toxicity of nanomaterials before introducing them to the human body and environment. This presents several unique challenges, including:

  • Nanomaterials are typically not amenable to standard toxicity tests run on bulk materials, requiring development of new testing procedures.
  • Nanomaterials often must be tested individually, since toxicity can vary significantly with even minor changes in parameters such as size and shape.
  • Traditional animal toxicity studies of every nanomaterial formulation would be prohibitively costly. Therefore, alternative test strategies, such as conducting more experiments in vitro (outside living organisms), need to be designed and established.

These challenges often lead to costly testing to assess human and environmental toxicity and increase risk to industry and time to commercialization.

Additionally, “The consolidation of nanomedicine” specifically highlights the importance of public funding to help drive nanomedicine research in new areas; however, the National Cancer Institute, which is the U.S. government’s primary agency for cancer research, recently canceled its established Centers of Cancer Nanotechnology Excellence in May 2019. Decisions such as this by government agencies may undermine development of new nanomedicines for cancer by failing to encourage and fund emerging research, therefore providing little incentive for industry to pursue these seemingly risky new nanomedicines.

The Science

Science Synopsis

Nanomedicine involves the use of nanomaterials to diagnose, monitor, control, prevent and treat diseases. Nanomaterials employed in medicine are composed of a wide array of materials for varying applications, including gold nanoparticles, iron oxide, carbon nanotubes, quantum dots, and silica nanoparticles. These nanomaterials, in addition to others, exhibit significant changes in their physical and chemical properties compared to their bulk counterparts. These altered properties are expected to be potent tools in advancing medicine.

Nanomaterials possess multiple unique traits, many of which are particularly advantageous to medical applications, that make them attractive over traditional medicines. One such trait is the high surface area of nanomaterials, which makes them particularly amenable for drug-delivery. High surface area allows scientists to attach a dense layer of drugs to the nanomaterial surface and use it to deliver the specific drug and dose to a targeted area within the body. Additionally, the properties of many nanomaterials can be easily engineered by tuning their size and shape. These changes can induce different optical and electronic properties, which could be employed for cancer treatments such as photothermal therapy. Nanomedicine has largely driven the design of theranostic agents, in which a single treatment can be used to both diagnose and treat a disease. For example, nanoparticles designed to specifically target breast cancer cells can serve as a diagnostic agent by enabling imaging of the size and location of tumor. That same treatment can also serve as a therapeutic agent by delivering drugs to treat the cancer. Nanomedicine also enabled improved transport across biological barriers compared to traditional medicine, allowing drugs to access sensitive organs.

Scientific Assumptions

Scientific Assumptions

Additional nanomedicine discoveries and applications are scientifically viable and could impact medicine (Section 1, paragraph 2): Academic researchers have demonstrated through fundamental and small-scale research that nanomaterials can be developed to solve medical problems beyond current industry capabilities. The scientific community is generally in agreement that scientific potential is not a barrier to the advancement and utilization of nanomedicine.


The Debate

Scientific Controversies / Uncertainties

Limited data is available for both the human and environmental toxicity of many nanomaterials that are promising for medicine. Indeed, the same properties that make nanomaterials attractive for medical products can also create unique and potentially adverse effects on the body. Nanomedicine introduces the potential for side effects including nanomaterial bioaccumulation in the body, unintended immune responses, and cytotoxicity. Further, slight variations in parameters such as size, shape, concentration, and surface chemistry can dramatically change nanomaterial toxicity. For instance, nanomaterials which are benign at low concentrations can be toxic to the blood-brain-barrier at higher concentrations. In some cases, inorganic nanomaterials, such as quantum dots, are made biocompatible with organic coatings, but the deterioration of such coatings is not well understood and can vary greatly based on the application. Safety testing required by the FDA ideally should screen for these possibilities; however, there is still concern that important test variables, such as toxicity in both healthy and sick individuals, may be overlooked and produce misleading toxicity data. Overall, more research is needed in nanotoxicology before the short- and long-term effects of nanomedicines will be apparent.

Similarly, the environmental exposure, fate, and toxicity of nanomedicines is largely unknown, despite the significant volumes being produced. In 2010, an estimated 141 metric tons of silver nanoparticles – a suspected environmental hazard – was produced for human medical purposes. The majority of these and other nanomaterials will ultimately end up in sewage, but existing environmental risk assessment methodologies were designed for traditional small-molecule pharmaceuticals, not nanomedicines. Specific information on a nanomedicine’s physical and chemical properties is needed to complete nano-specific assessments. Further, the diversity of nanomaterials used in medicine will present a future challenge in adapting sewage treatment plants to appropriately handle nanomedicines.

Potential Impacts

"The consolidation of nanomedicine" adds to a growing body of literature suggesting that (1) nanomedicine has yet to deliver on the promises that researchers believe to be scientifically possible; and (2) that regulatory uncertainty is at least partly responsible for nanomedicine’s stunted growth over the past several decades. Previous progress to clarify regulatory expectations of nanomedicine products has included the 21st Century Cures Act of 2016. This increased the transparency and consistency of FDA regulatory processes of combination medical products, which often includes nanomedicines. It is possible this article, in addition to others calling for more standardized regulations, will lead to future FDA regulatory policy specific to nanomedicines.